Jeffrey Norton, MD

All Publications

• JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle. Life science alliance Shrager, J. B., Randle, R., Lee, M., Ahmed, S. S., Trope, W., Lui, N., Poultsides, G., Liou, D., Visser, B., Norton, J. A., Nesbit, S. M., He, H., Kapula, N., Wallen, B., Fatodu, E., Sadeghi, C. A., Konsker, H. B., Elliott, I., Guenthart, B., Backhus, L., Cooke, R., Berry, M., Tang, H. 2024; 7 (11)

  Abstract

  Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

  View details for DOI 10.26508/lsa.202402885

  View details for PubMedID 39122555

  View details for PubMedCentralID PMC11316201

• Distal Pancreatectomy with and without Celiac Axis Resection for Adenocarcinoma: A Comparison in the Era of Neoadjuvant Therapy. Cancers Daniel, S. K., Hironaka, C. E., Ahmad, M. U., Delitto, D., Dua, M. M., Lee, B., Norton, J. A., Visser, B. C., Poultsides, G. A. 2024; 16 (20)

  Abstract

  Distal pancreatectomy with celiac axis resection (DP-CAR) has been used for selected patients with pancreatic cancer infiltrating the celiac axis. We compared the short- and long-term outcomes between DP-CAR and distal pancreatectomy alone (DP) in patients receiving neoadjuvant therapy.Patients undergoing DP-CAR from 2013 to 2022 were retrospectively reviewed. Clinicopathologic features, post-operative morbidity, and survival outcomes were compared with patients undergoing DP after neoadjuvant chemotherapy.Twenty-two DP-CAR and thirty-four DP patients who underwent neoadjuvant chemotherapy were identified. There were no differences in comorbidities or CA19-9 levels. OR time was longer for DP-CAR (304 vs. 240 min, p = 0.007), but there was no difference in the transfusion rate (22.7% vs. 14.7%). Vascular reconstruction was more common in DP-CAR (18.2% vs. 0% arterial, p = 0.05; 40.9% vs. 12.5% venous, p = 0.04). There was no difference in morbidity or mortality between the two groups. Although there was a trend towards larger tumors in DP-CAR (5.1 cm vs. 3.8 cm, p = 0.057), the overall survival from the initiation of treatment (32 vs. 28 months, p = 0.43) and surgery (30 vs. 24 months, p = 0.43) were similar.DP-CAR is associated with similar survival and morbidity compared to DP patients requiring neoadjuvant chemotherapy and should be pursued in appropriately selected patients.

  View details for DOI 10.3390/cancers16203467

  View details for PubMedID 39456561

• Revascularization techniques for complete portomesenteric venous occlusion in patients undergoing pancreatic resection. HPB : the official journal of the International Hepato Pancreato Biliary Association Harrison, J. M., Li, A. Y., Bergquist, J. R., Ngongoni, F., Norton, J. A., Dua, M. M., Poultsides, G. A., Visser, B. C. 2024

  Abstract

  Pancreatic pathologies causing portomesenteric occlusion complicate extirpative pancreatic resection due to portomesenteric hypertension and collateral venous drainage.Patients with portomesenteric occlusion undergoing pancreatectomy were identified between 2007 and 2020 at Stanford University Hospital. Demographic and clinical data, technique and perioperative factors, and post-operative outcomes were analyzed.Of twenty-seven (27) patients undergoing venous revascularization during pancreatectomy, most (15) were for pancreatic neuroendocrine tumor. Occlusions occurred mostly at the portosplenic confluence (15). Median occlusion length was 4.0 cm [3.1-5.8]. Regarding revascularization strategy, mesocaval shunting was used in 11 patients, in-line venous revascularization with internal jugular conduit in three patients, traditional venous resection and reconstruction in 9 patients, and thrombectomy in two patients. Median cohort operative time and estimated blood loss were 522 min [433-638] and 1000 mL [700-2500], respectively. Median length of stay was 10 days [8-14.5] with overall readmission rate of 37%. Significant complications occurred in 44% of patients despite only one (4%) perioperative mortality.Despite the technical complexity for managing portomesenteric occlusions, early revascularization strategies including mesocaval shunting or in-line venous revascularization are feasible and facilitate a safe pancreatic resection for surgically fit patients.

  View details for DOI 10.1016/j.hpb.2024.07.408

  View details for PubMedID 39060211

• Hematoxylin and Eosin Architecture Uncovers Clinically Divergent Niches in Pancreatic Cancer. Tissue engineering. Part A Guo, J. L., Lopez, D. M., Mascharak, S., Foster, D. S., Khan, A., Davitt, M. F., Nguyen, A. T., Burcham, A. R., Chinta, M. S., Guardino, N. J., Griffin, M., Miller, E., Januszyk, M., Raghavan, S. S., Longacre, T. A., Delitto, D. J., Norton, J. A., Longaker, M. T. 2024

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) represents one of the only cancers with an increasing incidence rate and is often associated with intra- and peri-tumoral scarring, referred to as desmoplasia. This scarring is highly heterogeneous in extracellular matrix (ECM) architecture and plays complex roles in both tumor biology and clinical outcomes that are not yet fully understood. Using hematoxylin and eosin (H&E), a routine histological stain utilized in existing clinical workflows, we quantified ECM architecture in 85 patient samples to assess relationships between desmoplastic architecture and clinical outcomes such as survival time and disease recurrence. By utilizing unsupervised machine learning (ML) to summarize a latent space across 147 local (e.g. fiber length, solidity) and global (e.g. fiber branching, porosity) H&E-based features, we identified a continuum of histological architectures that were associated with differences in both survival and recurrence. Further, we mapped H&E architectures to a CO-Detection by indEXing (CODEX) reference atlas, revealing localized cell- and protein-based niches associated with outcome-positive vs. outcome-negative scarring in the tumor microenvironment. Overall, our study utilizes standard H&E staining to uncover clinically relevant associations between desmoplastic organization and PDAC outcomes, offering a translatable pipeline to support prognostic decision-making and a blueprint of spatial-biological factors for modeling by tissue engineering methods.

  View details for DOI 10.1089/ten.TEA.2024.0039

  View details for PubMedID 38874979

• Postoperative outcomes and costs of laparoscopic versus robotic distal pancreatectomy: a propensity-matched analysis. Surgical endoscopy Timmerhuis, H. C., Jensen, C. W., Ngongoni, R. F., Baiocchi, M., DeLong, J. C., Ohkuma, R., Dua, M. M., Norton, J. A., Poultsides, G. A., Worth, P. J., Visser, B. C. 2024

  Abstract

  Minimally invasive distal pancreatectomy (MIDP) has established advantages over the open approach. The costs associated with robotic DP (RDP) versus laparoscopic DP (LDP) make the robotic approach controversial. We sought to compare outcomes and cost of LDP and RDP using propensity matching analysis at our institution.Patients undergoing LDP or RDP between 2000 and 2021 were retrospectively identified. Patients were optimally matched using age, gender, American Society of Anesthesiologists status, body mass index, and tumor size. Between-group differences were analyzed using the Wilcoxon signed-rank test for continuous data, and the McNemar's test for categorical data. Outcomes included operative duration, conversion to open surgery, postoperative length of stay, pancreatic fistula rate, pseudocyst requiring intervention, and costs.298 patients underwent MIDP, 180 (60%) were laparoscopic and 118 (40%) were robotic. All RDPs were matched 1:1 to a laparoscopic case with absolute standardized mean differences for all matching covariates below 0.10, except for tumor type (0.16). RDP had longer operative times (268 vs 178 min, p < 0.01), shorter length of stay (2 vs 4 days, p < 0.01), fewer biochemical pancreatic leaks (11.9% vs 34.7%, p < 0.01), and fewer interventional radiological drainage (0% vs 5.9%, p = 0.01). The number of pancreatic fistulas (11.9% vs 5.1%, p = 0.12), collections requiring antibiotics or intervention (11.9% vs 5.1%, p = 0.12), and conversion rates (3.4% vs 5.1%, p = 0.72) were comparable between the two groups. The total direct index admission costs for RDP were 1.01 times higher than for LDP for FY16-19 (p = 0.372), and 1.33 times higher for FY20-22 (p = 0.031).Although RDP required longer operative times than LDP, postoperative stays were shorter. The procedure cost of RDP was modestly more expensive than LDP, though this was partially offset by reduced hospital stay and reintervention rate.

  View details for DOI 10.1007/s00464-024-10728-8

  View details for PubMedID 38438677

  View details for PubMedCentralID 1877036

• Distal Pancreatectomy With and Without Celiac Axis Resection for Adenocarcinoma: A Comparison in the Era of Neoadjuvant Therapy Daniel, S. K., Hironaka, C., Ahmad, M., Delitto, D., Dua, M., Lee, B., Norton, J., Visser, B., Poultsides, G. SPRINGER. 2024: S202-S203

  View details for Web of Science ID 001185577500451

• IL-1RA and IL-12 Decrease Pancreatic Ductal Adenocarcinoma Tumor Mass and Prolong Survival by Inhibiting Mechanoresponsive Cafs Morgan, A., Griffin, M., Downer, M., Lindsay, H., Parker, J. B., Guo, J. L., Longaker, M. T., Norton, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2023: S455-S456

  View details for Web of Science ID 001094086301392

• Where There Is Fat, There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Kim, A., Griffin, M., Liang, N., Foster, D., Guo, J. L., Norton, J. A., Longaker, M. T., Hyun, J. S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S365-S366

  View details for Web of Science ID 001094086301190

• Optimized Nuclei Isolation from Fresh and Frozen Solid Tumor Specimens for Multiome Sequencing. Journal of visualized experiments : JoVE Foster, D. S., Griffin, M., Januszyk, M., Delitto, D., Norton, J. A., Longaker, M. T. 2023

  Abstract

  Multiome sequencing, which provides same-cell/paired single-cell RNA- and the assay for transposase-accessible chromatin with sequencing (ATAC-sequencing) data, represents a breakthrough in our ability to discern tumor cell heterogeneity-a primary focus of translational cancer research at this time. However, the quality of sequencing data acquired using this advanced modality is highly dependent on the quality of the input material. Digestion conditions need to be optimized to maximize cell yield without sacrificing quality. This is particularly challenging in the context of solid tumors with dense desmoplastic matrices that must be gently broken down for cell release. Freshly isolated cells from solid tumor tissue are more fragile than those isolated from cell lines. Additionally, as the cell types isolated are heterogeneous, conditions should be selected to support the total cell population. Finally, nuclear isolation conditions must be optimized based on these qualities in terms of lysis times and reagent types/ratios. In this article, we describe our experience with nuclear isolation for the 10x Genomics multiome sequencing platform from solid tumor specimens. We provide recommendations for tissue digestion, storage of single-cell suspensions (if desired), and nuclear isolation and assessment.

  View details for DOI 10.3791/65831

  View details for PubMedID 37902368

• Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma. Cell reports. Medicine Mascharak, S., Guo, J. L., Foster, D. S., Khan, A., Davitt, M. F., Nguyen, A. T., Burcham, A. R., Chinta, M. S., Guardino, N. J., Griffin, M., Lopez, D. M., Miller, E., Januszyk, M., Raghavan, S. S., Longacre, T. A., Delitto, D. J., Norton, J. A., Longaker, M. T. 2023: 101248

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.

  View details for DOI 10.1016/j.xcrm.2023.101248

  View details for PubMedID 37865092

• Comparison of Spleen-Preservation Versus Splenectomy in Minimally Invasive Distal Pancreatectomy. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract Timmerhuis, H. C., Ngongoni, R. F., Jensen, C. W., Baiocchi, M., DeLong, J. C., Dua, M. M., Norton, J. A., Poultsides, G. A., Worth, P. J., Visser, B. C. 2023

  Abstract

  Spleen-preservation during minimally invasive distal pancreatectomy (MIDP) can be technically challenging and remains controversial. Our primary aim was to compare MIDP and splenectomy with spleen-preserving MIDP. Secondarily, we compared two spleen-preserving techniques.Adults undergoing MIDP (2007-2021) were retrospectively included in this single-center study. Intraoperative and postoperative outcomes between spleen-preservation and splenectomy and between the two spleen-preserving techniques were compared using the Mann-Whitney U test for continuous data, and Fisher's exact test for categorical data.Of the 293 patients who underwent MIDP, preservation of the spleen was intended in 208 (71%) patients. Spleen-preservation was achieved in 174 patients (84%) via the Warshaw technique (130; 75%) or vessel-preservation (44; 25%). The spleen-preserving group had shorter length of stay (3 vs 4 days, p < 0.01), fewer conversions to open (1 vs 12, p < 0.01) and less blood loss (p < 0.01) compared to the splenectomy group. Operative (OR) times were comparable (229 vs 214 min, p = 0.67). Except for the operative time, which was longer for the Warshaw technique (245 vs 183 min, p = 0.01), no other differences between the two spleen-preserving techniques were found. At a median follow-up of 43 (IQR 18-79) months after spleen-preservation, only 2 (1.1%) patients had required splenectomy (1 partial splenectomy for infarct/abscess after Warshaw, 1 for variceal bleeding after vessel-preserving).Spleen-preservation is not associated with increased risk of blood loss, longer hospital stay, conversion, nor lengthy OR times. Late splenectomy is very rarely required. Given the immune consequences of splenectomy, spleen-preservation should be strongly considered in MIDP.

  View details for DOI 10.1007/s11605-023-05809-3

  View details for PubMedID 37653153

  View details for PubMedCentralID 3912973

• Medical Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer. Biology Morgan, A., Griffin, M., Kameni, L., Wan, D. C., Longaker, M. T., Norton, J. A. 2023; 12 (8)

  Abstract

  Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF-tumor cell interaction, as well as CAF-immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary.

  View details for DOI 10.3390/biology12081044

  View details for PubMedID 37626931

• Mechanoresponsive Pancreatic Ductal Adenocarcinoma Cancer Associated Fibroblasts Shows an FAK-Dependent Subtype Divergent from Canonical Fibrotic TGFB-Pathway Dependence Foster, D., Delitto, D., Januszyk, M., Yost, K., Griffin, M., Guo, J., Guardino, N., Delitto, A., Chinta, M., Burcham, A., Nguyen, A., Bauer-, K., Berry, C., Kim, A., Nosrati, F., Wapnir, I., Chang, H., Norton, J. A., Longaker, M. SPRINGER. 2023: S30-S31

  View details for Web of Science ID 001046841200059

• ASO Visual Abstract: Calcifications and Cystic Morphology on Preoperative Imaging Predict Survival After Resection of Pancreatic Neuroendocrine Tumors. Annals of surgical oncology Makris, E. A., Cannon, J. G., Norton, J. A., Lopez-Aguiar, A. G., Dillhoff, M., Beal, E., Idrees, K., Smith, P. M., Rocha, F. G., Kanji, Z., Cho, C., Beems, M., Weber, S., Fisher, A., Krasnick, B. A., Fields, R. C., Maithel, S. K., Poultsides, G. A. 2022

  View details for DOI 10.1245/s10434-022-12981-4

  View details for PubMedID 36587171

• Calcifications and Cystic Morphology on Preoperative Imaging Predict Survival After Resection of Pancreatic Neuroendocrine Tumors. Annals of surgical oncology Makris, E. A., Cannon, J. G., Norton, J. A., Lopez-Aguiar, A. G., Dillhoff, M., Beal, E., Idrees, K., Smith, P. M., Rocha, F. G., Kanji, Z., Cho, C., Beems, M., Weber, S., Fisher, A., Krasnick, B. A., Fields, R. C., Maithel, S. K., Poultsides, G. A. 2022

  Abstract

  BACKGROUND: Radiographic calcifications and cystic morphology are associated with higher and lower tumor grade, respectively, in pancreatic neuroendocrine tumors (PNETs). Whether calcifications and/or cystic morphology could be used preoperatively to predict post-resection survival in patients with PNETs remains elusive.METHODS: Patients undergoing curative-intent resection of well-differentiated PNETs from 2000 to 2017 at eight academic institutions participating in the US Neuroendocrine Tumor Study Group were identified. Preoperative cross-sectional imaging reports were reviewed to identify the presence of calcifications and of a cystic component occupying >50% of the total tumor area. Clinicopathologic characteristics and recurrence-free survival (RFS) were compared.RESULTS: Of 981 patients studied, 18% had calcifications and 17% had cystic tumors. Tumors with calcifications were more commonly associated with Ki-67 ≥3% (47% vs. 33%; p=0.029), lymph node metastasis (36% vs. 24%; p=0.011), and distant metastasis (13% vs. 4%; p<0.001). In contrast, cystic tumors were less commonly associated with lymph node metastasis (12% vs. 30%; p<0.001). Five-year RFS after resection was most favorable for cystic tumors without calcifications (91%), intermediate for solid tumors without calcifications (77%), and least favorable for any calcified PNET (solid 69%, cystic 67%; p=0.043). Calcifications remained an independent predictor of RFS on multivariable analysis (p=0.043) controlling for nodal (p<0.001) and distant metastasis (p=0.001).CONCLUSIONS: Easily detectable radiographic features, such as calcifications and cystic morphology, can be used preoperatively to stratify prognosis in patients with PNETs and possibly inform the decision to operate or not, as well as guide the extent of resection and potential use of neoadjuvant therapy.

  View details for DOI 10.1245/s10434-022-12783-8

  View details for PubMedID 36434481

• Machine Learning-Based Desmoplastic Signatures Predict Patient Outcomes in Pancreatic Ductal Adenocarcinoma Guo, J. L., Mascharak, S., Foster, D. S., Guardino, N. J., Griffin, M., Miller, E., Raghavan, S., Longacre, T. A., Norton, J. A., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S53-S54

  View details for Web of Science ID 000867877000135

• Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Kim, A., Griffin, M., Foster, D., Guardino, N., Guo, J. L., Talbott, H. E., Norton, J. A., Hyun, J. S., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S59-S60

  View details for DOI 10.1097/01.XCS.0000893384.03562.27

  View details for Web of Science ID 000867889300098

• Comparison of Spleen-Preservation vs Splenectomy in Minimally Invasive Distal Pancreatectomy: A Propensity-Matched Analysis Timmerhuis, H. C., Ngongoni, R. F., Jensen, C., Baiocchi, M., DeLong, J. C., Dua, M. M., Norton, J. A., Poultsides, G. A., Worth, P. J., Visser, B. C. LIPPINCOTT WILLIAMS & WILKINS. 2022: S52

  View details for Web of Science ID 000867877000130

• Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer cell Foster, D. S., Januszyk, M., Delitto, D., Yost, K. E., Griffin, M., Guo, J., Guardino, N., Delitto, A. E., Chinta, M., Burcham, A. R., Nguyen, A. T., Bauer-Rowe, K. E., Titan, A. L., Salhotra, A., Jones, R. E., da Silva, O., Lindsay, H. G., Berry, C. E., Chen, K., Henn, D., Mascharak, S., Talbott, H. E., Kim, A., Nosrati, F., Sivaraj, D., Ransom, R. C., Matthews, M., Khan, A., Wagh, D., Coller, J., Gurtner, G. C., Wan, D. C., Wapnir, I. L., Chang, H. Y., Norton, J. A., Longaker, M. T. 2022

  Abstract

  Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.

  View details for DOI 10.1016/j.ccell.2022.09.015

  View details for PubMedID 36270275

• Clinical features and postoperative survival in patients with sporadic versus multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: An international cohort study. Surgery Bergquist, J. R., Shariq, O. A., Li, A. Y., Worth, P. J., Chatzizacharias, N., Soonawalla, Z., Athanasopoulos, P., Toumpanakis, C., Hansen, P., Parks, R. W., Connor, S., Parker, K., Koea, J., Srinivasa, S., Ielpo, B., Lopez, E. V., Norton, J. A., Lawrence, B., Visser, B. C., International Neuroendocrine Tumor Study Group 2022

  Abstract

  BACKGROUND: The optimal surgical management of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 is controversial. This study sought to compare clinicopathologic characteristics and outcomes of multiple endocrine neoplasia type 1-associated and sporadic pancreatic neuroendocrine tumors from a large multi-national database.METHODS: A multi-institutional, international database of patients with surgically resected pancreatic neuroendocrine tumors was analyzed. The cohort was divided into 2 groups: those with multiple endocrine neoplasia type 1 versus those with sporadic disease. Clinicopathologic comparisons were made. Overall and disease-free survival were analyzed. Propensity score matching was used to reduce bias.RESULTS: Of 651 patients included, 45 (6.9%) had multiple endocrine neoplasia type 1 and 606 sporadic pancreatic neuroendocrine tumors. Multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors were more common in younger patients and associated with multifocal disease at the time of surgery and higher T-stage. Lymph node involvement and the presence of metastasis were similar. Total pancreatectomy rate was 5-fold higher in the multiple endocrine neoplasia type 1 cohort. Median survival did not differ (disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). After matching, survival remained similar (overall survival not reached in either cohort, disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). Equivalence in overall survival and disease-free survival persisted even when patients who underwent subtotal and total pancreatectomy were excluded.CONCLUSION: Multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors are more common in younger patients and are associated with multifocality and higher T-stage. Survival for patients with multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors is comparable to those with sporadic pancreatic neuroendocrine tumors, even in the absence of radical pancreatectomy. Consideration should be given to parenchymal-sparing surgery to preserve pancreatic function.

  View details for DOI 10.1016/j.surg.2022.04.011

  View details for PubMedID 35577612

• Radiographic, Biochemical, or Pathologic Response to Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: Which Is Best? Javadi, C., Chang, J., Forgo, E., Ahmad, M., Fisher, G. A., Chang, D. T., Delitto, D. J., Dua, M. M., Lee, B., Visser, B. C., Norton, J. A., Poultsides, G. A. SPRINGER. 2022: 351

  View details for Web of Science ID 000789811800041

• Enhanced Operative Detection of Colorectal Liver Metastases. Journal of the American College of Surgeons Norton, J. A. 2022; 234 (2): 138

  View details for DOI 10.1097/XCS.0000000000000023

  View details for PubMedID 35213434

• Detection of MDM2 amplification by shallow whole genome sequencing of cell-free DNA of patients with dedifferentiated liposarcoma. PloS one Przybyl, J., Spans, L., Ganjoo, K., Bui, N., Mohler, D., Norton, J., Poultsides, G., Debiec-Rychter, M., van de Rijn, M. 2022; 17 (1): e0262272

  Abstract

  High-level amplification of MDM2 and other genes in the 12q13-15 locus is a hallmark genetic feature of well-differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS, respectively). Detection of this genomic aberration in plasma cell-free DNA may be a clinically useful assay for non-invasive distinction between these liposarcomas and other retroperitoneal tumors in differential diagnosis, and might be useful for the early detection of disease recurrence. In this study, we performed shallow whole genome sequencing of cell-free DNA extracted from 10 plasma samples from 3 patients with DDLPS and 1 patient with WDLPS. In addition, we studied 31 plasma samples from 11 patients with other types of soft tissue tumors. We detected MDM2 amplification in cell-free DNA of 2 of 3 patients with DDLPS. By applying a genome-wide approach to the analysis of cell-free DNA, we also detected amplification of other genes that are known to be recurrently affected in DDLPS. Based on the analysis of one patient with DDLPS with longitudinal plasma samples available, we show that tracking MDM2 amplification in cell-free DNA may be potentially useful for evaluation of response to treatment. The patient with WDLPS and patients with other soft tissue tumors in differential diagnosis were negative for the MDM2 amplification in cell-free DNA. In summary, we demonstrate the feasibility of detecting amplification of MDM2 and other DDLPS-associated genes in plasma cell-free DNA using technology that is already routinely applied for other clinical indications. Our results may have clinical implications for improved diagnosis and surveillance of patients with retroperitoneal tumors.

  View details for DOI 10.1371/journal.pone.0262272

  View details for PubMedID 34986184

• Surgery for Hereditary Diffuse Gastric Cancer: Long-Term Outcomes. Cancers Forrester, J. D., Foster, D., Ford, J. M., Longacre, T. A., Ladabaum, U., Fry, S., Norton, J. A. 2022; 14 (3)

  Abstract

  Gastric cancer is inherited as an autosomal dominant condition in hereditary diffuse gastric cancer (HDGC). The gene associated with HDGC is an E-cadherin gene CDH1. At the time of initiation of this study, it was estimated that 70% of patients who inherited the CDH1 gene mutation would develop gastric cancer. We hypothesized that the rate of signet ring cell cancer in asymptomatic patients with CDH1 mutations may be higher than anticipated and that the surgery could be conducted with acceptable short-term and long-term complications suggesting that the quality of life with the surgery is acceptable.We prospectively studied the role of total gastrectomy in symptomatic and asymptomatic patients with CDH1 mutations. A total of 43 patients with mutations of the CDH1 gene were studied prospectively, including 8 with symptoms and 35 without symptoms. Total gastrectomy was recommended to each. Quality of life was assessed in patients who underwent prophylactic gastrectomy. Proportions are compared with Fisher's exact test.In total, 13 (30%) asymptomatic patients declined surgery. Total gastrectomy was performed in 8 symptomatic patients and 22 asymptomatic patients of whom only 3 asymptomatic patients (14%) had endoscopically proven signet ring cell cancer preoperatively, while 21 of 22 (95%) had it on final pathology (p = 0.05). Each asymptomatic patient was T1, N0, while seven out of eight symptomatic patients had T3-T4 tumors and six had positive lymph nodes. None had operative complications or operative death. The median follow-up was 7 years. Five (63%) symptomatic patients died, while only one (95%) prophylactic patient died of a non-gastric cancer- or surgery-related issue (p = 0.05). A total of 15 prophylactic patients had long-term follow-up. Each had significant weight loss (mean 23%) but all had a normal body mass index. In total, 40% had bile reflux gastritis controlled with sucralfate. Each returned to work and, if given the choice, said that they would undergo the surgery again.Total gastrectomy is indicated for patients who have an inherented CDH1 mutation. Endoscopic screening is not reliable for diagnosing signet ring cell stomach cancer. If patients wait for symptoms, they will have a more advanced disease and significantly reduced survival. Operative complications of prophylactic gastrectomy are minimal, and long-term quality of life is acceptable.

  View details for DOI 10.3390/cancers14030728

  View details for PubMedID 35158993

• Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Griffin, M., Foster, D., desJardins-Park, H. E., Mascharak, S., Norton, J. A., Hyun, J. S., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S65

  View details for Web of Science ID 000718303100105

• Cancer-Associated Fibroblasts Share Highly Conserved Phenotypes and Functions Across Tumor Types and Species Foster, D. S., Januszyk, M., Yost, K. E., Chinta, M., Titan, A. L., Wapnir, I. L., Gurtner, G. C., Chang, H. Y., Norton, J. A., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S243-S244

  View details for Web of Science ID 000718303100463

• More Than an ERAS Pathway is Needed to Meet Target Length of Stay After Pancreaticoduodenectomy. The Journal of surgical research Ayala, C. I., Li, A. Y., Lu, A., Wilson, A., Bergquist, J. R., Poultsides, G. A., Norton, J. A., Visser, B. C., Dua, M. M. 2021; 270: 195-202

  Abstract

  BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols have been successfully instituted for pancreaticoduodenectomy (PD). This study evaluates reasons patients fail to meet length of stay (LOS) and areas for pathway improvement.MATERIALS AND METHODS: A multidisciplinary team developed and implemented an ERAS protocol for open PD in 2017. The study includes a medical record review of all patients who were perioperatively managed with the ERAS protocol and failed to meet LOS after PD procedures. Target LOS was defined as 7 d.RESULTS: From 2017 to 2020, 44% (93 of 213) of patients using ERAS protocol after PD procedures failed to meet target LOS. The most common reason to fail target LOS was ileus or delayed gastric emptying (47 of 93, LOS 11). Additional reasons included work-up of leukocytosis or pancreatic leak (17 of 93, LOS 14), additional "night" of observation (14 of 93, LOS 8), and orthostatic hypotension (3 of 93, LOS 10). Of these additional 46 patients, 19 patients underwent computed tomography (on or after POD 7) and only four patients received additional inpatient intervention.CONCLUSIONS: The most common reason for PD pathway failure included slow return of gastrointestinal function, a known complication after PD. The remaining patients were often kept for observation without additional intervention. This group represents an actionable cohort to target for improving LOS through surgeon awareness rather than protocol modification.

  View details for DOI 10.1016/j.jss.2021.08.034

  View details for PubMedID 34688991

• Integrated spatial multiomics reveals fibroblast fate during tissue repair. Proceedings of the National Academy of Sciences of the United States of America Foster, D. S., Januszyk, M., Yost, K. E., Chinta, M. S., Gulati, G. S., Nguyen, A. T., Burcham, A. R., Salhotra, A., Ransom, R. C., Henn, D., Chen, K., Mascharak, S., Tolentino, K., Titan, A. L., Jones, R. E., da Silva, O., Leavitt, W. T., Marshall, C. D., des Jardins-Park, H. E., Hu, M. S., Wan, D. C., Wernig, G., Wagh, D., Coller, J., Norton, J. A., Gurtner, G. C., Newman, A. M., Chang, H. Y., Longaker, M. T. 2021; 118 (41)

  Abstract

  In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive, in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to skin injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to reveal potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.

  View details for DOI 10.1073/pnas.2110025118

  View details for PubMedID 34620713

• Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction. Respiratory medicine Shrager, J. B., Wang, Y., Lee, M., Nesbit, S., Trope, W., Konsker, H., Fatodu, E., Berry, M. S., Poulstides, G., Norton, J., Burdon, T., Backhus, L., Cooke, R., Tang, H. 2021; 189: 106620

  Abstract

  INTRODUCTION: Ventilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after 7 vs 1h of MV during a thoracic surgical procedure.MATERIALS AND METHODS: The NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6h of MV.DISCUSSION: This trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.

  View details for DOI 10.1016/j.rmed.2021.106620

  View details for PubMedID 34655959

• Regional lymph node sampling in hepatoma resection: insight into prognosis. HPB : the official journal of the International Hepato Pancreato Biliary Association Bergquist, J. R., Li, A. Y., Javadi, C. S., Lee, B., Norton, J. A., Poultsides, G. A., Dua, M. M., Visser, B. C. 2021

  Abstract

  BACKGROUND: The importance of regional lymph node sampling (LNS) during resection of hepatocellular carcinoma (HCC) is poorly understood. This study sought to ameliorate this knowledge gap through a nationwide population-based analysis.METHODS: Patients who underwent liver resection (LR) for HCC were identified from Surveillance, Epidemiology and End Results (SEER-18) database (2003-2015). Cohort-based clinicopathologic comparisons were made based on completion of regional LNS. Propensity-score matching reduced bias. Overall and disease-specific survival (OS/DSS) were analyzed.RESULTS: Among 5395 patients, 835 (15.4%) underwent regional LNS. Patients undergoing LNS had larger tumors (7.0vs4.8cm) and higher T-stage (30.9 vs. 17.6% T3+, both p<0.001). Node-positive rate was 12.0%. Median OS (50 months for both) and DSS (28 vs. 29 months) were similar between cohorts, but node-positive patients had decreased OS/DSS (20/16 months, p<0.01). Matched patients undergoing LNS had equivalent OS (46 vs. 43 months, p=0.869) and DSS (27 vs. 29 months, p=0.306) to non-LNS patients. The prognostic impact of node positivity persisted after matching (OS/DSS 24/19 months, p<0.01). Overall disease-specific mortality were both independently elevated (overall HR 1.71-unmatched, 1.56-matched, p<0.01; disease-specific HR 1.40-unmatched, p<0.01, 1.25-matched, p=0.09).CONCLUSION: Regional LNS is seldom performed during resection for HCC, but it provides useful prognostic information. As the era of adjuvant therapy for HCC begins, surgeons should increasingly consider performing regional LNS to facilitate optimal multidisciplinary management.

  View details for DOI 10.1016/j.hpb.2021.01.006

  View details for PubMedID 33563547

• Subtle endoscopic manifestations of diffuse signet cell gastric adenocarcinoma in patients with CDH1 mutations. Gastrointestinal endoscopy Ladabaum, U., Ford, J. M., Poultsides, G., Norton, J. 2021

  View details for DOI 10.1016/j.gie.2021.08.006

  View details for PubMedID 34416278

• Surgical resection of leiomyosarcoma of the inferior vena cava: A case series and literature review. Surgical oncology Zhou, M., Javadi, C., Charville, G. W., Bui, N. Q., Harris, E. J., Poultsides, G. A., Norton, J. A., Visser, B., Lee, B., Dua, M. M., Ganjoo, K. N. 2021; 39: 101670

  Abstract

  We review our institution's experience in treating leiomyosarcomas involving the inferior vena cava, and we offer guidance on the management.A text-based search was performed to identify all patients who underwent surgical resection between January 2002 and October 2020. Clinicopathologic data, intraoperative variables, and outcomes were extracted from chart review.Twelve of 16 patients (75%) had localized disease; the remaining had limited metastatic disease. Seven of 16 patients (44%) received neoadjuvant chemotherapy or radiation; three patients had partial responses, and four patients had stable disease using RECIST 1.1 criteria. IVC reconstruction was performed in 14 of 16 patients (88%); IVC was ligated for the remaining two patients. Half of all patients had R0 resection on final pathology; the remaining had R1 resections. Progression-free survival (PFS) and overall survival (OS) were not statistically different between patients with R0 and R1 resection. Median PFS was 1.8 years (95% CI 0.89 - not reached); median OS was 6.5 years (1.8 - not reached). Only one patient (6%) experienced local disease recurrence; 4 of 16 patients (25%) experienced disease recurrence distally without local recurrence.Resection of IVC leiomyosarcomas at a sarcoma referral center with experience in vascular reconstruction can lead to many years of recurrence-free survival. Surgical resection should be offered to patients with a low volume of metastatic disease to reduce local complications from the primary tumor, many of which exert significant mass effect on surrounding organs. For patients with metastatic disease or large, high-risk tumors, neoadjuvant chemotherapy can provide a biologic test of disease stability prior to resection.

  View details for DOI 10.1016/j.suronc.2021.101670

  View details for PubMedID 34710646

• Peripheral Motor Neuron Activity Influences over Local Sarcoma Progression Davitt, M., Foster, D., Mascharak, S., desJardins-Park, H., Norton, J., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S230–S231

  View details for Web of Science ID 000582792300421

• Neoadjuvant Capecitabine/Temozolomide for Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors. Pancreas Squires, M. H., Worth, P. J., Konda, B., Shah, M. H., Dillhoff, M. E., Abdel-Misih, S., Norton, J. A., Visser, B. C., Dua, M., Pawlik, T. M., Schmidt, C. R., Poultsides, G., Cloyd, J. M. 2020

  Abstract

  OBJECTIVES: The combination chemotherapy regimen capecitabine/temozolomide (CAPTEM) is efficacious for metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs), but its role in the neoadjuvant setting has not been established.METHODS: The outcomes of all patients with locally advanced or resectable metastatic PNETs who were treated with neoadjuvant CAPTEM between 2009 and 2017 at 2 high-volume institutions were retrospectively reviewed.RESULTS: Thirty patients with locally advanced PNET (n = 10) or pancreatic neuroendocrine hepatic metastases (n = 20) received neoadjuvant CAPTEM. Thirteen patients (43%) exhibited partial radiographic response (PR), 16 (54%) had stable disease, and 1 (3%) developed progressive disease. Twenty-six (87%) patients underwent resection (pancreatectomy [n = 12], combined pancreatectomy and liver resection [n = 8], or major hepatectomy alone [n = 6]); 3 (18%) declined surgery despite radiographic PR, and 1 (3%) underwent aborted pancreatoduodenectomy. Median primary tumor size was 5.5 cm, and median Ki-67 index was 3.5%. Rates of PR were similar across tumor grades (P = 0.24). At median follow-up of 49 months, median progression-free survival was 28.2 months and 5-year overall survival was 63%.CONCLUSIONS: Neoadjuvant CAPTEM is associated with favorable radiographic objective response rates for locally advanced or metastatic PNET and may facilitate selection of patients appropriate for surgical resection.

  View details for DOI 10.1097/MPA.0000000000001500

  View details for PubMedID 32132509

• Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment. Cancers Norton, J. n., Foster, D. n., Chinta, M. n., Titan, A. n., Longaker, M. n. 2020; 12 (5)

  Abstract

  Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

  View details for DOI 10.3390/cancers12051347

  View details for PubMedID 32466266

• Northstar enables automatic classification of known and novel cell types from tumor samples. Scientific reports Zanini, F. n., Berghuis, B. A., Jones, R. C., Nicolis di Robilant, B. n., Nong, R. Y., Norton, J. A., Clarke, M. F., Quake, S. R. 2020; 10 (1): 15251

  Abstract

  Single cell transcriptomics is revolutionising our understanding of tissue and disease heterogeneity, yet cell type identification remains a partially manual task. Published algorithms for automatic cell annotation are limited to known cell types and fail to capture novel populations, especially cancer cells. We developed northstar, a computational approach to classify thousands of cells based on published data within seconds while simultaneously identifying and highlighting new cell states such as malignancies. We tested northstar on data from glioblastoma, melanoma, and seven different healthy tissues and obtained high accuracy and robustness. We collected eleven pancreatic tumors and identified three shared and five private neoplastic cell populations, offering insight into the origins of neuroendocrine and exocrine tumors. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases.

  View details for DOI 10.1038/s41598-020-71805-1

  View details for PubMedID 32943655

• Elucidating the fundamental fibrotic processes driving abdominal adhesion formation. Nature communications Foster, D. S., Marshall, C. D., Gulati, G. S., Chinta, M. S., Nguyen, A. n., Salhotra, A. n., Jones, R. E., Burcham, A. n., Lerbs, T. n., Cui, L. n., King, M. E., Titan, A. L., Ransom, R. C., Manjunath, A. n., Hu, M. S., Blackshear, C. P., Mascharak, S. n., Moore, A. L., Norton, J. A., Kin, C. J., Shelton, A. A., Januszyk, M. n., Gurtner, G. C., Wernig, G. n., Longaker, M. T. 2020; 11 (1): 4061

  Abstract

  Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.

  View details for DOI 10.1038/s41467-020-17883-1

  View details for PubMedID 32792541

• Evaluation of Outcomes Following Surgery for Locally Advanced Pancreatic Neuroendocrine Tumors. JAMA network open Titan, A. L., Norton, J. A., Fisher, A. T., Foster, D. S., Harris, E. J., Worhunsky, D. J., Worth, P. J., Dua, M. M., Visser, B. C., Poultsides, G. A., Longaker, M. T., Jensen, R. T. 2020; 3 (11): e2024318

  Abstract

  Although outcome of surgical resection of liver metastases from pancreatic neuroendocrine tumors (PNETs) has been extensively studied, little is known about surgery for locally advanced PNETs; it was listed recently by the European neuroendocrine tumor society as a major unmet need.To evaluate the outcome of patients who underwent surgery for locally aggressive PNETs.This retrospective single-center case series reviewed consecutive patients who underwent resection of T3/T4 PNETs at a single academic institution. Data collection occurred from 2003 to 2018. Data analysis was performed in August 2019.Disease-free survival (primary outcome) and overall mortality (secondary outcome) were assessed with Kaplan-Meier analysis. Recurrence risk (secondary outcome, defined as identification of tumor recurrence on imaging) was assessed with Cox proportional hazard models adjusting for covariates.In this case series, 99 patients with locally advanced nondistant metastatic PNET (56 men [57%]) with a mean (SEM) age of 57.0 (1.4) years and a mean (SEM) follow-up of 5.3 (0.1) years underwent surgically aggressive resections. Of those, 4 patients (4%) underwent preoperative neoadjuvant treatment (including peptide receptor radionuclide therapy and chemotherapy); 18 patients (18%) underwent pancreaticoduodenectomy, 68 patients (69%) had distal or subtotal pancreatic resection, 10 patients (10%) had total resection, and 3 patients (3%) had other pancreatic procedures. Additional organ resection was required in 86 patients (87%): spleen (71 patients [71%]), major blood vessel (17 patients [17%]), bowel (2 patients [2%]), stomach (4 patients [4%]), and kidney (2 patients [2%]). Five-year disease-free survival was 61% (61 patients) and 5-year overall survival was 91% (91 patients). Of those living, 75 patients (76%) had an Eastern Cooperative Oncology Group score of less than or equal to 1 at last followup. Lymph node involvement (HR, 7.66; 95% CI, 2.78-21.12; P < .001), additional organ resected (HR, 6.15; 95% CI, 1.61-23.55; P = .008), and male sex (HR, 3.77; 95% CI, 1.68-8.97; P = .003) were associated with increased risk of recurrence. Functional tumors had a lower risk of recurrence (HR, 0.23; CI, 0.06-0.89; P = .03). Required resection of blood vessels was not associated with a significant increase recurrence risk.In this case series, positive lymph node involvement and resection of organs with tumor involvement were associated with an increased recurrence risk. These subgroups may require adjuvant systemic treatment. These findings suggest that patients with locally advanced PNETs who undergo surgical resection have excellent disease-free and overall survival.

  View details for DOI 10.1001/jamanetworkopen.2020.24318

  View details for PubMedID 33146734

• Intratumoral immunotherapy for early stage solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research Hong, W. X., Haebe, S. n., Lee, A. n., Westphalen, B. n., Norton, J. A., Jiang, W. n., Levy, R. n. 2020

  Abstract

  The unprecedented benefits of immunotherapy in advanced malignancies have resulted in increased interests in exploiting immune stimulatory agents in earlier stage solid tumors in the neoadjuvant setting. However, systemic delivery of immunotherapies may cause severe immune-related side-effects and hamper the development of combination treatments. Intratumoral delivery of neoadjuvant immunotherapy provides a promising strategy in harnessing the power of immunotherapy while minimizing off-target toxicities. The direct injection of immune stimulating agents into the tumor primes the local tumor-specific immunity to generate a systemic, durable clinical response. Intratumoral immunotherapy is a highly active area of investigation resulting in a plethora of agents, e.g. immune receptor agonists, non-oncolytic and oncolytic viral therapies, being tested in preclinical and clinical settings. Currently, more than 20 neoadjuvant clinical trials exploring distinct intratumoral immune stimulatory agents and their combinations are ongoing. Practical considerations including appropriate timing and optimal local delivery of immune stimulatory agents play an important role in safety and efficacy of this approach. Here we discuss promising approaches in drug delivery technologies and opportunity for combining intratumoral immunotherapy with other cancer treatments and summarize the recent preclinical and clinical evidences that highlighted its promise as a part of routine oncologic care.

  View details for DOI 10.1158/1078-0432.CCR-19-3642

  View details for PubMedID 32071116

• Postoperative Outcomes of Laparoscopic vs Robotic Distal Pancreatectomy: A Propensity-Matched Analysis Jensen, C. W., Baiocchi, M., Dua, M. M., Poultsides, G. A., Norton, J. A., Worth, P. J., Visser, B. C. ELSEVIER SCIENCE INC. 2019: S181–S182

  View details for Web of Science ID 000492740900344

• Cancer-Associated Fibroblasts Persist but Show Decreased Fibroblast Activation Protein Expression after Neoadjuvant Chemotherapy in Human Pancreatic Ductal Adenocarcinoma Foster, D. S., Nguyen, A. T., Chinta, M., Titan, A. L., Salhotra, A., Jones, R., Mascharak, S., Norton, J., Longaker, M. T. ELSEVIER SCIENCE INC. 2019: S257–S258

  View details for Web of Science ID 000492740900501

• Tumors Co-Opt Fibroblast Wound Healing Capacity Foster, D. S., Mascharak, S., Nguyen, A. T., Chinta, M., Salhotra, A., Titan, A. L., Jones, R., da Silva, O., Norton, J. A., Longaker, M. T. ELSEVIER SCIENCE INC. 2019: S231–S232

  View details for Web of Science ID 000492740900444

• Endogenous Breast Cancer Shows Clonal Proliferation of Cancer Associated Fibroblasts at Primary Tumor and Metastatic Sites Foster, D. S., Chinta, M., Nguyen, A. T., Salhotra, A., Ransom, R., Jones, R., Titan, A. L., Mascharak, S., Norton, J. A., Longaker, M. T. ELSEVIER SCIENCE INC. 2019: S262

  View details for Web of Science ID 000492740900510

• Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA. Molecular oncology Lee, J., Park, S. S., Lee, Y. K., Norton, J. A., Jeffrey, S. S. 2019

  Abstract

  Reliable biomarkers are required to evaluate and manage pancreatic ductal adenocarcinoma. Circulating tumor cells and circulating tumor DNA are shed into blood and can be relatively easily obtained from minimally invasive liquid biopsies for serial assays and characterization, thereby providing a unique potential for early diagnosis, forecast of disease prognosis, and monitoring of therapeutic response. In this review, we provide an overview of current technologies used to detect circulating tumor cells and circulating tumor DNA and describe recent advances regarding the multiple clinical applications of liquid biopsy in pancreatic ductal adenocarcinoma.

  View details for DOI 10.1002/1878-0261.12537

  View details for PubMedID 31243883

• Management of Ileal Neuroendocrine Tumors with Liver Metastases. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract Fisher, A. T., Titan, A. L., Foster, D. S., Worth, P. J., Poultsides, G. A., Visser, B. C., Dua, M. M., Norton, J. A. 2019

  Abstract

  Assessment of treating metastatic ileal neuroendocrine tumors (NETs) with complete resection of primary tumor, nodal and liver metastases, plus administration of long-acting somatostatin analogues (SSAs).A prospective database was queried for patients with ileal or pancreatic NETs with pathology-confirmed liver metastases and tumor somatostatin receptors. Patients did not have MEN-1 and had no previous treatment. The impacts of SSA treatment on the primary outcome of survival and secondary outcome of progression-free survival were assessed with Kaplan-Meier analysis. Log rank test was used to compare overall and progression-free survival among groups.Seventeen ileal NET patients and 36 pancreatic NET patients who underwent surgical resection between 2001 and 2018, who had pathology-confirmed liver metastases and confirmed tumor somatostatin receptors, did not have MEN-1, and had no previous treatment were identified. Median follow-up for patients with ileal NETs was 80 months (range 0-197 months) and 32 months (range 1-182 months) for pancreatic NETs. Five-year survival was 93% and 72% for ileal and pancreatic NET, respectively. Progression-free 5-year survival was 70% and 36% for ileal and pancreatic NET, respectively. Overall 5-year survival for pNETs was greater in those patients treated with SSA (79%) compared to those who underwent surgery alone (34%, p < 0.01). The average ECOG score was low for surviving patients with ileal (0.15) and pancreatic NET (0.73) indicating a good quality of life.Resection of primary lymph node and liver metastatic ileal or pancreatic NETs followed with continued SSAs is associated with an excellent progression-free and overall survival and minimal side effects.

  View details for DOI 10.1007/s11605-019-04309-7

  View details for PubMedID 31346887

• Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers. Science translational medicine Tsai, J. M., Sinha, R., Seita, J., Fernhoff, N., Christ, S., Koopmans, T., Krampitz, G. W., McKenna, K. M., Xing, L., Sandholzer, M., Sales, J. H., Shoham, M., McCracken, M., Joubert, L., Gordon, S. R., Poux, N., Wernig, G., Norton, J. A., Weissman, I. L., Rinkevich, Y. 2018; 10 (469)

  Abstract

  Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and are a major cause of postsurgical and infectious morbidity. The primary molecular chain of events leading to the initiation of adhesions has been elusive, chiefly due to the lack of an identifiable cell of origin. Using clonal analysis and lineage tracing, we have identified injured surface mesothelium expressing podoplanin (PDPN) and mesothelin (MSLN) as a primary instigator of peritoneal adhesions after surgery in mice. We demonstrate that an anti-MSLN antibody diminished adhesion formation in a mouse model where adhesions were induced by surgical ligation to form ischemic buttons and subsequent surgical abrasion of the peritoneum. RNA sequencing and bioinformatics analyses of mouse mesothelial cells from injured mesothelium revealed aspects of the pathological mechanism of adhesion development and yielded several potential regulators of this process. Specifically, we show that PDPN+MSLN+ mesothelium responded to hypoxia by early up-regulation of hypoxia-inducible factor 1 alpha (HIF1alpha) that preceded adhesion development. Inhibition of HIF1alpha with small molecules ameliorated the injury program in damaged mesothelium and was sufficient to diminish adhesion severity in a mouse model. Analyses of human adhesion tissue suggested that similar surface markers and signaling pathways may contribute to surgical adhesions in human patients.

  View details for PubMedID 30487249

• Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers SCIENCE TRANSLATIONAL MEDICINE Tsai, J. M., Sinha, R., Seita, J., Fernhoff, N., Christ, S., Koopmans, T., Krampitz, G. W., McKenna, K. M., Xing, L., Sandholzer, M., Sales, J., Shoham, M., McCracken, M., Joubert, L., Gordon, S. R., Poux, N., Wernig, G., Norton, J. A., Weissman, I. L., Rinkevich, Y. 2018; 10 (469)

  View details for DOI 10.1126/scitranslmed.aan6735

  View details for Web of Science ID 000451465600001

• Isolated pancreatic tail remnants after transgastric necrosectomy can be observed JOURNAL OF SURGICAL RESEARCH Dua, M. M., Jensen, C. W., Friedland, S., Worth, P. J., Poultsides, G. A., Norton, J. A., Park, W. G., Visser, B. C. 2018; 231: 109–15

  View details for DOI 10.1016/j.jss.2018.05.020

  View details for Web of Science ID 000445911700016

• Management of Liver Neuroendocrine Tumors in 2018 JAMA ONCOLOGY Foster, D. S., Jensen, R., Norton, J. A. 2018; 4 (11): 1605–6

  View details for DOI 10.1001/jamaoncol.2018.3035

  View details for Web of Science ID 000449559500022

• Isolated pancreatic tail remnants after transgastric necrosectomy can be observed. The Journal of surgical research Dua, M. M., Jensen, C. W., Friedland, S., Worth, P. J., Poultsides, G. A., Norton, J. A., Park, W. G., Visser, B. C. 2018; 231: 109–15

  Abstract

  BACKGROUND: Severe necrotizing pancreatitis may result in midbody necrosis and ductal disruption leaving an isolated pancreatic tail. The purpose of this study was to characterize outcomes among patients with an isolated tail remnant who underwent transgastric drainage or necrosectomy (endoscopic or surgical) and determine the need for subsequent operative management.MATERIALS AND METHODS: Patients with necrotizing pancreatitis and retrogastric walled-off collections treated by surgical transgastric necrosectomy or endoscopic cystgastrostomy± necrosectomy between 2009 and 2017 were identified by a retrospective chart review. All available preprocedure and postprocedure imaging was reviewed for evidence of isolated distal pancreatic tail remnants.RESULTS: Seventy-four patients were included (40 surgical and 34 endoscopic). All the patients in the surgical group underwent laparoscopic transgastric necrosectomy; the endoscopic group consisted of 26 patients for pseudocyst drainage and eight patients for necrosectomy. A disconnected pancreatic tail was identified in 22 (29%) patients (13 laparoscopic and nine endoscopic). After the creation of the "cystgastrostomy," there were no external fistulas despite the viable tail. Of the 22 patients, four patients developed symptoms at a median of 23months (two, recurrent episodic pancreatitis; two, intractable pain). Two patients (both initially in endoscopic group) ultimately required distal pancreatectomy and splenectomy at 24 and 6months after index procedure.CONCLUSIONS: Patients with a walled-off retrogastric collection and an isolated viable tail are effectively managed by a transgastric approach. Despite this seemingly "unstable anatomy," the creation of an internal fistula via surgical or endoscopic "cystgastrostomy" avoids external fistulas/drains and the short-term necessity of surgical distal pancreatectomy. A very small subset requires intervention for late symptoms.

  View details for PubMedID 30278917

• Monitoring gastric myoelectric activity after pancreaticoduodenectomy for diet "readiness" AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Dua, M. M., Navalgund, A., Axelrod, S., Axelrod, L., Worth, P. J., Norton, J. A., Poultsides, G. A., Triadafilopoulos, G., Visser, B. C. 2018; 315 (5): G743–G751

  View details for DOI 10.1152/ajpgi.00074.2018

  View details for Web of Science ID 000451199900009

• Clonal Analysis of Local Fibroblasts in Wound Healing and Tumor Stroma Foster, D. S., Ransom, R. C., Nguyen, A. T., Salhotra, A., Jones, R. E., Hu, M. S., Norton, J. A., Longaker, M. T. ELSEVIER SCIENCE INC. 2018: S236

  View details for DOI 10.1016/j.jamcollsurg.2018.07.623

  View details for Web of Science ID 000447760600466

• The evolving relationship of wound healing and tumor stroma. JCI insight Foster, D. S., Jones, R. E., Ransom, R. C., Longaker, M. T., Norton, J. A. 2018; 3 (18)

  Abstract

  The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.

  View details for DOI 10.1172/jci.insight.99911

  View details for PubMedID 30232274

• Gastrinomas: Medical or Surgical Treatment. Endocrinology and metabolism clinics of North America Norton, J. A., Foster, D. S., Ito, T., Jensen, R. T. 2018; 47 (3): 577–601

  Abstract

  This article reviews the role of surgical and medical management in patients with Zollinger-Ellison syndrome (ZES) due to a gastrin-secreting neuroendocrine tumor (gastrinoma). It concentrates on the status at present but also briefly reviews the changes over time in treatment approaches. Generally, surgical and medical therapy are complementary today; however, in some cases, such as patients with ZES and multiple endocrine neoplasia type 1, the treatment approach remains controversial.

  View details for PubMedID 30098717

• Gastrinomas Medical or Surgical Treatment ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA Norton, J. A., Foster, D. S., Ito, T., Jensen, R. T. 2018; 47 (3): 577-+

  View details for DOI 10.1016/j.ecl.2018.04.009

  View details for Web of Science ID 000444367100010

• Management of Liver Neuroendocrine Tumors in 2018. JAMA oncology Foster, D. S., Jensen, R., Norton, J. A. 2018

  View details for PubMedID 30178021

• Monitoring Gastric Myoelectric Activity After Pancreaticoduodenectomy for Diet "Readiness". American journal of physiology. Gastrointestinal and liver physiology Dua, M. M., Navalgund, A., Axelrod, S., Axelrod, L., Worth, P. J., Norton, J. A., Poultsides, G. A., Triadafilopoulos, G., Visser, B. C. 2018

  Abstract

  INTRODUCTION: Post-operative delayed gastric emptying (DGE) is a frustrating complication of pancreaticoduodenectomy (PD). We studied whether monitoring of post-operative gastric motor activity using a novel wireless patch system can identify patients at risk for DGE.METHODS: Eighty-one patients were prospectively studied since 2016; 75 patients were analyzed for this study. After PD, battery-operated wireless patches (G-Tech Medical) that acquire gastrointestinal myoelectrical signals are placed on the abdomen and transmit data by Bluetooth. Patients were divided into EARLY and LATE groups, by diet tolerance of 7 days (ERAS goal). Subgroup analysis was done of patients included after ERAS initiation.RESULTS: The EARLY and LATE groups had 50 and 25 patients, respectively, with length of stay (LOS) 7 and 11 days (p<0.05). Nasogastric insertion was required in 44% of the LATE group. Tolerance of food was noted by 6 vs 9 days in the EARLY vs LATE group (p<0.05) with higher cumulative gastric myoelectrical activity. Diminished gastric myoelectrical activity accurately identified delayed tolerance to regular diet in a logistical regression analysis (area under the curve (AUC), 0.81; 95% CI, 0.74-0.92). The gastric myoelectrical activity also identified delayed LOS status with an AUC of 0.75 (95% CI, 0.67-0.88). Stomach signal continued to be predictive in 90% of the ERAS cohort despite earlier oral intake.CONCLUSIONS: Measurement of gastric activity after PD can distinguish patients with shorter or longer times to diet. This non-invasive technology provides data to identify patients at risk for DGE and may guide timing of oral intake by gastric "readiness."

  View details for PubMedID 30048596

• Prospective Evaluation of Results of Reoperation in Zollinger-Ellison Syndrome. Annals of surgery Norton, J. A., Krampitz, G. W., Poultsides, G. A., Visser, B. C., Fraker, D. L., Alexander, H. R., Jensen, R. T. 2018; 267 (4): 782–88

  Abstract

  OBJECTIVE: To determine the role of reoperation in patients with persistent or recurrent Zollinger-Ellison Syndrome (ZES).BACKGROUND: Approximately, 0% to 60% of ZES patients are disease-free (DF) after an initial operation, but the tumor may recur.METHODS: A prospective database was queried.RESULTS: A total of 223 patients had an initial operation for possible cure of ZES and then were subsequently evaluated serially with cross sectional imaging-computed tomography, magnetic resonance imaging, ultrasound, more recently octreoscan-and functional studies for ZES activity. The mean age at first surgery was 49 years and with an 11-year mean follow-up 52 patients (23%) underwent reoperation when ZES recurred with imageable disease. Results in this group are analyzed in the current report. Reoperation occurred on a mean of 6 years after the initial surgery with a mean number of reoperations of 1 (range 1-5). After reoperation 18/52 patients were initially DF (35%); and after a mean follow-up of 8 years, 13/52 remained DF (25%). During follow-up, 9/52 reoperated patients (17%) died, of whom 7 patients died a disease-related death (13%). The overall survival from first surgery was 84% at 20 years and 68% at 30 years. Multiple endocrine neoplasia type 1 status did not affect survival, but DF interval and liver metastases did.CONCLUSIONS: These results demonstrate that a significant proportion of patients with ZES will develop resectable persistent or recurrent disease after an initial operation. These patients generally have prolonged survival after reoperation and 25% can be cured with repeat surgery, suggesting all ZES patients postresection should have systematic imaging, and if tumor recurs, advise repeat operation.

  View details for PubMedID 29517561

• Clinicopathologic score predicting lymph node metastasis in T1 gastric cancer Tran, T. B., Worhunsky, D. J., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Weber, S. M., Schmidt, C., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Norton, J. A., Poultsides, G. A. MOSBY-ELSEVIER. 2018: 889–93

  View details for DOI 10.1016/j.surg.2017.09.021

  View details for Web of Science ID 000428971700040

• Prospective Evaluation of Results of Reoperation in Zollinger-Ellison Syndrome ANNALS OF SURGERY Norton, J. A., Krampitz, G. W., Poultsides, G. A., Visser, B. C., Fraker, D. L., Alexander, H., Jensen, R. T. 2018; 267 (4): 782–88

  View details for DOI 10.1097/SLA.0000000000002122

  View details for Web of Science ID 000435846900047

• Clinicopathologic score predicting lymph node metastasis in T1 gastric cancer. Surgery Tran, T. B., Worhunsky, D. J., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Weber, S. M., Schmidt, C., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Norton, J. A., Poultsides, G. A. 2018; 163 (4): 889–93

  Abstract

  BACKGROUND: Although gastrectomy with adequate regional nodal examination is considered the standard of care for invasive gastric adenocarcinoma, endoscopic resection has been adopted increasingly in select patients with T1 gastric cancer. The objective of this study was to identify preoperative predictors of lymph node metastasis in patients in the United States with T1 gastric cancer.METHODS: Patients who underwent operative resection for T1 gastric cancer between 2000 and 2012 were identified from a multi-institutional database. Clinicopathologic predictors of lymph node metastasis were determined using univariate and multivariate logistic regression. A preoperative score was created, assigning points based on each variable's regression coefficient.RESULTS: Among 835 patients with gastric cancer undergoing curative-intent surgical resection, 176 patients (20.5%) had T1 disease confirmed on final pathology. Of those, 38 patients (22%) had lymph node metastasis. Independent predictors of lymph node involvement on multivariate analysis were poor differentiation, T1b stage, lymphovascular invasion, and tumor size >2cm. A clinicopathologic risk score composed of these 4 variables was created. Receiver operating curve analysis showed excellent discrimination (area under the curve=0.79) and 100% sensitivity in detecting lymph node metastasis when only one of the aforementioned factors was present.CONCLUSIONS: In this cohort of U.S. patients with T1 gastric adenocarcinoma, the lack of lymph node involvement could be predicted by the absence of several unfavorable factors, including T stage, poor differentiation, lymphovascular invasion, and size >2cm.

  View details for PubMedID 29398039

• Incidence and Prognosis of Primary Gastrinomas in the Hepatobiliary Tract JAMA SURGERY Norton, J. A., Foster, D. S., Blumgart, L. H., Poultsides, G. A., Visser, B. C., Fraker, D. L., Alexander, H., Jensen, R. T. 2018; 153 (3): e175083

  View details for PubMedID 29365025

• SSAT State-of-the-Art Conference: Current Surgical Management of Gastric Tumors JOURNAL OF GASTROINTESTINAL SURGERY Norton, J. A., Kim, T., Kim, J., McCarter, M. D., Kelly, K. J., Wong, J., Sicklick, J. K. 2018; 22 (1): 32–42

  Abstract

  The current era of gastric surgery is marked by low morbidity and mortality rates, innovative strategies to approach resections with a minimally invasive fashion or hyperthermic intraperitoneal chemotherapy (HIPEC), as well as improved understanding of the biology of sporadic and hereditary stromal, neuroendocrine, and epithelial malignancies.In 2017, the Society for Surgery of the Alimentary Tract convened a State-of-the-Art Conference on Current Surgical Management of Gastric Tumors with both international experts and emerging leaders in the field of gastric surgery.Martin D. McCarter, MD of the University of Colorado discussed the current management of gastric gastrointestinal stromal tumors (GIST). Kaitlyn J. Kelly, MD of the University of California, San Diego discussed the management of gastric carcinoid tumors. Jeffrey A. Norton of Stanford University discussed recent advances in the management of gastric adenocarcinoma including a focus on hereditary diffuse gastric cancer (HDGC). Joseph Kim, MD of Stony Brook University discussed a systematic approach to minimally invasive gastrectomy for cancer. Joyce Wong, MD of Pennsylvania State University discussed the role for cytoreductive surgery (CRS) and HIPEC for gastric adenocarcinoma.This review provides gastrointestinal surgeons with a concise update on the current surgical management of gastric tumors.

  View details for PubMedID 28808875

• The evolving relationship of wound healing and tumor stroma JCI Insight Foster, D. S., Jones, R., Ransom, R., Longaker, M. T., Norton, J. A. 2018

  Abstract

  The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.

  View details for DOI 10.1172/jci.insight.99911

• Transgastric pancreatic necrosectomy-expedited return to prepancreatitis health JOURNAL OF SURGICAL RESEARCH Dua, M. M., Worhunsky, D. J., Malhotra, L., Park, W. G., Poultsides, G. A., Norton, J. A., Visser, B. C. 2017; 219: 11–17

  Abstract

  The best operative strategy for necrotizing pancreatitis remains controversial. Traditional surgical necrosectomy is associated with significant morbidity; endoscopic and percutaneous strategies require repeated interventions with prolonged hospitalizations. We have developed a transgastric approach to pancreatic necrosectomy to overcome the shortcomings of the other techniques described.Patients with necrotizing pancreatitis treated from 2009 to 2016 at an academic center were retrospectively reviewed. Open or laparoscopic transgastric necrosectomy was performed if the area of necrosis was walled-off and in a retrogastric position on cross-sectional imaging. Study endpoints included postoperative complications and mortality.Forty-six patients underwent transgastric necrosectomy (nine open and 37 laparoscopic). Median (interquartile range) preoperative Acute Physiologic and Chronic Health Evaluation II score was 6 (3-12). Seventy percent of patients had >30% necrosis on preoperative imaging; infected necrosis was present in 35%. Median total length of stay (LOS) was 6 (3-12) d. No patient required a second operative debridement; four patients (9%) had short-term postoperative percutaneous drainage for residual fluid collections. Median follow-up was 1 y; there were no fistula or wound complications. Six patients (13%) had postoperative bleeding; five patients received treatment by image-guided embolization. There was one death in the cohort.Transgastric pancreatic necrosectomy allows for effective debridement with a single definitive operation. When anatomically suitable, this operative strategy offers expedited recovery and avoids long-term morbidity associated with fistulas and prolonged drainage.

  View details for PubMedID 29078869

• Gallbladder Cancer Presenting with Jaundice: Uniformly Fatal or Still Potentially Curable? Journal of gastrointestinal surgery Tran, T. B., Norton, J. A., Ethun, C. G., Pawlik, T. M., Buettner, S., Schmidt, C., Beal, E. W., Hawkins, W. G., Fields, R. C., Krasnick, B. A., Weber, S. M., Salem, A., Martin, R. C., Scoggins, C. R., Shen, P., Mogal, H. D., Idrees, K., Isom, C. A., Hatzaras, I., Shenoy, R., Maithel, S. K., Poultsides, G. A. 2017

  Abstract

  Jaundice as a presenting symptom of gallbladder cancer has traditionally been considered to be a sign of advanced disease, inoperability, and poor outcome. However, recent studies have demonstrated that a small subset of these patients can undergo resection with curative intent.Patients with gallbladder cancer managed surgically from 2000 to 2014 in 10 US academic institutions were stratified based on the presence of jaundice at presentation (defined as bilirubin ≥4 mg/ml or requiring preoperative biliary drainage). Perioperative morbidity, mortality, and overall survival were compared between jaundiced and non-jaundiced patients.Of 400 gallbladder cancer patients with available preoperative data, 108 (27%) presented with jaundice while 292 (73%) did not. The fraction of patients who eventually underwent curative-intent resection was much lower in the presence of jaundice (n = 33, 30%) than not (n = 218, 75%; P < 0.001). Jaundiced patients experienced higher perioperative morbidity (69 vs. 38%; P = 0.002), including a much higher need for reoperation (12 vs. 1%; P = 0.003). However, 90-day mortality (6.5 vs. 3.6%; P = 0.35) was not significantly higher. Overall survival after resection was worse in jaundiced patients (median 14 vs. 32 months; P < 0.001). Further subgroup analysis within the jaundiced patients revealed a more favorable survival after resection in the presence of low CA19-9 < 50 (median 40 vs. 12 months; P = 0.003) and in the absence of lymphovascular invasion (40 vs. 14 months; P = 0.014).Jaundice is a powerful preoperative clinical sign of inoperability and poor outcome among gallbladder cancer patients. However, some of these patients may still achieve long-term survival after resection, especially when preoperative CA19-9 levels are low and no lymphovascular invasion is noted pathologically.

  View details for DOI 10.1007/s11605-017-3440-z

  View details for PubMedID 28497252

• Treatment of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 Some Clarity But Continued Controversy PANCREAS Jensen, R. T., Norton, J. A. 2017; 46 (5): 589–94

  View details for PubMedID 28426491

  View details for PubMedCentralID PMC5407310

• Fukuoka and AGA Criteria Have Superior Diagnostic Accuracy for Advanced Cystic Neoplasms than Sendai Criteria. Digestive diseases and sciences Sighinolfi, M., Quan, S. Y., Lee, Y., Ibaseta, A., Pham, K., Dua, M. M., Poultsides, G. A., Visser, B. C., Norton, J. A., Park, W. G. 2017; 62 (3): 626-632

  Abstract

  The aim of this study was to compare the American Gastroenterological Association guidelines (AGA criteria), the 2012 (Fukuoka criteria), and 2006 (Sendai criteria) International Consensus Guidelines for the diagnosis of advanced pancreatic cystic neoplasms.All patients who underwent surgical resection of a pancreatic cyst from August 2007 through January 2016 were retrospectively analyzed at a single tertiary academic center. Relevant clinical and imaging variables along with pathology results were collected to determine appropriate classification for each guideline. Advanced pancreatic cystic neoplasms were defined by the presence of either high-grade dysplasia or cystic adenocarcinoma. Diagnostic accuracy was measured by ROC analysis.A total of 209 patients were included. Both the AGA and Fukuoka criteria had a higher diagnostic accuracy for advanced neoplastic cysts than the Sendai criteria: AGA ROC 0.76 (95% CI 0.69-0.81), Fukuoka ROC 0.78 (95% CI 0.74-0.82), and Sendai ROC 0.65 (95% CI 0.61-0.69) (p < 0.0001). There was no difference between the Fukuoka and the AGA criteria. While the sensitivity was higher in the Fukuoka criteria compared to the AGA criteria (97.7 vs. 88.6%), the specificity was higher in the AGA criteria compared to the Fukuoka criteria (62.4 vs. 58.2%).In a surgical series of patients with pancreatic cysts, the AGA and Fukuoka criteria had superior diagnostic accuracy for advanced neoplastic cysts compared to the original Sendai criteria.

  View details for DOI 10.1007/s10620-017-4460-y

  View details for PubMedID 28116593

• Met Activation Confers Increased Aggressiveness and Corresponds With Hypoenhancement on Contrast Enhanced Computed Tomography in Pancreatic Neuroendocrine Tumors Krampitz, G., Weissman, I., Norton, J. LIPPINCOTT WILLIAMS & WILKINS. 2017: 428

  View details for Web of Science ID 000394448600033

• Enumeration and targeted analysis of KRAS, BRAF and PIK3CA mutations in CTCs captured by a label-free platform: Comparison to ctDNA and tissue in metastatic colorectal cancer ONCOTARGET Kidess-Sigal, E., Liu, H. E., Triboulet, M. M., Che, J., Ramani, V. C., Visser, B. C., Poultsides, G. A., Longacre, T. A., Marziali, A., Vysotskaia, V., Wiggin, M., Heirich, K., Hanft, V., Keilholz, U., Tinhofer, I., Norton, J. A., Lee, M., Sollier-Christen, E., Jeffrey, S. S. 2016; 7 (51): 85349-85364

  Abstract

  Treatment of advanced colorectal cancer (CRC) requires multimodal therapeutic approaches and need for monitoring tumor plasticity. Liquid biopsy biomarkers, including CTCs and ctDNA, hold promise for evaluating treatment response in real-time and guiding therapeutic modifications. From 15 patients with advanced CRC undergoing liver metastasectomy with curative intent, we collected 41 blood samples at different time points before and after surgery for CTC isolation and quantification using label-free Vortex technology. For mutational profiling, KRAS, BRAF, and PIK3CA hotspot mutations were analyzed in CTCs and ctDNA from 23 samples, nine matched liver metastases and three primary tumor samples. Mutational patterns were compared. 80% of patient blood samples were positive for CTCs, using a healthy baseline value as threshold (0.4 CTCs/mL), and 81.4% of captured cells were EpCAM+ CTCs. At least one mutation was detected in 78% of our blood samples. Among 23 matched CTC and ctDNA samples, we found a concordance of 78.2% for KRAS, 73.9% for BRAF and 91.3% for PIK3CA mutations. In several cases, CTCs exhibited a mutation that was not detected in ctDNA, and vice versa. Complementary assessment of both CTCs and ctDNA appears advantageous to assess dynamic tumor profiles.

  View details for DOI 10.18632/oncotarget.13350

  View details for PubMedID 27863403

• Actual 10-Year Survivors Following Resection of Adrenocortical Carcinoma JOURNAL OF SURGICAL ONCOLOGY Tran, T. B., Postlewait, L. M., Maithel, S. K., Prescott, J. D., Wang, T. S., Glenn, J., Phay, J. E., Keplinger, K., Fields, R. C., Jin, L. X., Weber, S. M., Salem, A., Sicklick, J. K., Gad, S., Yopp, A. C., Mansour, J. C., Duh, Q., Seiser, N., Solorzano, C. C., Kiernan, C. M., Votanopoulos, K. I., Levine, E. A., Hatzaras, I., Shenoy, R., Pawlik, T. M., Norton, J. A., Poultsides, G. A. 2016; 114 (8): 971-976

  Abstract

  Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long-term survivors following surgical resection for ACC have not been previously reported.Patients who underwent resection for ACC at one of 13 academic institutions participating in the US Adrenocortical Carcinoma Group from 1993 to 2014 were analyzed. Patients were stratified into four groups: early mortality (died within 2 years), late mortality (died within 2-5 years), actual 5-year survivor (survived at least 5 years), and actual 10-year survivor (survived at least 10 years). Patients with less than 5 years of follow-up were excluded.Among the 180 patients available for analysis, there were 49 actual 5-year survivors (27%) and 12 actual 10-year survivors (7%). Patients who experienced early mortality had higher rates of cortisol-secreting tumors, nodal metastasis, synchronous distant metastasis, and R1 or R2 resections (all P < 0.05). The need for multi-visceral resection, perioperative blood transfusion, and adjuvant therapy correlated with early mortality. However, nodal involvement, distant metastasis, and R1 resection did not preclude patients from becoming actual 10-year survivors. Ten of twelve actual 10-year survivors were women, and of the seven 10-year survivors who experienced disease recurrence, five had undergone repeat surgery to resect the recurrence.Surgery for ACC can offer a 1 in 4 chance of actual 5-year survival and a 1 in 15 chance of actual 10-year survival. Long-term survival was often achieved with repeat resection for local or distant recurrence, further underscoring the important role of surgery in managing patients with ACC. J. Surg. Oncol. 2016;114:971-976. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jso.24439

  View details for PubMedID 27633419

• Lymphadenectomy for Adrenocortical Carcinoma: Is There a Therapeutic Benefit? ANNALS OF SURGICAL ONCOLOGY Gerry, J. M., Tran, T. B., Postlewait, L. M., Maithel, S. K., Prescott, J. D., Wang, T. S., Glenn, J. A., Phay, J. E., Keplinger, K., Fields, R. C., Jin, L. X., Weber, S. M., Salem, A., Sicklick, J. K., Gad, S., Yopp, A. C., Mansour, J. C., Duh, Q., Seiser, N., Solorzano, C. C., Kiernan, C. M., Votanopoulos, K. I., Levine, E. A., Hatzaras, I., Shenoy, R., Pawlik, T. M., Norton, J. A., Poultsides, G. A. 2016; 23: S708-S713

  Abstract

  Lymph node metastasis is an established predictor of poor outcome for adrenocortical carcinoma (ACC); however, routine lymphadenectomy during surgical resection of ACC is not widely performed and its therapeutic role remains unclear.Patients undergoing margin-negative resection for localized ACC were identified from a multi-institutional database. Patients were stratified into 2 groups based on the surgeon's effort or not to perform a lymphadenectomy as documented in the operative note. Clinical, pathologic, and outcome data were compared between the 2 groups.Of 120 patients who met inclusion criteria from 1993 to 2014, 32 (27 %) underwent lymphadenectomy. Factors associated with lymphadenectomy were tumor size (12 vs. 9.5 cm; p = .007), palpable mass at presentation (26 vs. 12 %; p = .07), suspicious lymph nodes on preoperative imaging (44 vs. 7 %; p < .001), and need for multivisceral resection (78 vs. 36 %; p < .001). Median number of lymph nodes harvested was higher in the lymphadenectomy group (5.5 vs. 0; p < .001). In-hospital mortality (0 vs. 1.3 %; p = .72) and grade 3/4 complication rates (0 vs. 12 %; p = .061) were not significantly different. Patients who underwent lymphadenectomy had improved overall survival (5-year 76 vs. 59 %; p = .041). The benefit of lymphadenectomy on overall survival persisted on multivariate analysis (HR = 0.17; p = .006) controlling for adverse preoperative and intraoperative factors associated with lymphadenectomy, such as tumor size, palpable mass, irregular tumor edges, suspicious nodes on imaging, and multivisceral resection.In this multicenter study of adrenocortical carcinoma patients undergoing R0 resection, the surgeon's effort to dissect peritumoral lymph nodes was independently associated with improved overall survival.

  View details for DOI 10.1245/s10434-016-5536-1

  View details for Web of Science ID 000391508800027

  View details for PubMedCentralID PMC5257294

• Lymphadenectomy for Adrenocortical Carcinoma: Is There a Therapeutic Benefit? Annals of surgical oncology Gerry, J. M., Tran, T. B., Postlewait, L. M., Maithel, S. K., Prescott, J. D., Wang, T. S., Glenn, J. A., Phay, J. E., Keplinger, K., Fields, R. C., Jin, L. X., Weber, S. M., Salem, A., Sicklick, J. K., Gad, S., Yopp, A. C., Mansour, J. C., Duh, Q., Seiser, N., Solorzano, C. C., Kiernan, C. M., Votanopoulos, K. I., Levine, E. A., Hatzaras, I., Shenoy, R., Pawlik, T. M., Norton, J. A., Poultsides, G. A. 2016; 23: 708-713

  Abstract

  Lymph node metastasis is an established predictor of poor outcome for adrenocortical carcinoma (ACC); however, routine lymphadenectomy during surgical resection of ACC is not widely performed and its therapeutic role remains unclear.Patients undergoing margin-negative resection for localized ACC were identified from a multi-institutional database. Patients were stratified into 2 groups based on the surgeon's effort or not to perform a lymphadenectomy as documented in the operative note. Clinical, pathologic, and outcome data were compared between the 2 groups.Of 120 patients who met inclusion criteria from 1993 to 2014, 32 (27 %) underwent lymphadenectomy. Factors associated with lymphadenectomy were tumor size (12 vs. 9.5 cm; p = .007), palpable mass at presentation (26 vs. 12 %; p = .07), suspicious lymph nodes on preoperative imaging (44 vs. 7 %; p < .001), and need for multivisceral resection (78 vs. 36 %; p < .001). Median number of lymph nodes harvested was higher in the lymphadenectomy group (5.5 vs. 0; p < .001). In-hospital mortality (0 vs. 1.3 %; p = .72) and grade 3/4 complication rates (0 vs. 12 %; p = .061) were not significantly different. Patients who underwent lymphadenectomy had improved overall survival (5-year 76 vs. 59 %; p = .041). The benefit of lymphadenectomy on overall survival persisted on multivariate analysis (HR = 0.17; p = .006) controlling for adverse preoperative and intraoperative factors associated with lymphadenectomy, such as tumor size, palpable mass, irregular tumor edges, suspicious nodes on imaging, and multivisceral resection.In this multicenter study of adrenocortical carcinoma patients undergoing R0 resection, the surgeon's effort to dissect peritumoral lymph nodes was independently associated with improved overall survival.

  View details for PubMedID 27590329

• Laparoscopic hepatectomy in cirrhotics: safe if you adjust technique. Surgical endoscopy Worhunsky, D. J., Dua, M. M., Tran, T. B., Siu, B., Poultsides, G. A., Norton, J. A., Visser, B. C. 2016; 30 (10): 4307-4314

  Abstract

  Minimally invasive liver surgery is a growing field, and a small number of recent reports have suggested that laparoscopic liver resection (LLR) is feasible even in patients with cirrhosis. However, parenchymal transection of the cirrhotic liver is challenging due to fibrosis and portal hypertension. There is a paucity of data regarding the technical modifications necessary to safely transect the diseased parenchyma.Patients undergoing LLR by a single surgeon between 2008 and 2015 were reviewed. Patients with cirrhosis were compared to those without cirrhosis to examine differences in surgical technique, intraoperative characteristics, and outcomes (including liver-related morbidity and general postoperative complication rates).A total of 167 patients underwent LLR during the study period. Forty-eight (29 %) had cirrhosis, of which 43 (90 %) had hepatitis C. Most had Child-Pugh class A disease (85 %). Compared to noncirrhotics, patients with cirrhosis were older, had more comorbidities, and were more likely to have hepatocellular carcinoma. Precoagulation before parenchymal transection was used more frequently in cirrhotics (65 vs. 15 %, P < 0.001), and mean portal triad clamping time was longer (32 vs. 22 min, P = 0.002). There were few conversions to open surgery, though hand-assisted laparoscopy was used as an alternative to converting to open in three patients with cirrhosis. Blood loss was relatively low for both groups. Although there were more postoperative complications among cirrhotics (38 vs. 13 %, P = 0.001), this was almost entirely due to a higher rate of minor (Clavien-Dindo I or II) complications. Liver-related morbidity, major complications, and mortality rates were similar.LLR is safe for selected patients with cirrhosis. The added complexity associated with the division of diseased liver parenchyma may be overcome with some form of technique modification, including more liberal use of precoagulation, portal triad clamping, or a hand-assist port.

  View details for DOI 10.1007/s00464-016-4748-6

  View details for PubMedID 26895906

• The significance of underlying cardiac comorbidity on major adverse cardiac events after major liver resection. HPB Tran, T. B., Worhunsky, D. J., Spain, D. A., Dua, M. M., Visser, B. C., Norton, J. A., Poultsides, G. A. 2016; 18 (9): 742-747

  Abstract

  The risk of postoperative adverse events in patients with underlying cardiac disease undergoing major hepatectomy remains poorly characterized.The NSQIP database was used to identify patients undergoing hemihepatectomy and trisectionectomy. Patient characteristics and postoperative outcomes were evaluated.From 2005 to 2012, 5227 patients underwent major hepatectomy. Of those, 289 (5.5%) had prior major cardiac disease: 5.6% angina, 3.1% congestive heart failure, 1% myocardial infarction, 54% percutaneous coronary intervention, and 46% cardiac surgery. Thirty-day mortality was higher in patients with cardiac comorbidity (6.9% vs. 3.7%, P = 0.008), including the incidence of postoperative cardiac arrest requiring cardiopulmonary resuscitation (3.8% vs. 1.2%, P = 0.001) and myocardial infarction (1.7% vs. 0.4%, P = 0.011). Multivariate analysis revealed that functional impairment, older age, and malnutrition, but not cardiac comorbidity, were significant predictors of 30-day mortality. However, prior percutaneous coronary intervention was independently associated with postoperative cardiac arrest (OR 2.999, P = 0.008).While cardiac comorbidity is not a predictor of mortality after major hepatectomy, prior percutaneous coronary intervention is independently associated with postoperative cardiac arrest. Careful patient selection and preoperative optimization is fundamental in patients with prior percutaneous coronary intervention being considered for major hepatectomy as restrictive fluid management and low central venous pressure anesthesia may not be tolerated well by all patients.

  View details for DOI 10.1016/j.hpb.2016.06.012

  View details for PubMedID 27593591

• Neuroendocrine tumors of the pancreas: Degree of cystic component predicts prognosis. Surgery Cloyd, J. M., Kopecky, K. E., Norton, J. A., Kunz, P. L., Fisher, G. A., Visser, B. C., Dua, M. M., Park, W. G., Poultsides, G. A. 2016; 160 (3): 708-713

  Abstract

  Although most pancreatic neuroendocrine tumors are solid, approximately 10% are cystic. Some studies have suggested that cystic pancreatic neuroendocrine tumors are associated with a more favorable prognosis.A retrospective review of all patients with pancreatic neuroendocrine tumors who underwent operative resection between 1999 and 2014 at a single academic medical center was performed. Based on cross-sectional imaging performed before operation, pancreatic neuroendocrine tumors were classified according to the size of the cystic component relative to the total tumor size: purely cystic (100%), mostly cystic (≥50%), mostly solid (<50%), and purely solid (0%). Clinicopathologic characteristics and recurrence-free survival were assessed between groups.In the study, 214 patients met inclusion criteria: 8 with purely cystic tumors, 7 with mostly cystic tumors, 15 with mostly solid tumors, and 184 with purely solid tumors. The groups differed in terms of tumor size (1.5 ± 0.5, 3.0 ± 1.7, 3.7 ± 2.6, and 4.0 ± 3.5 cm), lymph node positivity (0%, 0%, 26.7%, and 34.2%), intermediate or high grade (0%, 16.7%, 20.0%, and 31.0%), synchronous liver metastases (0%, 14.3%, 20.0%, and 26.6%) and need for pancreaticoduodenectomy (0%, 0%, 6.7%, and 25.0%), respectively. No cases of purely cystic pancreatic neuroendocrine tumors were associated with synchronous liver or lymph node metastasis, intermediate/high grade, recurrence, or death due to disease. Among patients presenting without metastatic disease, 10-year recurrence-free survival was 100% in patients with purely and mostly cystic tumors versus 53.0% in patients with purely and mostly solid tumors; however, this difference did not reach statistical significance.Pancreatic neuroendocrine tumors demonstrate a spectrum of biologic behavior with an increasing cystic component being associated with more favorable clinicopathologic features and prognosis. Purely cystic pancreatic neuroendocrine tumors may represent 1 subset that can be safely observed without immediate resection.

  View details for DOI 10.1016/j.surg.2016.04.005

  View details for PubMedID 27216830

• Pancreatic Cancer Surgical Resection Margins: Molecular Assessment by Mass Spectrometry Imaging. PLoS medicine Eberlin, L. S., Margulis, K., Planell-Mendez, I., Zare, R. N., Tibshirani, R., Longacre, T. A., Jalali, M., Norton, J. A., Poultsides, G. A. 2016; 13 (8)

  Abstract

  Surgical resection with microscopically negative margins remains the main curative option for pancreatic cancer; however, in practice intraoperative delineation of resection margins is challenging. Ambient mass spectrometry imaging has emerged as a powerful technique for chemical imaging and real-time diagnosis of tissue samples. We applied an approach combining desorption electrospray ionization mass spectrometry imaging (DESI-MSI) with the least absolute shrinkage and selection operator (Lasso) statistical method to diagnose pancreatic tissue sections and prospectively evaluate surgical resection margins from pancreatic cancer surgery.Our methodology was developed and tested using 63 banked pancreatic cancer samples and 65 samples (tumor and specimen margins) collected prospectively during 32 pancreatectomies from February 27, 2013, to January 16, 2015. In total, mass spectra for 254,235 individual pixels were evaluated. When cross-validation was employed in the training set of samples, 98.1% agreement with histopathology was obtained. Using an independent set of samples, 98.6% agreement was achieved. We used a statistical approach to evaluate 177,727 mass spectra from samples with complex, mixed histology, achieving an agreement of 81%. The developed method showed agreement with frozen section evaluation of specimen margins in 24 of 32 surgical cases prospectively evaluated. In the remaining eight patients, margins were found to be positive by DESI-MSI/Lasso, but negative by frozen section analysis. The median overall survival after resection was only 10 mo for these eight patients as opposed to 26 mo for patients with negative margins by both techniques. This observation suggests that our method (as opposed to the standard method to date) was able to detect tumor involvement at the margin in patients who developed early recurrence. Nonetheless, a larger cohort of samples is needed to validate the findings described in this study. Careful evaluation of the long-term benefits to patients of the use of DESI-MSI for surgical margin evaluation is also needed to determine its value in clinical practice.Our findings provide evidence that the molecular information obtained by DESI-MSI/Lasso from pancreatic tissue samples has the potential to transform the evaluation of surgical specimens. With further development, we believe the described methodology could be routinely used for intraoperative surgical margin assessment of pancreatic cancer.

  View details for DOI 10.1371/journal.pmed.1002108

  View details for PubMedID 27575375

• To Roux or not to Roux: a comparison between Roux-en-Y and Billroth II reconstruction following partial gastrectomy for gastric cancer GASTRIC CANCER Tran, T. B., Worhunsky, D. J., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Cho, C. S., Weber, S. M., Schmidt, C., Levine, E. A., Bloomston, M., Fields, R. C., Pawlik, T. M., Maithel, S. K., Norton, J. A., Poultsides, G. A. 2016; 19 (3): 994-1001

  Abstract

  Although the extent of resection frequently dictates the method of reconstruction following distal subtotal gastrectomy, it is unclear whether Roux-en-Y gastrojejunostomy compared with Billroth II gastrojejunostomy is associated with superior perioperative outcomes.Patients who underwent resection for gastric cancer with Roux-en-Y or Billroth II reconstruction between 2000 and 2012 in seven academic institutions (US Gastric Cancer Collaborative) were identified. Patients who underwent total gastrectomy, gastric wedge, or palliative resections (metastatic disease or R2 resections) were excluded.Of a total of 965 patients, 447 met the inclusion criteria. A comparison between the Roux-en-Y (n = 257) and Billroth II (n = 190) groups demonstrated no differences in patient and tumor characteristics, except for Billroth II patients having a higher proportion of antral tumors (71 % vs. 50 %, p < 0.001). Roux-en-Y operations were slightly longer (244 min vs. 212 min, p < 0.001) and associated with somewhat higher blood loss (243 ml vs. 205 ml, p = 0.033). However, there were no significant differences in the length of hospital stay (8 days vs. 7 days), readmission rate (17 % vs. 18 %), 90-day mortality (5.1 % vs. 4.7 %), incidence (39 % vs. 41 %) and severity of complications, dependency on jejunostomy tube feeding at discharge (13 % vs. 12 %), same-patient decrease in serum albumin level from the preoperative to the postoperative value at 30, 60, and 90 days, receipt of adjuvant therapy (50 % vs. 53 %), or 5-year survival (44 % vs. 41 %).Although long-term quality-of-life parameters were not compared, this study did not show an advantage of Roux-en-Y gastrojejunostomy over Billroth II gastrojejunostomy in short-term perioperative outcomes. Both techniques should be regarded as equally acceptable reconstructive options following partial gastrectomy for gastric cancer.

  View details for DOI 10.1007/s10120-015-0547-3

  View details for PubMedID 26400843

• Rates and Outcomes of Parathyroidectomy for Secondary Hyperparathyroidism in the United States CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Kim, S. M., Long, J., Montez-Rath, M. E., Leonard, M. B., Norton, J. A., Chertow, G. M. 2016; 11 (7): 1260-1267

  Abstract

  Secondary hyperparathyroidism is common among patients with ESRD. Although medical therapy for secondary hyperparathyroidism has changed dramatically over the last decade, rates of parathyroidectomy for secondary hyperparathyroidism across the United States population are unknown. We examined temporal trends in rates of parathyroidectomy, in-hospital mortality, length of hospital stay, and costs of hospitalization.Using the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, a representative national database on hospital stay regardless of age and payer in the United States, we identified parathyroidectomies for secondary hyperparathyroidism from 2002 to 2011. Data from the US Renal Data System reports were used to calculate the rate of parathyroidectomy.We identified 32,971 parathyroidectomies for secondary hyperparathyroidism between 2002 and 2011. The overall rate of parathyroidectomy was approximately 5.4/1000 patients (95% confidence interval [95% CI], 5.0/1000 to 6.0/1000). The rate decreased from 2003 (7.9/1000 patients; 95% CI, 6.2/1000 to 9.6/1000), reached a nadir in 2005 (3.3/1000 patients; 95% CI, 2.6/1000 to 4.0/1000), increased again through 2006 (5.4/1000 patients; 95% CI, 4.4/1000 to 6.4/1000), and remained stable since that time. Rates of in-hospital mortality decreased from 1.7% (95% CI, 0.8% to 2.6%) in 2002 to 0.8% (95% CI, 0.1% to 1.6%) in 2011 (P for trend <0.001). In-hospital mortality rates were significantly higher in patients with heart failure (odds ratio [OR], 4.23; 95% CI, 2.59 to 6.91) and peripheral vascular disease (OR, 4.59; 95% CI, 2.75 to 7.65) and lower among patients with prior kidney transplantation (OR, 0.20; 95% CI, 0.06 to 0.65).Despite the use of multiple medical therapies, rates of parathyroidectomy of secondary hyperparathyroidism have not declined in recent years.

  View details for DOI 10.2215/CJN.10370915

  View details for PubMedID 27269300

• An economic analysis of pancreaticoduodenectomy: should costs drive consumer decisions? AMERICAN JOURNAL OF SURGERY Tran, T. B., Dua, M. M., Worhunsky, D. J., Poultsides, G. A., Norton, J. A., Visser, B. C. 2016; 211 (6): 991-?

  Abstract

  Consumer groups campaign for cost transparency believing that patients will select hospitals accordingly. We sought to determine whether the cost of pancreaticoduodenectomy (PD) should be considered in choosing a hospital.Using the Nationwide Inpatient Sample database, we analyzed charges for patients who underwent PD from 2000 to 2010. Outcomes were stratified by hospital volume.A total of 15,599 PDs were performed in 1,186 hospitals. The median cost was $87,444 (interquartile range $16,015 to $144,869). High volume hospitals (HVH) had shorter hospital stay (11 vs 15 days, P < .001) and mortality (3% vs 7.6%, P < .001). PD performed at low volume hospitals had higher charges compared with HVH ($97,923 vs $81,581, P < .001). On multivariate analysis, HVH was associated with a lower risk of mortality, while extremes in hospital costs, cardiac comorbidity, and any complication were significant predictors of mortality.Although PDs performed at HVH are associated with better outcomes and lower hospital charges, costs should not be the primary determinant when selecting a hospital.

  View details for DOI 10.1016/j.amjsurg.2015.10.028

  View details for PubMedID 26902956

• The First Decade of Laparoscopic Pancreaticoduodenectomy in the United States: Costs and Outcomes Using the Nationwide Inpatient Sample SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES Tran, T. B., Dua, M. M., Worhunsky, D. J., Poultsides, G. A., Norton, J. A., Visser, B. C. 2016; 30 (5): 1778-1783

  Abstract

  Minimally invasive pancreaticoduodenectomy (PD) remains an uncommon procedure, and the safety and efficacy remain uncertain beyond single institution case series. The aim of this study is to compare outcomes and costs between laparoscopic (LPD) and open PD (OPD) using a large population-based database.The Nationwide Inpatient Sample database (a sample of approximately 20 % of all hospital discharges) was analyzed to identify patients who underwent PD from 2000 to 2010. Patient demographics, comorbidities, hospital characteristics, inflation-adjusted total charges, and complications were evaluated using univariate and multivariate logistic regression. Hospitals were categorized as high-volume hospitals (HVH) if more than 20 PD (open and laparoscopic) were performed annually, while those performing fewer than 20 PD were classified as low-volume hospitals.Of the 15,574 PD identified, 681 cases were LPD (4.4 %). Compared to OPD, patients who underwent LPD were slightly older (65 vs. 67 years; p = 0.001) and were more commonly treated at HVH (56.6 vs. 66.1 %; p < 0.001). Higher rates of complications were observed in OPD than LPD (46 vs. 39.4 %; p = 0.001), though mortality rates were comparable (5 vs. 3.8 %, p = 0.27). Inflation-adjusted median hospital charges were similar between OPD and LPD ($87,577 vs. $81,833, p = 0.199). However, hospital stay was slightly longer in the OPD group compared to LPD group (12 vs. 11 days, p < 0.001). Stratifying outcomes by hospital volume, LPD at HVH resulted in shorter hospital stays (9 vs. 13 days, p < 0.001), which translated into significantly lower median hospital charges ($76,572 vs. $106,367, p < 0.001).Contrary to fears regarding the potential for compromised outcomes early in the learning curve, LPD morbidity in its first decade is modestly reduced, while hospital costs are comparable to OPD. In high-volume pancreatic hospitals, LPD is associated with a reduction in length of stay and hospital costs.

  View details for DOI 10.1007/s00464-015-4444-y

  View details for PubMedID 26275542

• Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Krampitz, G. W., George, B. M., Willingham, S. B., Volkmer, J., Weiskopf, K., Jahchan, N., Newman, A. M., Sahoo, D., Zemek, A. J., Yanovsky, R. L., Nguyen, J. K., Schnorr, P. J., Mazur, P. K., Sage, J., Longacre, T. A., Visser, B. C., Poultsides, G. A., Norton, J. A., Weissman, I. L. 2016; 113 (16): 4464-4469

  Abstract

  Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90(hi)cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo.

  View details for DOI 10.1073/pnas.1600007113

  View details for PubMedID 27035983

• Stage-Specific Prognostic Effect of Race in Patients with Resectable Gastric Adenocarcinoma: An 8-Institution Study of the US Gastric Cancer Collaborative. Journal of the American College of Surgeons Wang, A., Squires, M. H., Melis, M., Poultsides, G. A., Norton, J. A., Jin, L. X., Fields, R. C., Spolverato, G., Pawlik, T. M., Votanopoulos, K. I., Levine, E. A., Schmidt, C., Bloomston, M., Cho, C. S., Weber, S., Berman, R., Pachter, H. L., Newman, E., Staley, C. A., Maithel, S. K., Hatzaras, I. 2016; 222 (4): 633-643

  Abstract

  Gastric cancer constitutes a major public health problem. This study sought to evaluate the relevance of race in gastric cancer and its prognostic effect in the overall outcomes of patients with gastric adenocarcinoma.Patients who underwent curative intent resection of gastric adenocarcinoma in 8 institutions of the US Gastric Cancer Collaborative were included, from 2000 to 2012. Nonparametric descriptive statistics were used to evaluate characteristics of standard demographic data. Multivariate Cox proportional hazards regression was used to identify factors associated with recurrence-free survival and overall survival.There were 1,077 patients included in the study, the majority of whom were of Caucasian race (n = 698, 68%), followed by African-American (n = 164, 15%), Asian (n = 132, 12%), Hispanic (n = 34, 3.2%), and other (n = 49, 4.5%). Clinicopathologic data were similarly distributed among the 5 groups. Mean follow-up was 27.1 months. By multivariate, stage-specific analysis, Asian race was a significant predictor of recurrence (all stages hazard ratio [HR] 0.45 95% CI [0.23, 0.97], p = 0.041) and of overall survival (all stages HR 0.35 95% CI [0.18, 0.68], p = 0.002). Recurrence-free survival was significantly increased in the Asian population compared with the non-Asian population (25th percentile: 38.6 vs 17.7 months, p = 0.0096), as was overall median survival (141 vs 38.8 months, p < 0.001).Patients of Asian race undergoing curative gastrectomy for gastric adenocarcinoma appear to have a better prognosis stage for stage. Further studies are required to elucidate the underlying etiology of this phenomenon.

  View details for DOI 10.1016/j.jamcollsurg.2015.12.043

  View details for PubMedID 26905187

• In situ vaccine, immunological memory and cancer cure. Human vaccines & immunotherapeutics Tsung, K., Norton, J. A. 2016; 12 (1): 117-119

  Abstract

  As surgery is able to remove primary tumors and limit metastases, the major challenge in cancer management is the prevention of post-resection recurrence and metastases. From the immune point of view, tumor resection removes the supply of tumor antigens that maintain an active concomitant antitumor immunity elicited by the primary tumor, and may also signal for deposition of immunological memory against future metastases. However, the natural course of this antitumor immunity in many cancer patients following complete tumor resection may not be favorable because protection is often lost after 1-3 years. Recent studies suggest that chemotherapy is able to activate this pre-existing antitumor immunity, and tumor resection following immune activation may lead to higher levels of immunological memory against future tumor antigens (in the form of metastases). Interleukin-12 added to chemotherapy mimics the function of a vaccine adjuvant in that it helps to enhance the antitumor immunity activated by chemotherapy and leaves a much stronger antitumor immune memory. This finding, when applied to cancer management, may help to maintain a strong and long lasting antitumor immunity following complete tumor resection, thus eliminating post-surgery recurrence and metastases.

  View details for DOI 10.1080/21645515.2015.1073427

  View details for PubMedID 26360526

• Statin and Metformin Use Prolongs Survival in Patients With Resectable Pancreatic Cancer. Pancreas Kozak, M. M., Anderson, E. M., von Eyben, R., Pai, J. S., Poultsides, G. A., Visser, B. C., Norton, J. A., Koong, A. C., Chang, D. T. 2016; 45 (1): 64-70

  Abstract

  The aim of this study was to investigate the impact of statin and metformin therapy on disease outcome for patients with pancreatic ductal adenocarcinoma (PDAC).This retrospective study included 171 PDAC patients who underwent surgical resection at the Stanford Cancer Institute between 1998 and 2013. No patients received neoadjuvant therapy. Statin and metformin use was defined as use during initial consult and continuing upon discharge from the hospital after surgery. Dose of each medication was recorded, as was the type of statin taken.The median follow-up for all patients was 11.23 months (range, 0.2-105.0 months). Among the 171 patients included in our analysis, 18 patients (10.5%) took metformin and 34 patients (19.9%) took statins. Statin use was associated with better overall survival (OS) in patients with PDAC (P = 0.011). Metformin use was also associated with better OS (P = 0.035). The use of statins remained significant on multivariate analysis for OS (P = 0.014; hazards ratio, 0.33; 95% confidence interval, 0.139-0.799), but metformin use did not (P = 0.33; hazards ratio 0.60, 95% confidence interval, 0.211-1.675).Statin and metformin use is associated with improved OS in patients with resectable PDAC. These medications should be further investigated for possible long-term use in the general population.

  View details for DOI 10.1097/MPA.0000000000000470

  View details for PubMedID 26474429

• Declining Rates of Inpatient Parathyroidectomy for Primary Hyperparathyroidism in the US. PloS one Kim, S. M., Shu, A. D., Long, J., Montez-Rath, M. E., Leonard, M. B., Norton, J. A., Chertow, G. M. 2016; 11 (8)

  Abstract

  Parathyroidectomy is the only curative therapy for patients with primary hyperparathyroidism. However, the incidence, correlates and consequences of parathyroidectomy for primary hyperparathyroidism across the entire US population are unknown. We evaluated temporal trends in rates of inpatient parathyroidectomy for primary hyperparathyroidism, and associated in-hospital mortality, length of stay, and costs. We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) from 2002-2011. Parathyroidectomies for primary hyperparathyroidism were identified using International Classification of Diseases, Ninth Revision codes. Unadjusted and age- and sex- adjusted rates of inpatient parathyroidectomy for primary hyperparathyroidism were derived from the NIS and the annual US Census. We estimated 109,583 parathyroidectomies for primary hyperparathyroidism between 2002 and 2011. More than half (55.4%) of patients were younger than age 65, and more than three-quarters (76.8%) were female. The overall rate of inpatient parathyroidectomy was 32.3 cases per million person-years. The adjusted rate decreased from 2004 (48.3 cases/million person-years) to 2007 (31.7 cases/million person-years) and was sustained thereafter. Although inpatient parathyroidectomy rates declined over time across all geographic regions, a steeper decline was observed in the South compared to other regions. Overall in-hospital mortality rates were 0.08%: 0.02% in patients younger than 65 years and 0.14% in patients 65 years and older. Inpatient parathyroidectomy rates for primary hyperparathyroidism have declined in recent years.

  View details for DOI 10.1371/journal.pone.0161192

  View details for PubMedID 27529699

• Gastric Remnant Cancer: A Distinct Entity or Simply Another Proximal Gastric Cancer? JOURNAL OF SURGICAL ONCOLOGY Tran, T. B., Hatzaras, I., Worhunsky, D. J., Vitiello, G. A., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Norton, J. A., Poultsides, G. A. 2015; 112 (8): 877-882

  Abstract

  The purpose of this study was to compare outcomes following resection of gastric remnant (GRC) and conventional gastric cancer.Patients who underwent resection for gastric cancer in 8 academic institutions from 2000-2012 were evaluated to compare morbidity, mortality, and survival based on history of prior gastrectomy.Of the 979 patients who underwent gastrectomy with curative-intent during the 12-year study period, 55 patients (5.8%) presented with GRC and 924 patients (94.4%) presented with conventional gastric cancer. Patients with GRC were slightly older (median 69 vs. 66 years). GRC was associated with higher rates of complication (56% vs. 41%, P = 0.028), longer operative times (301 vs. 237 min, P < 0.001), higher intraoperative blood loss (300 vs. 200 ml, P = 0.012), and greater need for blood transfusion (43% vs. 23%, P = 0.001). There were no significant differences in 30-day (3.6% vs. 4%) or 90-day mortality (9% vs. 8%) between the two groups. Overall survival rates were similar between GRC and conventional gastric cancer (5-year 20.3% vs. 38.6%, P = 0.446). Multivariate analysis revealed that history of gastrectomy was not predictive of survival while established predictors (older age, advanced T-stage, nodal involvement, blood transfusion, multivisceral resection, and any complication) were associated with poor survival.Despite higher morbidity, prognosis after resection of gastric remnant cancer is similar to conventional gastric cancer. J. Surg. Oncol. 2015;112:877-882. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jso.24080

  View details for Web of Science ID 000367671700015

• Multivisceral Resection for Gastric Cancer: Results from the US Gastric Cancer Collaborative ANNALS OF SURGICAL ONCOLOGY Tran, T. B., Worhunsky, D. J., Norton, J. A., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Poultsides, G. A. 2015; 22: S840-S847

  Abstract

  Resection of an adjacent organ during gastrectomy for gastric cancer is occasionally necessary to achieve margin clearance. The short- and long-term outcomes of this approach remain unclear.Patients who underwent gastric cancer resection in seven U.S. academic institutions from 2000 to 2012 were evaluated to compare perioperative morbidity, mortality, and survival outcomes, stratified by the need for and type of multivisceral resection (MVR).Of 835 patients undergoing curative-intent gastrectomy, 159 (19 %) had MVR. The most common adjacent organs resected were the spleen (48 %), pancreas (27 %), liver segments 2/3 (14 %), and colon (13 %). As extent of resection increased (gastrectomy only, n = 676; MVR without pancreatectomy, n = 116; and MVR with pancreatectomy, n = 43), perioperative morbidity was higher: any complication (45, 60, 59 %, p = 0.012), major complication (17, 31, 33 %, p = 0.001), anastomotic leak (5, 11, 19 %, p < 0.001), and respiratory failure (9, 15, 22 %, p = 0.012). However, perioperative mortality did not significantly increase (30-day: 3, 4, 2 %, p = 0.74; 90-day: 6, 8, 9 %, p = 0.61). Overall survival after resection decreased as extent of resection increased (5-year: 42, 28, 6 %). After controlling for age, race, T stage, N stage, grade, margin status, perineural invasion, adjuvant therapy, and blood transfusion, MVR with pancreatectomy (HR 1.67, p = 0.044), but not MVR without pancreatectomy (HR 0.97, p = 0.759), remained an independent predictor of poor survival.In this modern, multi-institutional cohort of gastric cancer patients, multivisceral resection was associated with higher perioperative morbidity but not significantly higher perioperative mortality. If concomitant pancreatectomy is anticipated, patients should be selected with extreme caution because long-term survival remains poor.

  View details for DOI 10.1245/s10434-015-4694-x

  View details for Web of Science ID 000367288100076

• Gastric remnant cancer: A distinct entity or simply another proximal gastric cancer? Journal of surgical oncology Tran, T. B., Hatzaras, I., Worhunsky, D. J., Vitiello, G. A., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Norton, J. A., Poultsides, G. A. 2015; 112 (8): 877-882

  Abstract

  The purpose of this study was to compare outcomes following resection of gastric remnant (GRC) and conventional gastric cancer.Patients who underwent resection for gastric cancer in 8 academic institutions from 2000-2012 were evaluated to compare morbidity, mortality, and survival based on history of prior gastrectomy.Of the 979 patients who underwent gastrectomy with curative-intent during the 12-year study period, 55 patients (5.8%) presented with GRC and 924 patients (94.4%) presented with conventional gastric cancer. Patients with GRC were slightly older (median 69 vs. 66 years). GRC was associated with higher rates of complication (56% vs. 41%, P = 0.028), longer operative times (301 vs. 237 min, P < 0.001), higher intraoperative blood loss (300 vs. 200 ml, P = 0.012), and greater need for blood transfusion (43% vs. 23%, P = 0.001). There were no significant differences in 30-day (3.6% vs. 4%) or 90-day mortality (9% vs. 8%) between the two groups. Overall survival rates were similar between GRC and conventional gastric cancer (5-year 20.3% vs. 38.6%, P = 0.446). Multivariate analysis revealed that history of gastrectomy was not predictive of survival while established predictors (older age, advanced T-stage, nodal involvement, blood transfusion, multivisceral resection, and any complication) were associated with poor survival.Despite higher morbidity, prognosis after resection of gastric remnant cancer is similar to conventional gastric cancer. J. Surg. Oncol. 2015;112:877-882. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jso.24080

  View details for PubMedID 26511335

• Multivisceral Resection for Gastric Cancer: Results from the US Gastric Cancer Collaborative. Annals of surgical oncology Tran, T. B., Worhunsky, D. J., Norton, J. A., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Poultsides, G. A. 2015; 22: 840-847

  Abstract

  Resection of an adjacent organ during gastrectomy for gastric cancer is occasionally necessary to achieve margin clearance. The short- and long-term outcomes of this approach remain unclear.Patients who underwent gastric cancer resection in seven U.S. academic institutions from 2000 to 2012 were evaluated to compare perioperative morbidity, mortality, and survival outcomes, stratified by the need for and type of multivisceral resection (MVR).Of 835 patients undergoing curative-intent gastrectomy, 159 (19 %) had MVR. The most common adjacent organs resected were the spleen (48 %), pancreas (27 %), liver segments 2/3 (14 %), and colon (13 %). As extent of resection increased (gastrectomy only, n = 676; MVR without pancreatectomy, n = 116; and MVR with pancreatectomy, n = 43), perioperative morbidity was higher: any complication (45, 60, 59 %, p = 0.012), major complication (17, 31, 33 %, p = 0.001), anastomotic leak (5, 11, 19 %, p < 0.001), and respiratory failure (9, 15, 22 %, p = 0.012). However, perioperative mortality did not significantly increase (30-day: 3, 4, 2 %, p = 0.74; 90-day: 6, 8, 9 %, p = 0.61). Overall survival after resection decreased as extent of resection increased (5-year: 42, 28, 6 %). After controlling for age, race, T stage, N stage, grade, margin status, perineural invasion, adjuvant therapy, and blood transfusion, MVR with pancreatectomy (HR 1.67, p = 0.044), but not MVR without pancreatectomy (HR 0.97, p = 0.759), remained an independent predictor of poor survival.In this modern, multi-institutional cohort of gastric cancer patients, multivisceral resection was associated with higher perioperative morbidity but not significantly higher perioperative mortality. If concomitant pancreatectomy is anticipated, patients should be selected with extreme caution because long-term survival remains poor.

  View details for DOI 10.1245/s10434-015-4694-x

  View details for PubMedID 26148757

• Outcomes of Gastric Cancer Resection in Octogenarians: A Multi-institutional Study of the US Gastric Cancer Collaborative ANNALS OF SURGICAL ONCOLOGY Tran, T. B., Worhunsky, D. J., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Norton, J. A., Poultsides, G. A. 2015; 22 (13): 4371-4379

  Abstract

  As the U.S. population ages, an increasing number of elderly patients with gastric adenocarcinoma are being evaluated for surgical resection. This study aimed to describe the short- and long-term outcomes after gastric cancer resection for patients 80 years of age or older.Patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012 at seven U.S. academic institutions were analyzed. The main outcome measures included postoperative morbidity, mortality, survival, and failure to rescue (defined as death after any complication).Of 953 patients who underwent distal or total gastrectomy during the 12-year study period, 127 (13 %) were 80 years of age or older. Although the type of postoperative complications did not differ between the two groups, octogenarians had a higher incidence of any (54 vs 41 %; p = 0.006) and of major (28 vs 17 %; p = 0.006) postoperative complications. This translated into higher 30-day (10.2 vs 3.6 %; p = 0.001) and 90-day mortality (19.7 vs 7.9 %; p = 0.001) rates, with correspondingly higher failure-to-rescue rates (17.4 vs 8 %; p = 0.015). However, disease-specific survival after resection was equivalent between the two groups (5-year survival: 46 vs 53 %; p = 0.676). In the multivariate analysis, age of 80 years or older, blood transfusion, and albumin and creatinine levels all were independent predictors of 90-day mortality. Stage, tumor grade, race, blood transfusion, and adjuvant therapy, but not age, were independently associated with disease-specific survival.Perioperative mortality and failure-to-rescue from complications is substantial for octogenarians undergoing gastric cancer resection. However, if the operation can be performed safely, the long-term cancer-specific outcome appears similar to that for younger patients.

  View details for DOI 10.1245/s10434-015-4530-3

  View details for PubMedID 25822782

• Severe acute pancreatitis in the community: confusion reigns JOURNAL OF SURGICAL RESEARCH Dua, M. M., Worhunsky, D. J., Tran, T. B., Rumma, R. T., Poultsides, G. A., Norton, J. A., Park, W. G., Visser, B. C. 2015; 199 (1): 44-50

  Abstract

  The management of acute pancreatitis (AP) has evolved through enhanced understanding of the disease. Despite several evidence-based practice guidelines for AP, our hypothesis is that many hospitals still use historical treatments rather than adhere to the current guidelines, which have demonstrated shorter hospital stays, decreased infectious complications, decreased morbidity, and decreased mortality.Seventy-eight patients transferred to our institution with AP from 2010-2014 were retrospectively studied to compare pretransfer versus posttransfer adherence to current practice guidelines. Primary measures included use of antibiotics (abx), enteral nutrition, drainage of asymptomatic pseudocysts, and interventions for necrosis in the early phase (<4 wk).Pretransfer, abx were given to 51 patients; however, posttransfer, abx were discontinued in 33 patients and started in 6 patients within 24 h of admission (pretransfer versus posttransfer abx, 51 versus 24, P < 0.001). Empiric abx for AP were used in 36 patients pretransfer versus 9 patients posttransfer (P < 0.001). Patients were initially nil per os or on total parenteral nutrition in 89%; this was reduced to 17% within 72 h by starting a diet or enteric feeds (pretransfer versus posttransfer feeding, 9 versus 65 patients, P < 0.001). Fifteen transfer patients had pseudocysts that were believed to "require drainage"; five patients received intervention but >4 wk from initial episode of AP. Pretransfer, five patients had pancreatic debridement in the early phase, which resulted in prolonged postoperative length of stay compared with eight patients requiring debridement, which were delayed (early versus late, 56 versus 16 d, P < 0.05).There is still great confusion in the treatment of AP in community hospitals. Primary principles in the care of these patients are not routinely followed despite established guidelines. Increased dissemination is required to prevent lengthy hospitalizations and long-term morbidity.

  View details for DOI 10.1016/j.jss.2015.04.054

  View details for PubMedID 25972313

• Sarcoma Resection With and Without Vascular Reconstruction: A Matched Case-control Study ANNALS OF SURGERY Poultsides, G. A., Tran, T. B., Zambrano, E., Janson, L., Mohler, D. G., Mell, M. W., Avedian, R. S., Visser, B. C., Lee, J. T., Ganjoo, K., Harris, E. J., Norton, J. A. 2015; 262 (4): 632-640

  Abstract

  To examine the impact of major vascular resection on sarcoma resection outcomes.En bloc resection and reconstruction of involved vessels is being increasingly performed during sarcoma surgery; however, the perioperative and oncologic outcomes of this strategy are not well described.Patients undergoing sarcoma resection with (VASC) and without (NO-VASC) vascular reconstruction were 1:2 matched on anatomic site, histology, grade, size, synchronous metastasis, and primary (vs. repeat) resection. R2 resections were excluded. Endpoints included perioperative morbidity, mortality, local recurrence, and survival.From 2000 to 2014, 50 sarcoma patients underwent VASC resection. These were matched with 100 NO-VASC patients having similar clinicopathologic characteristics. The rates of any complication (74% vs. 44%, P = 0.002), grade 3 or higher complication (38% vs. 18%, P = 0.024), and transfusion (66% vs. 33%, P < 0.001) were all more common in the VASC group. Thirty-day (2% vs. 0%, P = 0.30) or 90-day mortality (6% vs. 2%, P = 0.24) were not significantly higher. Local recurrence (5-year, 51% vs. 54%, P = 0.11) and overall survival after resection (5-year, 59% vs. 53%, P = 0.67) were similar between the 2 groups. Within the VASC group, overall survival was not affected by the type of vessel involved (artery vs. vein) or the presence of histology-proven vessel wall invasion.Vascular resection and reconstruction during sarcoma resection significantly increases perioperative morbidity and requires meticulous preoperative multidisciplinary planning. However, the oncologic outcome appears equivalent to cases without major vascular involvement. The anticipated need for vascular resection and reconstruction should not be a contraindication to sarcoma resection.

  View details for DOI 10.1097/SLA.0000000000001455

  View details for Web of Science ID 000367999800009

• Sarcoma Resection With and Without Vascular Reconstruction: A Matched Case-control Study. Annals of surgery Poultsides, G. A., Tran, T. B., Zambrano, E., Janson, L., Mohler, D. G., Mell, M. W., Avedian, R. S., Visser, B. C., Lee, J. T., Ganjoo, K., Harris, E. J., Norton, J. A. 2015; 262 (4): 632-40

  Abstract

  To examine the impact of major vascular resection on sarcoma resection outcomes.En bloc resection and reconstruction of involved vessels is being increasingly performed during sarcoma surgery; however, the perioperative and oncologic outcomes of this strategy are not well described.Patients undergoing sarcoma resection with (VASC) and without (NO-VASC) vascular reconstruction were 1:2 matched on anatomic site, histology, grade, size, synchronous metastasis, and primary (vs. repeat) resection. R2 resections were excluded. Endpoints included perioperative morbidity, mortality, local recurrence, and survival.From 2000 to 2014, 50 sarcoma patients underwent VASC resection. These were matched with 100 NO-VASC patients having similar clinicopathologic characteristics. The rates of any complication (74% vs. 44%, P = 0.002), grade 3 or higher complication (38% vs. 18%, P = 0.024), and transfusion (66% vs. 33%, P < 0.001) were all more common in the VASC group. Thirty-day (2% vs. 0%, P = 0.30) or 90-day mortality (6% vs. 2%, P = 0.24) were not significantly higher. Local recurrence (5-year, 51% vs. 54%, P = 0.11) and overall survival after resection (5-year, 59% vs. 53%, P = 0.67) were similar between the 2 groups. Within the VASC group, overall survival was not affected by the type of vessel involved (artery vs. vein) or the presence of histology-proven vessel wall invasion.Vascular resection and reconstruction during sarcoma resection significantly increases perioperative morbidity and requires meticulous preoperative multidisciplinary planning. However, the oncologic outcome appears equivalent to cases without major vascular involvement. The anticipated need for vascular resection and reconstruction should not be a contraindication to sarcoma resection.

  View details for DOI 10.1097/SLA.0000000000001455

  View details for PubMedID 26366542

• Identification of Tumorigenic Cells and Therapeutic Targets in Pancreatic Neuroendocrine Cancers Krampitz, G. W., Willingham, S. B., Volkmer, J. P., Weiskopf, K. A., George, B. M., Sage, J., Visser, B. C., Poultsides, G. A., Norton, J. A., Weissman, I. L. ELSEVIER SCIENCE INC. 2015: S59–S60

  View details for DOI 10.1016/j.jamcollsurg.2015.07.130

  View details for Web of Science ID 000361119700110

• Hepato-pancreatectomy: perioperative and long term outcomes of synchronous hepatic and pancreatic resection Tran, T. B., Dua, M. M., Visser, B. C., Norton, J. A., Poultsides, G. A. ELSEVIER SCIENCE INC. 2015: E95

  View details for DOI 10.1016/j.jamcollsurg.2015.08.151

  View details for Web of Science ID 000386899000230

• The Effect of Chronic Kidney Disease on Postoperative Outcomes after Major Hepatectomy: Results from the National Surgical Quality Improvement Program Tran, T. B., Dua, M. M., Spain, D. A., Poultsides, G. A., Norton, J. A., Visser, B. C. ELSEVIER SCIENCE INC. 2015: S94–S95

  View details for DOI 10.1016/j.jamcollsurg.2015.07.217

  View details for Web of Science ID 000361119700188

• Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surgical oncology clinics of North America Norton, J. A., Krampitz, G., Jensen, R. T. 2015; 24 (4): 795-832

  Abstract

  Early diagnosis of multiple endocrine neoplasia (MEN) syndromes is critical for optimal clinical outcomes; before the MEN syndromes can be diagnosed, they must be suspected. Genetic testing for germline alterations in both the MEN type 1 (MEN1) gene and RET proto-oncogene is crucial to identifying those at risk in affected kindreds and directing timely surveillance and surgical therapy to those at greatest risk of potentially life-threatening neoplasia. Pancreatic, thymic, and bronchial neuroendocrine tumors are the leading cause of death in patients with MEN1 and should be aggressively considered by at least biannual computed tomography imaging.

  View details for DOI 10.1016/j.soc.2015.06.008

  View details for PubMedID 26363542

  View details for PubMedCentralID PMC4571281

• Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surgical oncology clinics of North America Norton, J. A., Krampitz, G., Jensen, R. T. 2015; 24 (4): 795-832

  Abstract

  Early diagnosis of multiple endocrine neoplasia (MEN) syndromes is critical for optimal clinical outcomes; before the MEN syndromes can be diagnosed, they must be suspected. Genetic testing for germline alterations in both the MEN type 1 (MEN1) gene and RET proto-oncogene is crucial to identifying those at risk in affected kindreds and directing timely surveillance and surgical therapy to those at greatest risk of potentially life-threatening neoplasia. Pancreatic, thymic, and bronchial neuroendocrine tumors are the leading cause of death in patients with MEN1 and should be aggressively considered by at least biannual computed tomography imaging.

  View details for DOI 10.1016/j.soc.2015.06.008

  View details for PubMedID 26363542

  View details for PubMedCentralID PMC4571281

• Hepato-pancreatectomy: how morbid? Results from the national surgical quality improvement project HPB Tran, T. B., Dua, M. M., Spain, D. A., Visser, B. C., Norton, J. A., Poultsides, G. A. 2015; 17 (9): 763-769

  Abstract

  Simultaneous resection of both the liver and the pancreas carries significant complexity. The objective of this study was to investigate peri-operative outcomes after a synchronous hepatectomy and pancreatectomy (SHP).The American College of Surgeons National Surgical Quality Improvement Project database was queried to identify patients who underwent SHP. Resections were categorized as '< hemihepatectomy', '≥ hemihepatectomy' (hemihepatectomy and trisectionectomy), 'PD' (pancreaticoduodenectomy and total pancreatectomy) and 'distal' (distal pancreatectomy and enucleation).From 2005 to 2013, 480 patients underwent SHP. Patients were stratified based on the extent of resection: '< hemihepatectomy + distal (n = 224)', '≥ hemihepatectomy + distal' (n = 49), '< hemihepatectomy + PD' (n = 83) and '≥ hemihepatectomy + PD' (n = 24). Although the first three groups had a reasonable and comparable safety profile (morbidity 33-51% and mortality 0-6.6%), the '≥ hemihepatectomy + PD' group was associated with an 87.5% morbidity (organ space infection 58.3%, re-intubation 12.5%, reoperation 25% and septic shock 25%), 8.3% 30-day mortality and 18.2% in-hospital mortality.A synchronous hemihepatectomy (or trisectionectomy) with PD remains a highly morbid combination and should be reserved for patients who have undergone extremely cautious selection.

  View details for DOI 10.1111/hpb.12426

  View details for Web of Science ID 000359853800004

• An immunological view of chemotherapy. Immunotherapy Tsung, K., Norton, J. A. 2015; 7 (9): 941-943

  View details for DOI 10.2217/imt.15.62

  View details for PubMedID 26310824

• Pancreatectomy with vein reconstruction: technique matters. HPB Dua, M. M., Tran, T. B., Klausner, J., Hwa, K. J., Poultsides, G. A., Norton, J. A., Visser, B. C. 2015; 17 (9): 824-831

  Abstract

  A variety of techniques have been described for portal vein (PV) and/or superior mesenteric vein (SMV) resection/reconstruction during a pancreatectomy. The ideal strategy remains unclear.Patients who underwent PV/SMV resection/reconstruction during a pancreatectomy from 2005 to 2014 were identified. Medical records and imaging were retrospectively reviewed for operative details and outcomes, with particular emphasis on patency.Ninety patients underwent vein resection/reconstruction with one of five techniques: (i) longitudinal venorrhaphy (LV, n = 17); (ii) transverse venorrhaphy (TV, n = 9); (iii) primary end-to-end (n = 28); (iv) patch venoplasty (PV, n = 17); and (v) interposition graft (IG, n = 19). With a median follow-up of 316 days, thrombosis was observed in 16/90 (18%). The rate of thrombosis varied according to technique. All patients with primary end-to-end or TV remained patent. LV, PV and IG were all associated with significant rates of thrombosis (P = 0.001 versus no thrombosis). Comparing thrombosed to patent, there were no differences with respect to pancreatectomy type, pre-operative knowledge of vein involvement and neoadjuvant therapy. Prophylactic aspirin was used in 69% of the total cohort (66% of patent, 81% of thrombosed) and showed no protective benefit.Primary end-to-end and TV have superior patency than the alternatives after PV/SMV resection and should be the preferred techniques for short (<3 cm) reconstructions.

  View details for DOI 10.1111/hpb.12463

  View details for PubMedID 26223388

• Hepato-pancreatectomy: how morbid? Results from the national surgical quality improvement project. HPB Tran, T. B., Dua, M. M., Spain, D. A., Visser, B. C., Norton, J. A., Poultsides, G. A. 2015; 17 (9): 763-769

  Abstract

  Simultaneous resection of both the liver and the pancreas carries significant complexity. The objective of this study was to investigate peri-operative outcomes after a synchronous hepatectomy and pancreatectomy (SHP).The American College of Surgeons National Surgical Quality Improvement Project database was queried to identify patients who underwent SHP. Resections were categorized as '< hemihepatectomy', '≥ hemihepatectomy' (hemihepatectomy and trisectionectomy), 'PD' (pancreaticoduodenectomy and total pancreatectomy) and 'distal' (distal pancreatectomy and enucleation).From 2005 to 2013, 480 patients underwent SHP. Patients were stratified based on the extent of resection: '< hemihepatectomy + distal (n = 224)', '≥ hemihepatectomy + distal' (n = 49), '< hemihepatectomy + PD' (n = 83) and '≥ hemihepatectomy + PD' (n = 24). Although the first three groups had a reasonable and comparable safety profile (morbidity 33-51% and mortality 0-6.6%), the '≥ hemihepatectomy + PD' group was associated with an 87.5% morbidity (organ space infection 58.3%, re-intubation 12.5%, reoperation 25% and septic shock 25%), 8.3% 30-day mortality and 18.2% in-hospital mortality.A synchronous hemihepatectomy (or trisectionectomy) with PD remains a highly morbid combination and should be reserved for patients who have undergone extremely cautious selection.

  View details for DOI 10.1111/hpb.12426

  View details for PubMedID 26058463

• Pancreatectomy with vein reconstruction: technique matters HPB Dua, M. M., Tran, T. B., Klausner, J., Hwa, K. J., Poultsides, G. A., Norton, J. A., Visser, B. C. 2015; 17 (9): 824-831

  Abstract

  A variety of techniques have been described for portal vein (PV) and/or superior mesenteric vein (SMV) resection/reconstruction during a pancreatectomy. The ideal strategy remains unclear.Patients who underwent PV/SMV resection/reconstruction during a pancreatectomy from 2005 to 2014 were identified. Medical records and imaging were retrospectively reviewed for operative details and outcomes, with particular emphasis on patency.Ninety patients underwent vein resection/reconstruction with one of five techniques: (i) longitudinal venorrhaphy (LV, n = 17); (ii) transverse venorrhaphy (TV, n = 9); (iii) primary end-to-end (n = 28); (iv) patch venoplasty (PV, n = 17); and (v) interposition graft (IG, n = 19). With a median follow-up of 316 days, thrombosis was observed in 16/90 (18%). The rate of thrombosis varied according to technique. All patients with primary end-to-end or TV remained patent. LV, PV and IG were all associated with significant rates of thrombosis (P = 0.001 versus no thrombosis). Comparing thrombosed to patent, there were no differences with respect to pancreatectomy type, pre-operative knowledge of vein involvement and neoadjuvant therapy. Prophylactic aspirin was used in 69% of the total cohort (66% of patent, 81% of thrombosed) and showed no protective benefit.Primary end-to-end and TV have superior patency than the alternatives after PV/SMV resection and should be the preferred techniques for short (<3 cm) reconstructions.

  View details for DOI 10.1111/hpb.12463

  View details for Web of Science ID 000359853800013

  View details for PubMedCentralID PMC4557658

• Prognostic relevance of lymph node ratio and total lymph node count for small bowel adenocarcinoma SURGERY Tran, T. B., Qadan, M., Dua, M. M., Norton, J. A., Poultsides, G. A., Visser, B. C. 2015; 158 (2): 486-493

  Abstract

  Nodal metastasis is a known prognostic factor for small bowel adenocarcinoma. The goals of this study were to evaluate the number of lymph nodes (LNs) that should be retrieved and the impact of lymph node ratio (LNR) on survival.Surveillance, Epidemiology, and End Results was queried to identify patients with small bowel adenocarcinoma who underwent resection from 1988 to 2010. Survival was calculated with the Kaplan-Meier method. Multivariate analysis identified predictors of survival.A total of 2,772 patients underwent resection with at least one node retrieved, and this sample included equal numbers of duodenal (n = 1,387) and jejunoileal (n = 1,386) adenocarcinomas. There were 1,371 patients with no nodal metastasis (N0, 49.4%), 928 N1 (33.5%), and 474 N2 (17.1%). The median numbers of LNs examined for duodenal and jejunoileal cancers were 9 and 8, respectively. Cut-point analysis demonstrated that harvesting at least 9 for jejunoileal and 5 LN for duodenal cancers resulted in the greatest survival difference. Increasing LNR at both sites was associated with decreased overall median survival (LNR = 0, 71 months; LNR 0-0.02, 35 months; LNR 0.21-0.4, 25 months; and LNR >0.4, 16 months; P < .001). Multivariate analysis confirmed number of LNs examined, T-stage, LN positivity, and LNR were independent predictors of survival.LNR has a profound impact on survival in patients with small bowel adenocarcinoma. To achieve adequate staging, we recommend retrieving a minimum of 5 LN for duodenal and 9 LN for jejunoileal adenocarcinomas.

  View details for DOI 10.1016/j.surg.2015.03.048

  View details for Web of Science ID 000358108500023

• Prognostic relevance of lymph node ratio and total lymph node count for small bowel adenocarcinoma. Surgery Tran, T. B., Qadan, M., Dua, M. M., Norton, J. A., Poultsides, G. A., Visser, B. C. 2015; 158 (2): 486-93

  Abstract

  Nodal metastasis is a known prognostic factor for small bowel adenocarcinoma. The goals of this study were to evaluate the number of lymph nodes (LNs) that should be retrieved and the impact of lymph node ratio (LNR) on survival.Surveillance, Epidemiology, and End Results was queried to identify patients with small bowel adenocarcinoma who underwent resection from 1988 to 2010. Survival was calculated with the Kaplan-Meier method. Multivariate analysis identified predictors of survival.A total of 2,772 patients underwent resection with at least one node retrieved, and this sample included equal numbers of duodenal (n = 1,387) and jejunoileal (n = 1,386) adenocarcinomas. There were 1,371 patients with no nodal metastasis (N0, 49.4%), 928 N1 (33.5%), and 474 N2 (17.1%). The median numbers of LNs examined for duodenal and jejunoileal cancers were 9 and 8, respectively. Cut-point analysis demonstrated that harvesting at least 9 for jejunoileal and 5 LN for duodenal cancers resulted in the greatest survival difference. Increasing LNR at both sites was associated with decreased overall median survival (LNR = 0, 71 months; LNR 0-0.02, 35 months; LNR 0.21-0.4, 25 months; and LNR >0.4, 16 months; P < .001). Multivariate analysis confirmed number of LNs examined, T-stage, LN positivity, and LNR were independent predictors of survival.LNR has a profound impact on survival in patients with small bowel adenocarcinoma. To achieve adequate staging, we recommend retrieving a minimum of 5 LN for duodenal and 9 LN for jejunoileal adenocarcinomas.

  View details for DOI 10.1016/j.surg.2015.03.048

  View details for PubMedID 26013988

• Number of Lymph Nodes Removed and Survival after Gastric Cancer Resection: An Analysis from the US Gastric Cancer Collaborative. Journal of the American College of Surgeons Gholami, S., Janson, L., Worhunsky, D. J., Tran, T. B., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S. M., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Efron, B., Norton, J. A., Poultsides, G. A. 2015; 221 (2): 291-9

  Abstract

  Examination of at least 16 lymph nodes (LNs) has been traditionally recommended during gastric adenocarcinoma resection to optimize staging, but the impact of this strategy on survival is uncertain. Because recent randomized trials have demonstrated a therapeutic benefit from extended lymphadenectomy, we sought to investigate the impact of the number of LNs removed on prognosis after gastric adenocarcinoma resection.We analyzed patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012, at 7 US academic institutions. Patients with M1 disease or R2 resections were excluded. Disease-specific survival (DSS) was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.Of 742 patients, 257 (35%) had 7 to 15 LNs removed and 485 (65%) had ≥16 LNs removed. Disease-specific survival was not significantly longer after removal of ≥16 vs 7 to 15 LNs (10-year survival, 55% vs 47%, respectively; p = 0.53) for the entire cohort, but was significantly improved in the subset of patients with stage IA to IIIA (10-year survival, 74% vs 57%, respectively; p = 0.018) or N0-2 disease (72% vs 55%, respectively; p = 0.023). Similarly, for patients who were classified to more likely be "true N0-2," based on frequentist analysis incorporating both the number of positive and of total LNs removed, the hazard ratio for disease-related death (adjusted for T stage, R status, grade, receipt of neoadjuvant and adjuvant therapy, and institution) significantly decreased as the number of LNs removed increased.The number of LNs removed during gastrectomy for adenocarcinoma appears itself to have prognostic implications for long-term survival.

  View details for DOI 10.1016/j.jamcollsurg.2015.04.024

  View details for PubMedID 26206635

• Number of Lymph Nodes Removed and Survival after Gastric Cancer Resection: An Analysis from the US Gastric Cancer Collaborative JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Gholami, S., Janson, L., Worhunsky, D. J., Tran, T. B., Squires, M. H., Jin, L. X., Spolverato, G., Votanopoulos, K. I., Schmidt, C., Weber, S. M., Bloomston, M., Cho, C. S., Levine, E. A., Fields, R. C., Pawlik, T. M., Maithel, S. K., Efron, B., Norton, J. A., Poultsides, G. A. 2015; 221 (2): 291-299

  Abstract

  Examination of at least 16 lymph nodes (LNs) has been traditionally recommended during gastric adenocarcinoma resection to optimize staging, but the impact of this strategy on survival is uncertain. Because recent randomized trials have demonstrated a therapeutic benefit from extended lymphadenectomy, we sought to investigate the impact of the number of LNs removed on prognosis after gastric adenocarcinoma resection.We analyzed patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012, at 7 US academic institutions. Patients with M1 disease or R2 resections were excluded. Disease-specific survival (DSS) was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.Of 742 patients, 257 (35%) had 7 to 15 LNs removed and 485 (65%) had ≥16 LNs removed. Disease-specific survival was not significantly longer after removal of ≥16 vs 7 to 15 LNs (10-year survival, 55% vs 47%, respectively; p = 0.53) for the entire cohort, but was significantly improved in the subset of patients with stage IA to IIIA (10-year survival, 74% vs 57%, respectively; p = 0.018) or N0-2 disease (72% vs 55%, respectively; p = 0.023). Similarly, for patients who were classified to more likely be "true N0-2," based on frequentist analysis incorporating both the number of positive and of total LNs removed, the hazard ratio for disease-related death (adjusted for T stage, R status, grade, receipt of neoadjuvant and adjuvant therapy, and institution) significantly decreased as the number of LNs removed increased.The number of LNs removed during gastrectomy for adenocarcinoma appears itself to have prognostic implications for long-term survival.

  View details for DOI 10.1016/j.jamcollsurg.2015.04.024

  View details for Web of Science ID 000358384400013

• Cyst Fluid Glucose is Rapidly Feasible and Accurate in Diagnosing Mucinous Pancreatic Cysts. American journal of gastroenterology Zikos, T., Pham, K., Bowen, R., Chen, A. M., Banerjee, S., Friedland, S., Dua, M. M., Norton, J. A., Poultsides, G. A., Visser, B. C., Park, W. G. 2015; 110 (6): 909-914

  Abstract

  Better diagnostic tools are needed to differentiate pancreatic cyst subtypes. A previous metabolomic study showed cyst fluid glucose as a potential marker to differentiate mucinous from non-mucinous pancreatic cysts. This study seeks to validate these earlier findings using a standard laboratory glucose assay, a glucometer, and a glucose reagent strip.Using an IRB-approved prospectively collected bio-repository, 65 pancreatic cyst fluid samples (42 mucinous and 23 non-mucinous) with histological correlation were analyzed.Median laboratory glucose, glucometer glucose, and percent reagent strip positive were lower in mucinous vs. non-mucinous cysts (P<0.0001 for all comparisons). Laboratory glucose<50 mg/dl had a sensitivity of 95% and a specificity of 57% (LR+ 2.19, LR- 0.08). Glucometer glucose<50 mg/dl had a sensitivity of 88% and a specificity of 78% (LR+ 4.05, LR- 0.15). Reagent strip glucose had a sensitivity of 81% and a specificity of 74% (LR+ 3.10, LR- 0.26). CEA had a sensitivity of 77% and a specificity of 83% (LR+ 4.67, LR- 0.27). The combination of having either a glucometer glucose<50 mg/dl or a CEA level>192 had a sensitivity of 100% but a low specificity of 33% (LR+ 1.50, LR- 0.00).Glucose, whether measured by a laboratory assay, a glucometer, or a reagent strip, is significantly lower in mucinous cysts compared with non-mucinous pancreatic cysts.

  View details for DOI 10.1038/ajg.2015.148

  View details for PubMedID 25986360

• Better Survival But Changing Causes of Death in Patients With Multiple Endocrine Neoplasia Type 1. Annals of surgery Norton, J. A., Krampitz, G., Zemek, A., Longacre, T., Jensen, R. T. 2015; 261 (6): e147-8

  View details for DOI 10.1097/SLA.0000000000001211

  View details for PubMedID 26291955

• Predictive Factors for Surgery Among Patients with Pancreatic Cysts in the Absence of High-Risk Features for Malignancy JOURNAL OF GASTROINTESTINAL SURGERY Quan, S. Y., Visser, B. C., Poultsides, G. A., Norton, J. A., Chen, A. M., Banerjee, S., Friedland, S., Park, W. G. 2015; 19 (6): 1101-1105

  Abstract

  Without a reliable biopsy technique for pancreatic cysts, consensus-based guidelines are used to guide surgical utilization. The primary objective of this study was to characterize the proportion of operations performed outside of these guidelines.A 5-year retrospective review between July 1, 2007, and June 30, 2012, was performed of consecutive patients seen at a single tertiary medical center for a pancreatic cyst. Manual chart review for relevant clinical variables and cyst characteristics was performed.During this period, 148 patients underwent surgery, and of these, 23 (16 %) patients had no high-risk criteria by the 2006 Sendai criteria. None of these harbored high-grade dysplastic or cancerous lesions. A high cyst carcinoembryonic antigen (CEA) level (35 %), patient anxiety (26 %), and physician concern (22 %) were explicit reasons to proceed to surgery. An elevated cyst CEA level >192 ng/ml was the most significant predictor (OR 5.14 (95 % confidence interval (CI) 1.47-18.0) for surgery without high-risk criteria.A high cyst CEA level was significantly associated with the decision to operate outside of consensus-based guidelines. The misuse of cyst CEA in the management of pancreatic cysts negatively impacts patient anxiety, increases physician uncertainty, and leads to surgery with minimal benefit.

  View details for DOI 10.1007/s11605-015-2786-3

  View details for PubMedID 25749855

• Extracorporeal Pringle for laparoscopic liver resection SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES Dua, M. M., Worhunsky, D. J., Hwa, K., Poultsides, G. A., Norton, J. A., Visser, B. C. 2015; 29 (6): 1348-1355

  Abstract

  A primary concern during laparoscopic liver resection (lapLR) is hemorrhage during parenchymal transection. Intermittent pedicle clamping is an effective method to minimize blood loss during open liver surgery; however, inflow occlusion techniques are challenging to reproduce during laparoscopy. The purpose of this study is to describe the safety and efficacy of a facile method for Pringle maneuver during lapLR.154 patients who underwent lapLR from 2007 to 2013 were retrospectively reviewed. For Pringle, the hepatoduodenal ligament is encircled with an umbilical tape which is externalized through a flexible Rumel tourniquet running alongside a port used for the operation. The internal end of the catheter is close to the pedicle and the external end is extracorporeal, allowing for easy external occlusion. Patients who underwent Pringle Maneuver (PM, n = 88) were compared to patients who had "No Occlusion" (NO, n = 66) with respect to patient characteristics, operative outcomes, changes in postoperative liver function, and complications.Annual placement of the tourniquet and vascular occlusion increased from 35.7 to 82.8 % (p = 0.004) and 21.4 to 62.1 % (p = 0.02), respectively. Median occlusion time was 24 min (IQR 15-34.3, min 5, max 70). Peak transaminase levels were comparable between groups (AST 298 ± 32 vs 405 ± 47 U/L, p = 0.15; ALT 272 ± 27 vs 372 ± 34 U/L, p = 0.14, NO and PM, respectively). Postoperative transaminase and bilirubin levels for both groups were not significantly different with similar recovery to baseline. Subgroup analysis of cirrhotic patients who underwent Pringle demonstrated similar transaminase profiles compared to non-cirrhotic patients. There were two conversions (1.3 %) and postoperative 30-day mortality was 0.65 %.Extracorporeal tourniquet placement in lapLR is a quick and safe method of gaining control for inflow occlusion. Routine adoption of laparoscopic Pringle maneuver facilitates low conversion rates without liver injury.

  View details for DOI 10.1007/s00464-014-3801-6

  View details for PubMedID 25159645

• Leiomyosarcoma: One Disease or Distinct Biologic Entities Based on Site of Origin? JOURNAL OF SURGICAL ONCOLOGY Worhunsky, D. J., Gupta, M., Gholami, S., Tran, T. B., Ganjoo, K. N., van de Rijn, M., Visser, B. C., Norton, J. A., Poultsides, G. A. 2015; 111 (7): 808-812

  Abstract

  Leiomyosarcoma (LMS) can originate from the retroperitoneum, uterus, extremity, and trunk. It is unclear whether tumors of different origin represent discrete entities. We compared clinicopathologic features and outcomes following surgical resection of LMS stratified by site of origin.Patients with LMS undergoing resection at a single institution were retrospectively reviewed. Clinicopathologic variables were compared across sites. Survival was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.From 1983 to 2011, 138 patients underwent surgical resection for LMS. Retroperitoneal and uterine LMS were larger, higher grade, and more commonly associated with synchronous metastases. However, disease-specific survival, recurrence-free survival, and recurrence patterns were not significantly different across the four sites. Synchronous metastases (HR 3.20, P < 0.001), but not site of origin, size, grade, or margin status, were independently associated with worse DSS. A significant number of recurrences and disease-related deaths were noted beyond 5 years.Although larger and higher grade, retroperitoneal and uterine LMS share similar survival and recurrence patterns with their trunk and extremity counterparts. LMS of various anatomic sites may not represent distinct disease processes based on clinical outcomes. The presence of metastatic disease remains the most important prognostic factor for LMS.

  View details for DOI 10.1002/jso.23904

  View details for PubMedID 25920434

• IL-12 Augments Antitumor Responses to Cycled Chemotherapy JOURNAL OF IMMUNOTHERAPY Zhang, L., Feng, D., Hu, Y., Tsung, K., Norton, J. A. 2015; 38 (4): 137-144

  Abstract

  Loss of antitumor response to repeated chemotherapy is a major cause of treatment failure in cancer patients. The development of acquired drug resistance is thought to come primarily from changes in tumor cells, and not host response to the tumor. Our recent study shows that antitumor immunity is activated and contributes significantly to the efficacy of chemotherapy. In this study of mouse tumor models, we demonstrate that loss of antitumor response during multiple cycles of chemotherapy is associated with a lack of immune activation, and not intrinsic tumor cell drug resistance. More importantly, we show that adding interleukin-12 (IL-12) to cycled chemotherapy maintains and even increases antitumor immune response in both immunogenic and nonimmunogenic murine tumors and significantly prolongs survival. In some instances, larger tumor burdens that relapse following an initial cycle of cyclophosphamide and IL-12 are eradicated by subsequent cycles of the same treatment at the same doses. Further analysis demonstrates that the initial cycle of the combined therapy increases antitumor immunity of the host. In other mice when tumors are not eradicated by the current cycle of therapy, it serves as a starting point for the subsequent cycles of treatment to generate higher levels of antitumor immunity and greater antitumor response. These results show that the status of host antitumor immunity is a critical factor affecting antitumor efficacy during repeated administration of chemotherapy. Further, IL-12 augments the antitumor immune response under such conditions.

  View details for DOI 10.1097/CJI.0000000000000074

  View details for PubMedID 25839439

• Compliance With Gastric Cancer Guidelines is Associated With Improved Outcomes. Journal of the National Comprehensive Cancer Network Worhunsky, D. J., Ma, Y., Zak, Y., Poultsides, G. A., Norton, J. A., Rhoads, K. F., Visser, B. C. 2015; 13 (3): 319-325

  Abstract

  Limited data are available on the implementation and effectiveness of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer.We sought to assess rates of compliance with NCCN Guidelines, specifically stage-specific therapy during the initial episode of care, and to determine its impact on outcomes.The California Cancer Registry was used to identify cases of gastric cancer from 2001 to 2006. Logistic regression and Cox proportional hazard models were used to predict guideline compliance and the adjusted hazard ratio for mortality. Patients with TNM staging or summary stage (SS) were also analyzed separately.Compliance with NCCN Guidelines occurred in just 45.5% of patients overall. Patients older than 55 years were less likely to receive guideline-compliant care, and compliance was associated with a median survival of 20 versus 7 months for noncompliant care (P<.001). Compliant care was also associated with a 55% decreased hazard of mortality (P<.001). Further analysis revealed that 50% of patients had complete TNM staging versus an SS, and TNM-staged patients were more likely to receive compliant care (odds ratio, 1.59; P<.001). TNM-staged patients receiving compliant care had a median survival of 25.3 months compared with 15.1 months for compliant SS patients.Compliance with NCCN Guidelines and stage-specific therapy at presentation for the treatment of patients with gastric cancer was poor, which was a significant finding given that compliant care was associated with a 55% reduction in the hazard of death. Additionally, patients with TNM-staged cancer were more likely to receive compliant care, perhaps a result of having received more intensive therapy. Combined with the improved survival among compliant TNM-staged patients, these differences have meaningful implications for health services research.

  View details for PubMedID 25736009

• Mutation profiling of tumor DNA from plasma and tumor tissue of colorectal cancer patients with a novel, high-sensitivity multiplexed mutation detection platform ONCOTARGET Kidess, E., Heirich, K., Wiggin, M., Vysotskaia, V., Visser, B. C., Marziali, A., Wiedenmann, B., Norton, J. A., Lee, M., Jeffrey, S. S., Poultsides, G. A. 2015; 6 (4): 2549-2561

  Abstract

  Circulating tumor DNA (ctDNA) holds promise as a non-invasive means for tumor monitoring in solid malignancies. Assays with high sensitivity and multiplexed analysis of mutations are needed to enable broad application.We developed a new assay based on sequence-specific synchronous coefficient of drag alteration (SCODA) technology, which enriches for mutant DNA to achieve high sensitivity and specificity. This assay was applied to plasma and tumor tissue from non-metastatic and metastatic colorectal cancer (CRC) patients, including patients undergoing surgical resection for CRC liver metastases.Across multiple characterization experiments, the assay demonstrated a limit of detection of 0.001% (1 molecule in 100,000) for the majority of the 46 mutations in the panel. In CRC patient samples (n=38), detected mutations were concordant in tissue and plasma for 93% of metastatic patients versus 54% of non-metastatic patients. For three patients, ctDNA identified additional mutations not detected in tumor tissue. In patients undergoing liver metastatectomy, ctDNA anticipated tumor recurrence earlier than carcinoembryonic antigen (CEA) value or imaging.The multiplexed SCODA mutation enrichment and detection method can be applied to mutation profiling and quantitation of ctDNA, and is likely to have particular utility in the metastatic setting, including patients undergoing metastatectomy.

  View details for PubMedID 25575824

• Does the extent of resection impact survival for duodenal adenocarcinoma? Analysis of 1,611 cases. Annals of surgical oncology Cloyd, J. M., Norton, J. A., Visser, B. C., Poultsides, G. A. 2015; 22 (2): 573-580

  Abstract

  Because duodenal adenocarcinoma (DA) is relatively rare, few studies have investigated the impact of resection type on long-term outcomes.The Surveillance, Epidemiology, and End Results database was used to identify all patients between 1988 and 2010 with DA. Patients were divided into two groups based on the type of surgery received: simple resection (SR), defined as a simple removal of the primary site, and radical resection (RR), defined as removal of the primary site with a resection in continuity with other organs. Differences in disease-specific survival (DSS) and overall survival (OS) were compared.Of the 1,611 patients included, 746 (46.3 %) underwent SR and 865 (53.7 %) underwent RR. As expected, patients undergoing RR were more likely to present with poorly differentiated and large tumors, as well as advanced stage disease. Despite greater lymph node (LN) retrieval (11.0 vs. 6.8; p < 0.0001), RR was not associated with improved survival (5-year DSS and OS rates of 52.8 and 41.3 % for SR vs. 48.8 and 37.6 % for RR; p > 0.05). On univariate Cox proportional hazards regression analysis, the type of surgery was not associated with OS (odds ratio [OR] 0.98; 95 % confidence interval [CI] 0.87-1.11). Increasing TNM stages, tumor grade, fewer LNs removed, LN ratio, and absence of radiation were associated with worse survival. After controlling for confounding factors, type of surgery still did not influence OS (OR 1.11; 95 % CI 0.97-1.27).Radical resection (e.g., in the form of pancreaticoduodenectomy) does not appear to impact survival compared with simple segmental resection for DA.

  View details for DOI 10.1245/s10434-014-4020-z

  View details for PubMedID 25160736

• Metastatic Lobular Breast Carcinoma Mimicking Primary Signet Ring Adenocarcinoma in a Patient With a Suspected CDH1 Mutation JOURNAL OF CLINICAL ONCOLOGY Mahmud, N., Ford, J. M., Longacre, T. A., Parent, R., Norton, J. A. 2015; 33 (4): E19-E21

  View details for DOI 10.1200/JCO.2013.49.1159

  View details for Web of Science ID 000352422900002

  View details for PubMedID 24590638

• Metastatic lobular breast carcinoma mimicking primary signet ring adenocarcinoma in a patient with a suspected CDH1 mutation. Journal of clinical oncology Mahmud, N., Ford, J. M., Longacre, T. A., Parent, R., Norton, J. A. 2015; 33 (4): e19-21

  View details for DOI 10.1200/JCO.2013.49.1159

  View details for PubMedID 24590638

• Pretreatment lab values to predict overall survival in patients with primary unresectable pancreatic adenocarcinoma treated with SBRT Alagappan, M., Pollom, E. L., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. M., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Columbo, L., Koong, A., Chang, D. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for DOI 10.1200/jco.2015.33.3_suppl.433

  View details for Web of Science ID 000356883800431

• Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast BREAST CANCER RESEARCH AND TREATMENT Cloyd, J. M., Yang, R. L., Allison, K. H., Norton, J. A., Hernandez-Boussard, T., Wapnir, I. L. 2014; 148 (3): 637-644

  Abstract

  Although rare, neuroendocrine carcinoma of the breast (NECB) is becoming an increasingly recognized entity. The current literature is limited to case reports and small series and therefore a comprehensive population-based analysis was conducted to investigate the clinicopathologic features and long-term outcomes associated with NECB. We included all patients in the SEER Database from 2003 to 2010 with a diagnosis of NECB. The 2012 WHO classification system was used to categorize patients based on histopathologic diagnosis: well-differentiated neuroendocrine tumors, small/oat cell or poorly differentiated neuroendocrine tumors, adenocarcinoma with neuroendocrine features (ANF), large cell neuroendocrine and carcinoid tumors. Survival analysis was performed for disease specific (DSS) and overall (OS) survival. Of the 284 cases identified, 52.1% were classified as well-differentiated, 25.7% small cell, 14.8% ANF, 4.9% large cell, and 2.5% carcinoid. In general, patients presented with advanced disease: 36.2% had positive lymph node metastases and 20.4% presented with systemic metastases. Five-year DSS rates for stage I-IV NECB were 88.1, 67.8, 60.5, and 12.4%, respectively, while five-year OS rates were 77.9, 57.3, 52.9, and 8.9%, respectively. DSS and OS were significantly different for well-differentiated neuroendocrine tumors and ANFs compared to small cell and carcinoid tumors. On univariate Cox proportional hazards regression, small cell carcinoma was significantly associated with worse DSS (OR 1.97, 95% CI 1.05-3.67) and OS (OR 2.66, 95% CI 1.49-4.72) compared to other neuroendocrine tumors. NECB is associated with advanced stage disease at presentation and an unfavorable prognosis for stage II-IV disease and small cell, large cell, and carcinoid histologic subtypes.

  View details for DOI 10.1007/s10549-014-3207-0

  View details for Web of Science ID 000345370600018

• Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast. Breast cancer research and treatment Cloyd, J. M., Yang, R. L., Allison, K. H., Norton, J. A., Hernandez-Boussard, T., Wapnir, I. L. 2014; 148 (3): 637-644

  Abstract

  Although rare, neuroendocrine carcinoma of the breast (NECB) is becoming an increasingly recognized entity. The current literature is limited to case reports and small series and therefore a comprehensive population-based analysis was conducted to investigate the clinicopathologic features and long-term outcomes associated with NECB. We included all patients in the SEER Database from 2003 to 2010 with a diagnosis of NECB. The 2012 WHO classification system was used to categorize patients based on histopathologic diagnosis: well-differentiated neuroendocrine tumors, small/oat cell or poorly differentiated neuroendocrine tumors, adenocarcinoma with neuroendocrine features (ANF), large cell neuroendocrine and carcinoid tumors. Survival analysis was performed for disease specific (DSS) and overall (OS) survival. Of the 284 cases identified, 52.1% were classified as well-differentiated, 25.7% small cell, 14.8% ANF, 4.9% large cell, and 2.5% carcinoid. In general, patients presented with advanced disease: 36.2% had positive lymph node metastases and 20.4% presented with systemic metastases. Five-year DSS rates for stage I-IV NECB were 88.1, 67.8, 60.5, and 12.4%, respectively, while five-year OS rates were 77.9, 57.3, 52.9, and 8.9%, respectively. DSS and OS were significantly different for well-differentiated neuroendocrine tumors and ANFs compared to small cell and carcinoid tumors. On univariate Cox proportional hazards regression, small cell carcinoma was significantly associated with worse DSS (OR 1.97, 95% CI 1.05-3.67) and OS (OR 2.66, 95% CI 1.49-4.72) compared to other neuroendocrine tumors. NECB is associated with advanced stage disease at presentation and an unfavorable prognosis for stage II-IV disease and small cell, large cell, and carcinoid histologic subtypes.

  View details for DOI 10.1007/s10549-014-3207-0

  View details for PubMedID 25399232

• Single-versus Multifraction Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma: Outcomes and Toxicity INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pollom, E. L., Alagappan, M., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. A., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Cox, V. L., Columbo, L. A., Koong, A. C., Chang, D. T. 2014; 90 (4): 918-925

  Abstract

  We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.

  View details for DOI 10.1016/j.ijrobp.2014.06.066

  View details for Web of Science ID 000344734300029

• Single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity. International journal of radiation oncology, biology, physics Pollom, E. L., Alagappan, M., von Eyben, R., Kunz, P. L., Fisher, G. A., Ford, J. A., Poultsides, G. A., Visser, B. C., Norton, J. A., Kamaya, A., Cox, V. L., Columbo, L. A., Koong, A. C., Chang, D. T. 2014; 90 (4): 918-925

  Abstract

  We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.

  View details for DOI 10.1016/j.ijrobp.2014.06.066

  View details for PubMedID 25585785

• Laparoscopic Transgastric Necrosectomy for the Management of Pancreatic Necrosis JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Worhunsky, D. J., Qadan, M., Dua, M. M., Park, W. G., Poultsides, G. A., Norton, J. A., Visser, B. C. 2014; 219 (4): 735-743

  Abstract

  Traditional open necrosectomy for pancreatic necrosis is associated with significant morbidity and mortality. Although minimally invasive techniques have been described and offer some promise, each has considerable limitations. This study assesses the safety and effectiveness of laparoscopic transgastric necrosectomy (LTN), a novel technique for the management of necrotizing pancreatitis.Between 2009 and 2013, patients with retrogastric pancreatic necrosis requiring debridement were evaluated for LTN. Debridement was performed via a laparoscopic transgastric approach using 2 to 3 ports and the wide cystgastrostomy left open. Patient demographics, disease severity, operative characteristics, and outcomes were collected and analyzed.Twenty-one patients (13 men, median age 54 years; interquartile range [IQR] 46 to 62 years) underwent LTN during the study period. The duration between pancreatitis onset and debridement was 65 days (IQR 53 to 124 years). Indications for operation included infection (7 patients) and persistent unwellness (14 patients). Median duration of LTN was 170 minutes (IQR 136 to 199 minutes); there were no conversions. Control of the necrosis was achieved via the single procedure in 19 of 21 patients. Median postoperative hospital stay was 5 days (IQR 3 to 14 days) and the majority (71%) of patients experienced no (n = 9) or only minor postoperative complications (n = 6) by Clavien-Dindo grade. Complications of Clavien-Dindo grade 3 or higher developed in 6 patients, including 1 death (5%). With a median follow-up of 11 months (IQR 7 to 22 months), none of the patients required additional operative debridement or had pancreatic/enteric fistulae or wound complications develop.Laparoscopic transgastric necrosectomy is a novel, minimally invasive technique for the management of pancreatic necrosis that allows for debridement in a single operation. When feasible, LTN can reduce the morbidity associated with traditional open necrosectomy and avoid the limitations of other minimally invasive approaches.

  View details for DOI 10.1016/j.jamcollsurg.2014.04.012

  View details for Web of Science ID 000342422500018

• Rapid Point-of-Care Measurement of Cyst Fluid Glucose Is Feasible and Accurate in Predicting Mucinous Pancreatic Cysts Zikos, T., Pham, K., Chen, A., Banerjee, S., Friedland, S., Dua, M., Norton, J., Poultsides, G., Visser, B., Park, W. NATURE PUBLISHING GROUP. 2014: S86

  View details for Web of Science ID 000344383100280

• Laparoscopic transgastric necrosectomy for the management of pancreatic necrosis. Journal of the American College of Surgeons Worhunsky, D. J., Qadan, M., Dua, M. M., Park, W. G., Poultsides, G. A., Norton, J. A., Visser, B. C. 2014; 219 (4): 735-743

  Abstract

  Traditional open necrosectomy for pancreatic necrosis is associated with significant morbidity and mortality. Although minimally invasive techniques have been described and offer some promise, each has considerable limitations. This study assesses the safety and effectiveness of laparoscopic transgastric necrosectomy (LTN), a novel technique for the management of necrotizing pancreatitis.Between 2009 and 2013, patients with retrogastric pancreatic necrosis requiring debridement were evaluated for LTN. Debridement was performed via a laparoscopic transgastric approach using 2 to 3 ports and the wide cystgastrostomy left open. Patient demographics, disease severity, operative characteristics, and outcomes were collected and analyzed.Twenty-one patients (13 men, median age 54 years; interquartile range [IQR] 46 to 62 years) underwent LTN during the study period. The duration between pancreatitis onset and debridement was 65 days (IQR 53 to 124 years). Indications for operation included infection (7 patients) and persistent unwellness (14 patients). Median duration of LTN was 170 minutes (IQR 136 to 199 minutes); there were no conversions. Control of the necrosis was achieved via the single procedure in 19 of 21 patients. Median postoperative hospital stay was 5 days (IQR 3 to 14 days) and the majority (71%) of patients experienced no (n = 9) or only minor postoperative complications (n = 6) by Clavien-Dindo grade. Complications of Clavien-Dindo grade 3 or higher developed in 6 patients, including 1 death (5%). With a median follow-up of 11 months (IQR 7 to 22 months), none of the patients required additional operative debridement or had pancreatic/enteric fistulae or wound complications develop.Laparoscopic transgastric necrosectomy is a novel, minimally invasive technique for the management of pancreatic necrosis that allows for debridement in a single operation. When feasible, LTN can reduce the morbidity associated with traditional open necrosectomy and avoid the limitations of other minimally invasive approaches.

  View details for DOI 10.1016/j.jamcollsurg.2014.04.012

  View details for PubMedID 25158913

• Laparoscopic spleen-preserving distal pancreatectomy: the technique must suit the lesion. Journal of gastrointestinal surgery Worhunsky, D. J., Zak, Y., Dua, M. M., Poultsides, G. A., Norton, J. A., Visser, B. C. 2014; 18 (8): 1445-1451

  Abstract

  Splenic preservation is currently recommended during minimally invasive surgery for benign tumors of the distal pancreas. The aim of this study was to evaluate the outcomes of patients undergoing laparoscopic spleen-preserving distal pancreatectomy, with particular attention paid to the technique used for spleen preservation (splenic vessel ligation vs preservation). A review of consecutive patients who underwent laparoscopic distal pancreatectomy with the intention of splenic preservation was conducted. Patient demographics, operative data, and outcomes were collected and analyzed. Fifty-five consecutive patients underwent laparoscopic distal pancreatectomy with the intention of splenic preservation; 5 required splenectomy (9 %). Of the remaining 50 patients, 31 (62 %) had splenic vessel ligation, and 19 (38 %) had vessel preservation. Patient demographics and tumor size were similar. The vessel ligation group had significantly more pancreas removed (95 vs 52 mm, P < 0.001) and longer operative times (256 vs 201 min, P = 0.008). Postoperative outcomes, complication rates, and splenic viability were similar between groups. Laparoscopic spleen-preserving distal pancreatectomy is a safe operation with a high rate of success (91 %). Vessel ligation was the chosen technical strategy for lesions that required resection of a greater length of pancreas. We found no advantage to either technique with respect to outcomes and splenic preservation. Operative approach should reflect technical considerations including location in the pancreas.

  View details for DOI 10.1007/s11605-014-2561-x

  View details for PubMedID 24939598

• RET Gene Mutations (Genotype and Phenotype) of Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma CANCER Krampitz, G. W., Norton, J. A. 2014; 120 (13): 1920-1931

  Abstract

  The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

  View details for DOI 10.1002/cncr.28661

  View details for Web of Science ID 000337763300006

• RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer Krampitz, G. W., Norton, J. A. 2014; 120 (13): 1920-1931

  Abstract

  The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

  View details for DOI 10.1002/cncr.28661

  View details for PubMedID 24699901

• Pancreatic neuroendocrine tumours: hypoenhancement on arterial phase computed tomography predicts biological aggressiveness. HPB Worhunsky, D. J., Krampitz, G. W., Poullos, P. D., Visser, B. C., Kunz, P. L., Fisher, G. A., Norton, J. A., Poultsides, G. A. 2014; 16 (4): 304-311

  Abstract

  Contrary to pancreatic adenocarcinoma, pancreatic neuroendocrine tumours (PNET) are commonly hyperenhancing on arterial phase computed tomography (APCT). However, a subset of these tumours can be hypoenhancing. The prognostic significance of the CT appearance of these tumors remains unclear.From 2001 to 2012, 146 patients with well-differentiated PNET underwent surgical resection. The degree of tumour enhancement on APCT was recorded and correlated with clinicopathological variables and overall survival.APCT images were available for re-review in 118 patients (81%). The majority had hyperenhancing tumours (n = 80, 68%), 12 (10%) were isoenhancing (including cases where no mass was visualized) and 26 (22%) were hypoenhancing. Hypoenhancing PNET were larger, more commonly intermediate grade, and had higher rates of lymph node and synchronous liver metastases. Hypoenhancing PNET were also associated with significantly worse overall survival after a resection as opposed to isoenhancing and hyperenhancing tumours (5-year, 54% versus 89% versus 93%). On multivariate analysis of factors available pre-operatively, only hypoenhancement (HR 2.32, P = 0.02) was independently associated with survival.Hypoenhancement on APCT was noted in 22% of well-differentiated PNET and was an independent predictor of poor outcome. This information can inform pre-operative decisions in the multidisciplinary treatment of these neoplasms.

  View details for DOI 10.1111/hpb.12139

  View details for PubMedID 23991643

• Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging. Proceedings of the National Academy of Sciences of the United States of America Eberlin, L. S., Tibshirani, R. J., Zhang, J., Longacre, T. A., Berry, G. J., Bingham, D. B., Norton, J. A., Zare, R. N., Poultsides, G. A. 2014; 111 (7): 2436-2441

  Abstract

  Surgical resection is the main curative option for gastrointestinal cancers. The extent of cancer resection is commonly assessed during surgery by pathologic evaluation of (frozen sections of) the tissue at the resected specimen margin(s) to verify whether cancer is present. We compare this method to an alternative procedure, desorption electrospray ionization mass spectrometric imaging (DESI-MSI), for 62 banked human cancerous and normal gastric-tissue samples. In DESI-MSI, microdroplets strike the tissue sample, the resulting splash enters a mass spectrometer, and a statistical analysis, here, the Lasso method (which stands for least absolute shrinkage and selection operator and which is a multiclass logistic regression with L1 penalty), is applied to classify tissues based on the molecular information obtained directly from DESI-MSI. The methodology developed with 28 frozen training samples of clear histopathologic diagnosis showed an overall accuracy value of 98% for the 12,480 pixels evaluated in cross-validation (CV), and 97% when a completely independent set of samples was tested. By applying an additional spatial smoothing technique, the accuracy for both CV and the independent set of samples was 99% compared with histological diagnoses. To test our method for clinical use, we applied it to a total of 21 tissue-margin samples prospectively obtained from nine gastric-cancer patients. The results obtained suggest that DESI-MSI/Lasso may be valuable for routine intraoperative assessment of the specimen margins during gastric-cancer surgery.

  View details for DOI 10.1073/pnas.1400274111

  View details for PubMedID 24550265

• Postoperative serum amylase predicts pancreatic fistula formation following pancreaticoduodenectomy. Journal of gastrointestinal surgery Cloyd, J. M., Kastenberg, Z. J., Visser, B. C., Poultsides, G. A., Norton, J. A. 2014; 18 (2): 348-353

  Abstract

  Early identification of patients at risk for developing pancreatic fistula (PF) after pancreaticoduodenectomy (PD) may facilitate prevention or treatment strategies aimed at reducing its associated morbidity.A retrospective review of 176 consecutive PD performed between 2006 and 2011 was conducted in order to analyze the association between the serum amylase on postoperative day 1 (POD1) and the development of PF.Serum amylase was recorded on POD1 in 146 of 176 PD cases (83.0 %). Twenty-seven patients (18.5 %) developed a postoperative PF: 6 type A, 19 type B, and 2 type C. Patients with a PF had a mean serum amylase on POD1 of 659 ± 581 compared to 246 ± 368 in those without a fistula (p < 0.001). On logistic regression, a serum amylase >140 U/L on POD1 was strongly associated with developing a PF (OR, 5.48; 95 % CI, 1.94-15.44). Sensitivity and specificity of a postoperative serum amylase >140 U/L was 81.5 and 55.5 %, respectively. Positive and negative predictive values were 29.3 and 93.0 %, respectively.An elevated serum amylase on POD1 may be used, in addition to other prognostic factors, to help stratify risk for developing PF following PD.

  View details for DOI 10.1007/s11605-013-2293-3

  View details for PubMedID 23903930

• Reassessment of the Current American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Tumors JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Qadan, M., Ma, Y., Visser, B. C., Kunz, P. L., Fisher, G. A., Norton, J. A., Poultsides, G. A. 2014; 218 (2): 188-195

  Abstract

  Adopting a unified staging system for pancreatic neuroendocrine tumors (PNETs) has been challenging. Currently, the American Joint Committee on Cancer (AJCC) recommends use of the pancreatic adenocarcinoma staging system for PNETs. We sought to explore the prognostic usefulness of the pancreatic adenocarcinoma staging system for PNETs.The Surveillance, Epidemiology, and End Results program data were used to identify patients with PNETs who underwent curative-intent surgical resection from 1983 to 2008. The discriminatory ability of the AJCC system was examined and a new TNM system was devised using extent of disease variables.In 1,202 patients identified, lymph node metastasis was associated with worse 10-year overall survival after resection (51% vs 63%; p < 0.0001), as was the presence of distant metastatic disease (35% vs 62%; p < 0.0001). The current AJCC system (recorded by the Surveillance, Epidemiology, and End Results program in 412 patients since 2004) distinguished 5-year overall survival only between stages I and II (p = 0.01), but not between stages II and III (p = 0.97), or stages III and IV (p = 0.36). By modifying the T stage to be based on size alone (0.1 to 1.0 cm, 1.1 to 2.0 cm, 2.1 to 4.0 cm, and >4.0 cm) and revising the TNM subgroups, we propose a novel TNM system with improved discriminatory ability between disease stages (stages I vs II; p = 0.16; II vs III; p < 0.0001; and III vs IV; p = 0.008).In this study evaluating the current AJCC staging system for PNETs, there were no significant differences detected between stages II and III or stages III and IV. We propose a novel TNM system that might better discriminate between outcomes after surgical resection of PNETs.

  View details for DOI 10.1016/j.jamcollsurg.2013.11.001

  View details for PubMedID 24321190

• Cardiac metastases and tumor embolization: A rare sequelae of primary undifferentiated liver sarcoma. International journal of surgery case reports Dua, M. M., Cloyd, J. M., Haddad, F., Beygui, R. E., Norton, J. A., Visser, B. C. 2014; 5 (12): 927-931

  Abstract

  Primary hepatic sarcomas are uncommon malignant neoplasms; prognostic features, natural history, and optimal management of these tumors are not well characterized.This report describes the management of a 51-year-old patient that underwent a right trisectionectomy for a large hepatic mass found to be a liver sarcoma on pathology. He subsequently developed tumor emboli to his lungs and was discovered to have cardiac intracavitary metastases from his primary tumor. The patient underwent cardiopulmonary bypass and resection of the right-sided heart metastases to prevent further pulmonary sequela of tumor embolization.The lack of distinguishing symptoms or imaging characteristics that clearly define hepatic sarcomas makes it challenging to achieve a diagnosis prior to pathologic examination. Metastatic spread is frequently to the lung or pleura, but very rarely seen within the heart. Failure to recognize cardiac metastatic disease will ultimately lead to progressive tumor embolization and cardiac failure if left untreated.The most effective therapy for primary liver sarcomas is surgery; radical resection should be performed if possible given the aggressive nature of these tumors to progress and metastasize.

  View details for DOI 10.1016/j.ijscr.2014.10.004

  View details for PubMedID 25460438

• Pancreatic neuroendocrine tumors CURRENT PROBLEMS IN SURGERY Krampitz, G. W., NORTON, J. A. 2013; 50 (11): 509-545

  View details for DOI 10.1067/j.cpsurg.2013.08.001

  View details for Web of Science ID 000327104300002

  View details for PubMedID 24206780

• Long-term Results of Adjuvant Imatinib Mesylate in Localized, High-Risk, Primary Gastrointestinal Stromal Tumor ACOSOG Z9000 (Alliance) Intergroup Phase 2 Trial ANNALS OF SURGERY DeMatteo, R. P., Ballman, K. V., Antonescu, C. R., Corless, C., Kolesnikova, V., von Mehren, M., McCarter, M. D., Norton, J., Maki, R. G., Pisters, P. W., Demetri, G. D., Brennan, M. F., Owzar, K. 2013; 258 (3): 422-429

  Abstract

  To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST).GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate.This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at ClinicalTrials.gov as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS).After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age.Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246).

  View details for DOI 10.1097/SLA.0b013e3182a15eb7

  View details for PubMedID 23860199

• Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine. Gastrointestinal endoscopy Park, W. G., Wu, M., Bowen, R., Zheng, M., Fitch, W. L., Pai, R. K., Wodziak, D., Visser, B. C., Poultsides, G. A., Norton, J. A., Banerjee, S., Chen, A. M., Friedland, S., Scott, B. A., Pasricha, P. J., Lowe, A. W., Peltz, G. 2013; 78 (2): 295-302 e2

  Abstract

  BACKGROUND: Better pancreatic cyst fluid biomarkers are needed. OBJECTIVE: To determine whether metabolomic profiling of pancreatic cyst fluid would yield clinically useful cyst fluid biomarkers. DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: Two independent cohorts of patients (n = 26 and n = 19) with histologically defined pancreatic cysts. INTERVENTION: Exploratory analysis for differentially expressed metabolites between (1) nonmucinous and mucinous cysts and (2) malignant and premalignant cysts was performed in the first cohort. With the second cohort, a validation analysis of promising identified metabolites was performed. MAIN OUTCOME MEASUREMENTS: Identification of differentially expressed metabolites between clinically relevant cyst categories and their diagnostic performance (receiver operating characteristic [ROC] curve). RESULTS: Two metabolites had diagnostic significance-glucose and kynurenine. Metabolomic abundances for both were significantly lower in mucinous cysts compared with nonmucinous cysts in both cohorts (glucose first cohort P = .002, validation P = .006; and kynurenine first cohort P = .002, validation P = .002). The ROC curve for glucose was 0.92 (95% confidence interval [CI], 0.81-1.00) and 0.88 (95% CI, 0.72-1.00) in the first and validation cohorts, respectively. The ROC for kynurenine was 0.94 (95% CI, 0.81-1.00) and 0.92 (95% CI, 0.76-1.00) in the first and validation cohorts, respectively. Neither could differentiate premalignant from malignant cysts. Glucose and kynurenine levels were significantly elevated for serous cystadenomas in both cohorts. LIMITATIONS: Small sample sizes. CONCLUSION: Metabolomic profiling identified glucose and kynurenine to have potential clinical utility for differentiating mucinous from nonmucinous pancreatic cysts. These markers also may diagnose serous cystadenomas.

  View details for DOI 10.1016/j.gie.2013.02.037

  View details for PubMedID 23566642

• Vascular Reconstruction During Major Oncologic Pancreatic Resections Pineda, C., Chandra, V., Krampitz, G., Poultsides, G. A., Norton, J. A., Harris, E. J. MOSBY-ELSEVIER. 2013: 559

  View details for DOI 10.1016/j.jvs.2013.05.065

  View details for Web of Science ID 000322759500065

• Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine GASTROINTESTINAL ENDOSCOPY Park, W. G., Wu, M., Bowen, R., Zheng, M., Fitch, W. L., Pai, R. K., Wodziak, D., Visser, B. C., Poultsides, G. A., Norton, J. A., Banerjee, S., Chen, A. M., Friedland, S., Scott, B. A., Pasricha, P. J., Lowe, A. W., Peltz, G. 2013; 78 (2): 295-?

  Abstract

  BACKGROUND: Better pancreatic cyst fluid biomarkers are needed. OBJECTIVE: To determine whether metabolomic profiling of pancreatic cyst fluid would yield clinically useful cyst fluid biomarkers. DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: Two independent cohorts of patients (n = 26 and n = 19) with histologically defined pancreatic cysts. INTERVENTION: Exploratory analysis for differentially expressed metabolites between (1) nonmucinous and mucinous cysts and (2) malignant and premalignant cysts was performed in the first cohort. With the second cohort, a validation analysis of promising identified metabolites was performed. MAIN OUTCOME MEASUREMENTS: Identification of differentially expressed metabolites between clinically relevant cyst categories and their diagnostic performance (receiver operating characteristic [ROC] curve). RESULTS: Two metabolites had diagnostic significance-glucose and kynurenine. Metabolomic abundances for both were significantly lower in mucinous cysts compared with nonmucinous cysts in both cohorts (glucose first cohort P = .002, validation P = .006; and kynurenine first cohort P = .002, validation P = .002). The ROC curve for glucose was 0.92 (95% confidence interval [CI], 0.81-1.00) and 0.88 (95% CI, 0.72-1.00) in the first and validation cohorts, respectively. The ROC for kynurenine was 0.94 (95% CI, 0.81-1.00) and 0.92 (95% CI, 0.76-1.00) in the first and validation cohorts, respectively. Neither could differentiate premalignant from malignant cysts. Glucose and kynurenine levels were significantly elevated for serous cystadenomas in both cohorts. LIMITATIONS: Small sample sizes. CONCLUSION: Metabolomic profiling identified glucose and kynurenine to have potential clinical utility for differentiating mucinous from nonmucinous pancreatic cysts. These markers also may diagnose serous cystadenomas.

  View details for DOI 10.1016/j.gie.2013.02.037

  View details for Web of Science ID 000321825200015

  View details for PubMedID 23566642

• The use of Permacol for the reconstruction of a complex thoraco-abdominal wall defect from a recurrent leiomyosarcoma EUROPEAN JOURNAL OF PLASTIC SURGERY Echo, A., Otake, L. R., Talley, J. R., Satterwhite, T., Norton, J. A., Lee, G. K. 2013; 36 (7): 457–62

  View details for DOI 10.1007/s00238-013-0814-7

  View details for Web of Science ID 000217689400010

• Preexisting antitumor immunity augments the antitumor effects of chemotherapy. Cancer immunology, immunotherapy : CII Zhang, L., Feng, D., Yu, L. X., Tsung, K., Norton, J. A. 2013; 62 (6): 1061-1071

  Abstract

  Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.

  View details for DOI 10.1007/s00262-013-1417-7

  View details for PubMedID 23595208

• Seventh Edition (2010) of the AJCC/UICC Staging System for Gastric Adenocarcinoma: Is there Room for Improvement? ANNALS OF SURGICAL ONCOLOGY Patel, M. I., Rhoads, K. F., Ma, Y., Ford, J. M., Visser, B. C., Kunz, P. L., Fisher, G. A., Chang, D. T., Koong, A., Norton, J. A., Poultsides, G. A. 2013; 20 (5): 1631-1638

  Abstract

  The gastric cancer AJCC/UICC staging system recently underwent significant revisions, but studies on Asian patients have reported a lack of adequate discrimination between various consecutive stages. We sought to validate the new system on a U.S. population database.California Cancer Registry data linked to the Office of Statewide Health Planning and Development discharge abstracts were used to identify patients with gastric adenocarcinoma (esophagogastric junction and gastric cardia tumors excluded) who underwent curative-intent surgical resection in California from 2002 to 2006. AJCC/UICC stage was recalculated based on the latest seventh edition. Overall survival probabilities were calculated using the Kaplan-Meier method.Of 1905 patients analyzed, 54 % were males with a median age of 70 years. Median number of pathologically examined lymph nodes was 12 (range, 1-90); 40 % of patients received adjuvant chemotherapy, and 31 % received adjuvant radiotherapy. The seventh edition AJCC/UICC system did not distinguish outcome adequately between stages IB and IIA (P = 0.40), or IIB and IIIA (P = 0.34). By merging stage II into 1 category and moving T2N1 to stage IB and T2N2, T1N3 to stage IIIA, we propose a new grouping system with improved discriminatory abilityIn this first study validating the new seventh edition AJCC/UICC staging system for gastric cancer on a U.S. population with a relatively limited number of lymph nodes examined, we found stages IB and IIA, as well as IIB and IIIA to perform similarly. We propose a revised stage grouping for the AJCC/UICC staging system that better discriminates between outcomes.

  View details for DOI 10.1245/s10434-012-2724-5

  View details for PubMedID 23149854

• Hospital readmission after a pancreaticoduodenectomy: an emerging quality metric? HPB Kastenberg, Z. J., Morton, J. M., Visser, B. C., Norton, J. A., Poultsides, G. A. 2013; 15 (2): 142-148

  Abstract

  Hospital readmission has attracted attention from policymakers as a measure of quality and a target for cost reduction. The aim of the study was to evaluate the frequency and patterns of rehospitalization after a pancreaticoduodenectomy (PD).The records of all patients undergoing a PD at an academic medical centre for malignant or benign diagnoses between January 2006 and September 2011 were retrospectively reviewed. The incidence, aetiology and predictors of subsequent readmission(s) were analysed.Of 257 consecutive patients who underwent a PD, 50 (19.7%) were readmitted within 30 days from discharge. Both the presence of any post-operative complication (P = 0.049) and discharge to a nursing/rehabilitation facility or to home with health care services (P = 0.018) were associated with readmission. The most common reasons for readmission were diet intolerance (36.0%), pancreatic fistula/abscess (26.0%) and superficial wound infection (8.0%). Nine (18.0%) readmissions had lengths of stay of 2 days or less and in four of those (8.0%) diagnostic evaluation was eventually negative.Approximately one-fifth of patients require hospital readmission within 30 days of discharge after a PD. A small fraction of these readmissions are short (2 days or less) and may be preventable or manageable in the outpatient setting.

  View details for DOI 10.1111/j.1477-2574.2012.00563.x

  View details for PubMedID 23297725

• Performance of a novel TNM staging system for pancreatic neuroendocrine tumors versus the current AJCC staging system Qadan, M., Ma, Y., Visser, B. C., Norton, J. A., Poultsides, G. A. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for DOI 10.1200/jco.2013.31.4_suppl.156

  View details for Web of Science ID 000333679000156

• Current management of the Zollinger-Ellison syndrome. Advances in surgery Krampitz, G. W., Norton, J. A. 2013; 47: 59-79

  Abstract

  In summary, ZES is a syndrome caused by gastrinoma, usually located within the gastrinoma triangle and associated with symptoms of peptic ulcer disease, GERD, and diarrhea. The diagnosis of ZES is made by measuring fasting levels of serum gastrin, BAO, and the secretin stimulation test. Because of the high association of ZES and MEN1, HPT must be excluded by obtaining a serum calcium and parathyroid hormone level. Treatment of ZES consists of medical control of symptoms with PPIs and evaluation for potentially curative surgical intervention. Noninvasive imaging studies including SRS, CT, and MRI should be performed initially to evaluate for metastases and identify resectable disease. Invasive imaging modalities such as EUS may be performed to further evaluate primary tumors. IOUS, palpation, and duodenotomy are used for intraoperative localization of gastrinomas. In patients with MEN1, surgical resection should be pursued only if there is an identifiable tumor larger than 2 cm and after surgery for the primary hyperparathyroidism (3 1/2-gland parathyroidectomy). All patients with resectable localized sporadic gastrinoma should undergo surgical exploration, even those with biochemical evidence but negative imaging studies. Tumor is most commonly found in the duodenum, and the cure rate is high. In patients with liver metastases, surgery should be considered if all identifiable tumor can be safely removed. A multidisciplinary approach including surgical and nonsurgical therapies should be taken in patients with advanced disease.

  View details for PubMedID 24298844

• Current management of the zollinger-ellison syndrome. Advances in surgery Krampitz, G. W., Norton, J. A. 2013; 47 (1): 59-79

  View details for DOI 10.1016/j.yasu.2013.02.004

  View details for PubMedID 25293453

• Diagnostic Utility of Metabolomic-Derived Biomarkers for Pancreatic Cysts Park, W. G., Wu, M., Bowen, R., Zheng, M., Fitch, W. L., Pai, R. K., Wodziak, D., Visser, B. C., Poultsides, G. A., NORTON, J. A., Banerjee, S., Chen, A. M., Friedland, S., Pasricha, P. J., Lowe, A. W., Peltz, G. LIPPINCOTT WILLIAMS & WILKINS. 2012: 1394–94

  View details for Web of Science ID 000310360500241

• Recurrent Duodenal Stricture Secondary to Untreated Crohn's Disease DIGESTIVE DISEASES AND SCIENCES Plerhoples, T. A., Norton, J. A. 2012; 57 (10): 2516-2518

  View details for DOI 10.1007/s10620-012-2080-0

  View details for PubMedID 22526582

• Value of Surgery in Patients With Negative Imaging and Sporadic Zollinger-Ellison Syndrome ANNALS OF SURGERY Norton, J. A., Fraker, D. L., Alexander, H. r., Jensen, R. T. 2012; 256 (3): 509-517

  Abstract

  To address the value of surgery in patients with sporadic Zollinger-Ellison syndrome (ZES) with negative imaging studies.Medical control of acid hypersecretion in patients with sporadic ZES is highly effective. This has led to these patients frequently not being sent to surgery, especially if preoperative imaging studies are negative, due, in large part, to existence of almost no data on the success of surgery in this group.Fifty-eight prospectively studied patients with sporadic ZES (17% of total studied) had negative imaging studies, and their surgical outcome was compared with 117 patients with positive imaging results.Thirty-five patients had negative imaging studies in the pre-somatostatin receptor scintigraphy (SRS) era, and 23 patients in the post-SRS era. Patients with negative imaging studies had long disease histories before surgery [mean ± SEM (from onset) = 7.9 ± 1 [range, -0.25 to 35 years]) and 25% were followed for 2 or more years from diagnosis. At surgery, gastrinoma was found in 57 of 58 patients (98%). Tumors were small (mean = 0.8 cm, 60% <1 cm). The most common primary sites were duodenal 64%, pancreatic 17%, and lymph node (10%). Fifty percent had a primary-only, 41% primary + lymph node, and 7% had liver metastases. Thirty-five of 58 patients (60%) were cured immediately postoperatively, and at last follow-up [mean = -9.4 years; range, 0.2-22 years], 27 patients (46%) remained cured. During follow-up, 3 patients died, each had liver metastases at surgery. In comparison to positive imaging patients, those with negative imaging studies had lower preoperative fasting gastrin levels; had a longer delay before surgery; more frequently had a small duodenal tumor; less frequently had a pancreatic tumor, multiple tumors, or developed a new lesion postoperatively; and had a longer survival.Sporadic ZES patients with negative imaging studies are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one half (46%) are cured, a rate similar to patients with positive imaging findings. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.

  View details for DOI 10.1097/SLA.0b013e318265f08d

  View details for PubMedID 22868363

• Lymph Nodes and Survival in Pancreatic Neuroendocrine Tumors ARCHIVES OF SURGERY Krampitz, G. W., Norton, J. A., Poultsides, G. A., Visser, B. C., Sun, L., Jensen, R. T. 2012; 147 (9): 820-827

  Abstract

  Lymph node metastases decrease survival in patients with pancreatic neuroendocrine tumors (pNETs).Prospective database searches.National Institutes of Health (NIH) and Stanford University Hospital (SUH).A total of 326 patients underwent surgical exploration for pNETs at the NIH (n = 216) and SUH (n = 110).Overall survival, disease-related survival, and time to development of liver metastases.Forty patients (12.3%) underwent enucleation and 305 (93.6%) underwent resection. Of the patients who underwent resection, 117 (35.9%) had partial pancreatectomy and 30 (9.2%) had a Whipple procedure. Forty-one patients also had liver resections, 21 had wedge resections, and 20 had lobectomies. Mean follow-up was 8.1 years (range, 0.3-28.6 years). The 10-year overall survival for patients with no metastases or lymph node metastases only was similar at 80%. As expected, patients with liver metastases had a significantly decreased 10-year survival of 30% (P < .001). The time to development of liver metastases was significantly reduced for patients with lymph node metastases alone compared with those with none (P < .001). For the NIH cohort with longer follow-up, disease-related survival was significantly different for those patients with no metastases, lymph node metastases alone, and liver metastases (P < .001). Extent of lymph node involvement in this subgroup showed that disease-related survival decreased as a function of the number of lymph nodes involved (P = .004).As expected, liver metastases decrease survival of patients with pNETs. Patients with lymph node metastases alone have a shorter time to the development of liver metastases that is dependent on the number of lymph nodes involved. With sufficient long-term follow-up, lymph node metastases decrease disease-related survival. Careful evaluation of number and extent of lymph node involvement is warranted in all surgical procedures for pNETs.

  View details for PubMedID 22987171

• Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes HPB Visser, B. C., Ma, Y., Zak, Y., Poultsides, G. A., Norton, J. A., Rhoads, K. F. 2012; 14 (8): 539-547

  Abstract

  There are little data available regarding compliance with the National Comprehensive Cancer Network (NCCN) guidelines. We investigated variation in the management of pancreatic cancer (PC) among large hospitals in California, USA, specifically to evaluate whether compliance with NCCN guidelines correlates with patient outcomes.The California Cancer Registry was used to identify patients treated for PC from 2001 to 2006. Only hospitals with ≥ 400 beds were included to limit evaluation to centres possessing resources to provide multimodality care (n= 50). Risk-adjusted multivariable models evaluated predictors of adherence to stage-specific NCCN guidelines for PC and mortality.In all, 3706 patients were treated for PC in large hospitals during the study period. Compliance with NCCN guidelines was only 34.5%. Patients were less likely to get recommended therapy with advanced age and low socioeconomic status (SES). Using multilevel analysis, controlling for patient factors (including demographics and comorbidities), hospital factors (e.g. size, academic affiliation and case volume), compliance with NCCN guidelines was associated with a reduced risk of mortality [odds ratio (OR) for death 0.64 (0.53-0.77, P < 0.0001)].There is relatively poor overall compliance with the NCCN PC guidelines in California's large hospitals. Higher compliance rates are correlated with improved survival. Compliance is an important potential measure of the quality of care.

  View details for DOI 10.1111/j.1477-2574.2012.00496.x

  View details for PubMedID 22762402

• Pancreatic Neuroendocrine Tumors: Radiographic Calcifications Correlate with Grade and Metastasis ANNALS OF SURGICAL ONCOLOGY Poultsides, G. A., Huang, L. C., Chen, Y., Visser, B. C., Pai, R. K., Jeffrey, R. B., Park, W. G., Chen, A. M., Kunz, P. L., Fisher, G. A., Norton, J. A. 2012; 19 (7): 2295-2303

  Abstract

  Studies to identify preoperative prognostic variables for pancreatic neuroendocrine tumor (PNET) have been inconclusive. Specifically, the prevalence and prognostic significance of radiographic calcifications in these tumors remains unclear.From 1998 to 2009, a total of 110 patients with well-differentiated PNET underwent surgical resection at our institution. Synchronous liver metastases present in 31 patients (28%) were addressed surgically with curative intent. Patients with high-grade PNET were excluded. The presence of calcifications in the primary tumor on preoperative computed tomography was recorded and correlated with clinicopathologic variables and overall survival.Calcifications were present in 16% of patients and were more common in gastrinomas and glucagonomas (50%), but never encountered in insulinomas. Calcified tumors were larger (median size 4.5 vs. 2.3 cm, P=0.04) and more commonly associated with lymph node metastasis (75 vs. 35%, P=0.01), synchronous liver metastasis (62 vs. 21%, P<0.01), and intermediate tumor grade (80 vs. 31%, P<0.01). On multivariate analysis of factors available preoperatively, calcifications (P=0.01) and size (P<0.01) remained independent predictors of lymph node metastasis. Overall survival after resection was significantly worse in the presence of synchronous liver metastasis (5-year, 64 vs. 86%, P=0.04), but not in the presence of radiographic calcifications.Calcifications on preoperative computed tomography correlate with intermediate grade and lymph node metastasis in well-differentiated PNET. This information is available preoperatively and supports the routine dissection of regional lymph nodes through formal pancreatectomy rather than enucleation in calcified PNET.

  View details for DOI 10.1245/s10434-012-2305-7

  View details for PubMedID 22396008

• Identification and molecular characterization of pancreatic tumor-initiating cells Vorvis, C., Poultsides, G. A., Norton, J. A., Iliopoulos, D. AMER ASSOC CANCER RESEARCH. 2012

  View details for DOI 10.1158/1538-7445.AM2012-5335

  View details for Web of Science ID 000209701504110

• Intensity-Modulated Radiotherapy for Pancreatic Adenocarcinoma 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Abelson, J. A., Murphy, J. D., Minn, A. Y., Chung, M., Fisher, G. A., Ford, J. M., Kunz, P., Norton, J. A., Visser, B. C., Poultsides, G. A., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: E595–E601

  Abstract

  To report the outcomes and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for pancreatic adenocarcinoma.Forty-seven patients with pancreatic adenocarcinoma were treated with IMRT between 2003 and 2008. Of these 47 patients, 29 were treated adjuvantly and 18 definitively. All received concurrent 5-fluorouracil chemotherapy. The treatment plans were optimized such that 95% of the planning target volume received the prescription dose. The median delivered dose for the adjuvant and definitive patients was 50.4 and 54.0 Gy, respectively.The median age at diagnosis was 63.9 years. For adjuvant patients, the 1- and 2-year overall survival rate was 79% and 40%, respectively. The 1- and 2-year recurrence-free survival rate was 58% and 17%, respectively. The local-regional control rate at 1 and 2 years was 92% and 80%, respectively. For definitive patients, the 1-year overall survival, recurrence-free survival, and local-regional control rate was 24%, 16%, and 64%, respectively. Four patients developed Grade 3 or greater acute toxicity (9%) and four developed Grade 3 late toxicity (9%).Survival for patients with pancreatic cancer remains poor. A small percentage of adjuvant patients have durable disease control, and with improved therapies, this proportion will increase. Systemic therapy offers the greatest opportunity. The present results have demonstrated that IMRT is well tolerated. Compared with those who received three-dimensional conformal radiotherapy in previously reported prospective clinical trials, patients with pancreatic adenocarcinoma treated with IMRT in our series had improved acute toxicity.

  View details for DOI 10.1016/j.ijrobp.2011.09.035

  View details for PubMedID 22197234

• Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts BMC GASTROENTEROLOGY Tun, M. T., Pai, R. K., Kwok, S., Dong, A., Gupta, A., Visser, B. C., Norton, J. A., Poultsides, G. A., Banerjee, S., Van Dam, J., Chen, A. M., Friedland, S., Scott, B. A., Verma, R., Lowe, A. W., Park, W. G. 2012; 12

  Abstract

  Accurate tests to diagnose adenocarcinoma and high-grade dysplasia among mucinous pancreatic cysts are clinically needed. This study evaluated the diagnostic utility of amphiregulin (AREG) as a pancreatic cyst fluid biomarker to differentiate non-mucinous, benign mucinous, and malignant mucinous cysts.A single-center retrospective study to evaluate AREG levels in pancreatic cyst fluid by ELISA from 33 patients with a histological gold standard was performed.Among the cyst fluid samples, the median (IQR) AREG levels for non-mucinous (n = 6), benign mucinous (n = 15), and cancerous cysts (n = 15) were 85 pg/ml (47-168), 63 pg/ml (30-847), and 986 pg/ml (417-3160), respectively. A significant difference between benign mucinous and malignant mucinous cysts was observed (p = 0.025). AREG levels greater than 300 pg/ml possessed a diagnostic accuracy for cancer or high-grade dysplasia of 78% (sensitivity 83%, specificity 73%).Cyst fluid AREG levels are significantly higher in cancerous and high-grade dysplastic cysts compared to benign mucinous cysts. Thus AREG exhibits potential clinical utility in the evaluation of pancreatic cysts.

  View details for DOI 10.1186/1471-230X-12-15

  View details for PubMedID 22333441

• Seventh edition (2010) of gastric adenocarcinoma AJCC staging system: Is there room for improvement? Patel, M. I., Rhoads, K. F., Ma, Y., Ford, J. M., Norton, J. A., Poultsides, G. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for DOI 10.1200/jco.2012.30.4_suppl.77

  View details for Web of Science ID 000209849300080

• Total Gastrectomy and Identified CDH1 Mutations: In Response ANNALS OF SURGICAL ONCOLOGY Norton, J. A., Chen, Y. 2011; 18: S208

  View details for DOI 10.1245/s10434-011-1838-5

  View details for Web of Science ID 000299394700012

• A Prospective Study of Total Gastrectomy for CDH1-Positive Hereditary Diffuse Gastric Cancer ANNALS OF SURGICAL ONCOLOGY Chen, Y., Kingham, K., Ford, J. M., Rosing, J., Van Dam, J., Jeffrey, R. B., Longacre, T. A., Chun, N., Kurian, A., Norton, J. A. 2011; 18 (9): 2594-2598

  Abstract

  Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome. Up to 30% of families with HDGC have mutations in the E-cadherin gene, CDH1. The role of prophylactic versus therapeutic gastrectomy for HDGC was studied prospectively.Eighteen consecutive patients with CDH1 mutations and positive family history were studied prospectively, including 13 without and 5 with symptoms. Proportions were compared by Fisher's exact test, and survival by the Breslow modification of the Wilcoxon rank-sum test.Each patient underwent total gastrectomy (TG), and 17 (94%) were found to have signet ring cell adenocarcinoma. Twelve of 13 asymptomatic patients had T1, N0 cancer, and only 2/12 (16%) had it diagnosed preoperatively despite state-of-the-art screening methods. Each asymptomatic patient did well postoperatively, and no patient has recurred. For five symptomatic patients, each (100%) was found to have signet ring cell adenocarcinoma (P = 0.002 versus asymptomatic) by preoperative endoscopy; three (60%) had lymph node involvement and two (40%) had distant metastases at time of operation. Two-year survival was 100% for asymptomatic and 40% for symptomatic patients (P < 0.01).The data show that asymptomatic patients with family history of HDGC and CDH1 mutation have high probability of having signet ring cell adenocarcinoma of the stomach that is not able to be diagnosed on endoscopy; when symptoms arise, the diagnosis can be made by endoscopy, but they have metastases and decreased survival. Surveillance endoscopy is of limited value, and prophylactic gastrectomy (PG) is recommended for patients with family history of HDGC and CDH1 mutations.

  View details for DOI 10.1245/s10434-011-1648-9

  View details for PubMedID 21424370

• SINGLE-FRACTION STEREOTACTIC BODY RADIATION THERAPY AND SEQUENTIAL GEMCITABINE FOR THE TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schellenberg, D., Kim, J., Ciristman-Skieller, C., Chun, C. L., Columbo, L. A., Ford, J. M., Fisher, G. A., Kunz, P. L., Van Dam, J., Quon, A., Desser, T. S., Norton, J., Hsu, A., Maxim, P. G., Xing, L., Goodman, K. A., Chang, D. T., Koong, A. C. 2011; 81 (1): 181-188

  Abstract

  This Phase II trial evaluated the toxicity, local control, and overall survival in patients treated with sequential gemcitabine and linear accelerator-based single-fraction stereotactic body radiotherapy (SBRT).Twenty patients with locally advanced, nonmetastatic pancreatic adenocarcinoma were enrolled on this prospective single-institution, institutional review board-approved study. Gemcitabine was administered on Days 1, 8, and 15, and SBRT on Day 29. Gemcitabine was restarted on Day 43 and continued for 3-5 cycles. SBRT of 25 Gy in a single fraction was delivered to the internal target volume with a 2- 3-mm margin using a nine-field intensity-modulated radiotherapy technique. Respiratory gating was used to account for breathing motion. Follow-up evaluations occurred at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT.All patients completed SBRT and a median of five cycles of chemotherapy. Follow-up for the 2 remaining alive patients was 25.1 and 36.4 months. No acute Grade 3 or greater nonhematologic toxicity was observed. Late Grade 3 or greater toxicities occurred in 1 patient (5%) and consisted of a duodenal perforation (G4). Three patients (15%) developed ulcers (G2) that were medically managed. Overall, median survival was 11.8 months, with 1-year survival of 50% and 2-year survival of 20%. Using serial computed tomography, the freedom from local progression was 94% at 1 year.Linear accelerator-delivered SBRT with sequential gemcitabine resulted in excellent local control of locally advanced pancreatic cancer. Future studies will address strategies for reducing long-term duodenal toxicity associated with SBRT.

  View details for DOI 10.1016/j.ijrobp.2010.05.006

  View details for Web of Science ID 000294093300025

  View details for PubMedID 21549517

• Surgical Management of Neuroendocrine Tumors of the Gastrointestinal Tract ONCOLOGY-NEW YORK Huang, L. C., Poultsides, G. A., Norton, J. A. 2011; 25 (9): 794-803

  Abstract

  Neuroendocrine tumors of the pancreas (islet cell tumors) and of the luminal gastrointestinal tract (carcinoids) are a heterogeneous group of epithelial neoplasms that share certain common characteristics. First, they are similar histologically and are difficult to distinguish under light microscopy. Second, they can be associated with hypersecretory syndromes. Third, they are generally slow-growing and have a better prognosis than adenocarcinomas at the same site; however, they do become incurable when they progress to unresectable metastatic disease. Surgery is the only curative treatment and is recommended for most patients for whom cross-sectional imaging suggests that complete resection is possible. This article reviews the surgical management of gastrointestinal neuroendocrine tumors, including the preoperative control of hormonal symptoms, extent of resection required, postoperative outcomes, and differing management strategies as determined by whether the tumor has arisen sporadically or as part of a familial disorder, such as multiple endocrine neoplasia type 1 (MEN1).

  View details for PubMedID 21936439

• Ruptured Biliary Cystadenoma Managed by Angiographic Embolization and Interval Partial Hepatectomy DIGESTIVE DISEASES AND SCIENCES Ghole, S. A., Bakhtary, S., Staudenmayer, K., Sze, D. Y., Pai, R. K., Visser, B. C., Norton, J. A., Poultsides, G. A. 2011; 56 (7): 1949-1953

  View details for DOI 10.1007/s10620-011-1677-z

  View details for PubMedID 21445579

• Pancreatic Endocrine Tumors With Major Vascular Abutment, Involvement, or Encasement and Indication for Resection ARCHIVES OF SURGERY Norton, J. A., Harris, E. J., Chen, Y., Visser, B. C., Poultsides, G. A., Kunz, P. C., Fisher, G. A., Jensen, R. T. 2011; 146 (6): 724-732

  Abstract

  Surgery for pancreatic endocrine tumors (PETs) with blood vessel involvement is controversial.Resection of PETs with major blood vessel involvement can be beneficial.The combined databases of the National Institutes of Health and Stanford University hospitals were queried.Operation, pathologic condition, complications, and disease-free and overall survival.Of 273 patients with PETs, 46 (17%) had preoperative computed tomography evidence of major vascular involvement. The mean size for the primary PET was 5.0 cm. The involved major vessel was as follows: portal vein (n = 20), superior mesenteric vein or superior mesenteric artery (n = 16), inferior vena cava (n = 4), splenic vein (n = 4), and heart (n = 2). Forty-two of 46 patients had a PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n = 7) or resection (n = 35). Resections included distal or subtotal pancreatectomy in 23, Whipple in 10, and total in 2. Eighteen patients had concomitant liver resection: 10 wedge resection and 8 anatomic resections. Nine patients had vascular reconstruction: each had reconstruction of the superior mesenteric vein and portal vein, and 1 had concomitant reconstruction of the superior mesenteric artery. There were no deaths, but 12 patients had complications. Eighteen patients (41%) were immediately disease free, and 5 recurred with follow-up, leaving 13 (30%) disease-free long term. The 10-year overall survival was 60%. Functional tumors were associated with a better overall survival (P < .001), and liver metastases decreased overall survival (P < .001).These findings suggest that surgical resection of PETs with vascular abutment/invasion and nodal or distant metastases is indicated.

  View details for PubMedID 21690450

• Pattern of Lymph Node Involvement and Prognosis in Pancreatic Adenocarcinoma: Direct Lymph Node Invasion Has Similar Survival to Node-Negative Disease AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Beck, A. H., Mitchem, J., Linehan, D. C., Chang, D. T., Norton, J. A., Pai, R. K. 2011; 35 (2): 228-234

  Abstract

  Lymph node status is one of the most important predictors of survival in pancreatic ductal adenocarcinoma. Surgically resected pancreatic adenocarcinoma is often locally invasive and may invade directly into peripancreatic lymph nodes. The significance of direct invasion into lymph nodes in the absence of true lymphatic metastases is unclear. The purpose of this study was to retrospectively compare clinical outcome in patients with pancreatic ductal adenocarcinoma with direct invasion into peripancreatic lymph nodes with patients with node-negative adenocarcinomas and patients with true lymphatic lymph node metastasis. A total of 380 patients with invasive pancreatic ductal adenocarcinoma classified as pT3, were evaluated: ductal adenocarcinoma with true lymphatic metastasis to regional lymph nodes (248 cases), ductal adenocarcinoma without lymph node involvement (97 cases), and ductal adenocarcinoma with regional lymph nodes involved only by direct invasion from the main tumor mass (35 cases). Isolated lymph node involvement by direct invasion occurred in 35 of 380 (9%) patients. Overall survival for patients with direct invasion of lymph nodes (median survival, 21 mo; 5-year overall survival, 36%) was not statistically different from patients with node-negative adenocarcinomas (median survival, 30 mo; 5-year overall survival, 31%) (P=0.609). Patients with node-negative adenocarcinomas had an improved survival compared with patients with lymph node involvement by true lymphatic metastasis (median survival, 15 mo; 5-year overall survival, 8%) (P<0.001) regardless of the number of lymph nodes involved by adenocarcinoma. There was a trend toward decreased overall survival for patients with 1 or 2 lymph nodes involved by true lymphatic metastasis compared with patients with direct invasion of tumor into lymph nodes (P=0.056). However, this did not reach statistical significance. Our results indicate that patients with isolated direct lymph node invasion have a comparable overall survival with patients with node-negative adenocarcinomas as opposed to true lymphatic lymph node metastasis.

  View details for DOI 10.1097/PAS.0b013e318206c37a

  View details for Web of Science ID 000286581700007

  View details for PubMedID 21263243

• Supercharged Jejunum Flap for Total Esophageal Reconstruction: Single-Surgeon 3-Year Experience and Outcomes Analysis PLASTIC AND RECONSTRUCTIVE SURGERY Barzin, A., Norton, J. A., Whyte, R., Lee, G. K. 2011; 127 (1): 173-180

  Abstract

  Esophageal reconstruction after total esophagectomy remains a formidable task irrespective of the conduit chosen. Historically, the gastric pull-up and colonic interposition have served as primary choices for such defects. However, where the stomach and colon are unavailable or unsuitable, the jejunum serves as a reliable alternative for the reconstruction of total esophageal defects.The authors performed an outcomes analysis of a single surgeon's surgical technique and experience. Patients who received supercharged pedicled jejunum flaps for reconstruction of total esophageal defects over a 3-year period were included in this study. Data were collected prospectively evaluating operative technique, length of hospital stay, operative time, complications, postoperative diet, and quality-of-life outcomes analysis.Five patients underwent supercharged pedicled jejunal flap surgery during this study period. All flaps had complete viability and no microvascular complications. One patient had a radiographic anastomotic leak detected by barium swallow that was reexplored and closed primarily and reinforced with a pectoralis advancement flap with subsequent resolution. All patients are currently tolerating a regular diet and there are no symptoms of reflux or dumping. No conduit strictures or redundancy has been found to date, and there has been no need for reoperation in the long term.The supercharged jejunum flap is a reliable alternative to the gastric pull-up and colonic interposition for total esophageal reconstruction. In our experience, the key maneuver in this technique is a substernal tunnel for the jejunal conduit and exposure of recipient vessels and the esophageal stump by means of a manubriectomy, clavicle resection, partial first rib resection and, occasionally, a second rib resection.

  View details for DOI 10.1097/PRS.0b013e3181f95a36

  View details for PubMedID 21200211

• Expression of p16(INK4A) But Not Hypoxia Markers or Poly Adenosine Diphosphate-Ribose Polymerase Is Associated With Improved Survival in Patients With Pancreatic Adenocarcinoma 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Chang, D. T., Chapman, C. H., Norton, J. A., Visser, B., Fisher, G. A., Kunz, P., Ford, J. M., Koong, A. C., Pai, R. K. WILEY-BLACKWELL. 2010: 5179–87

  Abstract

  Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma.Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS).Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS.Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .

  View details for DOI 10.1002/cncr.25481

  View details for PubMedID 20665497

• The role of surgery in cancer prevention. Current problems in surgery Jatoi, I., Benson, J. R., Liau, S., Chen, Y., Cisco, R. M., Norton, J. A., Moley, J. F., Khalifeh, K. W., Choti, M. A. 2010; 47 (10): 750-830

  View details for DOI 10.1067/j.cpsurg.2010.06.002

  View details for PubMedID 20816140

• Comparison of Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy as Adjuvant Therapy for Gastric Cancer 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Minn, A. Y., Hsu, A., La, T., Kunz, P., Fisher, G. A., Ford, J. M., Norton, J. A., Visser, B., Goodman, K. A., Koong, A. C., Chang, D. T. JOHN WILEY & SONS INC. 2010: 3943–52

  Abstract

  The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT).Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n=31), 5-fluorouracil (5-FU) (n=25), or none (n=1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups.The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P=.5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade>or=2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P=.02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P=.05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P=.17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P=.19). The median liver V30 was 16.1% and 28%, respectively (P<.001).Adjuvant chemoradiotherapy was well tolerated. IMRT was found to provide sparing to the liver and possibly renal function.

  View details for DOI 10.1002/cncr.25246

  View details for PubMedID 20564136

• Role of Factor VII in Correcting Dilutional Coagulopathy and Reducing Re-operations for Bleeding Following Non-traumatic Major Gastrointestinal and Abdominal Surgery JOURNAL OF GASTROINTESTINAL SURGERY Tsai, T. C., Rosing, J. H., Norton, J. A. 2010; 14 (8): 1311-1318

  Abstract

  The objective of this study is to evaluate the effectiveness of rfVIIa in reducing blood product requirements and re-operation for postoperative bleeding after major abdominal surgery.Hemorrhage is a significant complication after major gastrointestinal and abdominal surgery. Clinically significant bleeding can lead to shock, transfusion of blood products, and re-operation. Recent reports suggest that activated rfVIIa may be effective in correcting coagulopathy and decreasing the need for re-operation.This study was a retrospective review over a 4-year period of 17 consecutive bleeding postoperative patients who received rfVIIa to control hemorrhage and avoid re-operation. Outcome measures were blood and clotting factor transfusions, deaths, thromboembolic complications, and number of re-operations for bleeding.Seventeen patients with postoperative hemorrhage following major abdominal gastrointestinal surgery (nine pancreas, four sarcoma, two gastric, one carcinoid, and one fistula) were treated with rfVIIa. In these 17 patients, rfVIIa was administered for 18 episodes of bleeding (dose 2,400-9,600 mcg, 29.8-100.8 mcg/kg). Transfusion requirement of pRBC and FFP were each significantly less than pre-rfVIIa. Out of the 18 episodes, bleeding was controlled in 17 (94%) without surgery, and only one patient returned to the operating room for hemorrhage. There were no deaths and two thrombotic complications. Coagulopathy was corrected by rfVIIa from 1.37 to 0.96 (p < 0.0001).Use of rfVIIa in resuscitation for hemorrhage after non-traumatic major abdominal and gastrointestinal surgery can correct dilutional coagulopathy, reducing blood product requirements and need for re-operation.

  View details for DOI 10.1007/s11605-010-1227-6

  View details for PubMedID 20517651

• Pancreatic Mass Resection and Revascularization Tedesco, M. M., Norton, J. A., Cisco, R. M., Song, T. K., Harris, E. MOSBY-ELSEVIER. 2010: 530

  View details for DOI 10.1016/j.jvs.2010.05.046

  View details for Web of Science ID 000280455900073

• Hyperparathyroidism with hypercalcaemia in chronic kidney disease: primary or tertiary? NDT plus Lunn, M. R., Muñoz Mendoza, J., Pasche, L. J., Norton, J. A., Ayco, A. L., Chertow, G. M. 2010; 3 (4): 366-371

  Abstract

  Objective . This study aims to highlight the challenges in the diagnosis of hyperparathyroidism (HPT) in patients with advanced chronic kidney disease (CKD). Methods . In this report, we describe a middle-aged Filipino gentleman with underlying CKD who presented with intractable nausea, vomiting, severe and medically refractory hypercalcaemia and parathyroid hormone (PTH) concentrations in excess of 2400 pg/mL. The underlying pathophysiology as well as the aetiologies and current relevant literature are discussed. We also suggest an appropriate diagnostic approach to identify and promptly treat patients with CKD, HPT and hypercalcaemia. Results . Evaluation confirmed the presence of a large parathyroid adenoma; HPT and hypercalcaemia resolved rapidly following resection. Conclusion . This case report is remarkable for its severe hypercalcaemia requiring haemodialysis, large adenoma size, acute-on-chronic kidney injury and markedly elevated PTH concentration in association with primary HPT in CKD.

  View details for DOI 10.1093/ndtplus/sfq077

  View details for PubMedID 25949433

• Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research JOURNAL OF MEDICAL GENETICS Fitzgerald, R. C., Hardwick, R., Huntsman, D., Carneiro, F., Guilford, P., Blair, V., Chung, D. C., Norton, J., Ragunath, K., Van Krieken, J. H., Dwerryhouse, S., Caldas, C. 2010; 47 (7): 436-444

  Abstract

  25-30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

  View details for DOI 10.1136/jmg.2009.074237

  View details for Web of Science ID 000279326400002

  View details for PubMedID 20591882

  View details for PubMedCentralID PMC2991043

• A NOVEL PRKAR1A MUTATION ASSOCIATED WITH PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE AND THE CARNEY COMPLEX ENDOCRINE PRACTICE Peck, M. C., Visser, B. C., Norton, J. A., Pasche, L., Katznelson, L. 2010; 16 (2): 198-204

  Abstract

  To delineate the genetic and phenotypic features of Carney complex in a family with multiple cases of primary pigmented nodular adrenocortical disease (PPNAD).Detailed clinical, laboratory, genetic, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed.A 17-year-old girl presented with symptoms and physical findings suggestive of hypercortisolemia, in addition to facial lentigines. She was found to have adrenocorticotropic hormone (ACTH)-independent Cushing syndrome. The adrenal glands appeared normal on computed tomographic scanning. Bilateral surgical adrenalectomy revealed PPNAD. Evaluation of her 14-year-old sister revealed ACTH-independent Cushing syndrome as well as facial lentigines, and adrenalectomy revealed PPNAD as well. Genetic testing of the 2 sisters and their mother (who also had multiple facial lentigines but did not have Cushing syndrome) revealed a novel mutation in the PRKAR1A gene.We describe a novel mutation in the PRKAR1A gene in a family with Carney complex and multiple members with PPNAD. PPNAD should be suspected in cases of ACTH-independent Cushing syndrome, and screening for Carney complex and its complications is recommended in all cases of PPNAD, including first-degree relatives.

  View details for DOI 10.4158/EP09245.OR

  View details for PubMedID 19833579

• Solid Pseudopapillary Tumor of the Pancreas: An Unexpected Finding After Minor Abdominal Trauma DIGESTIVE DISEASES AND SCIENCES Cisco, R., Jeffrey, R. B., Norton, J. A. 2010; 55 (2): 240-241

  View details for DOI 10.1007/s10620-009-1030-y

  View details for PubMedID 19890713

• INTERFRACTIONAL UNCERTAINTY IN THE TREATMENT OF PANCREATIC CANCER WITH RADIATION INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Jayachandran, P., Minn, A. Y., Van Dam, J., Norton, J. A., Koong, A. C., Chang, D. T. 2010; 76 (2): 603-607

  Abstract

  To compare the interfractional variation in pancreatic tumor position using bony anatomy and implanted fiducial markers.Five consecutively treated patients with pancreatic adenocarcinoma who received definitive intensity-modulated radiation therapy at Stanford University (Stanford, CA) underwent fiducial seed placement and treatment on the Varian Trilogy system (Varian, Palo Alto, CA) with respiratory gating. Daily orthogonal kilovoltage imaging was performed to verify patient positioning, and isocenter shifts were made initially to match bony anatomy. Next, a final shift to the fiducial seeds was made under fluoroscopic guidance to confirm the location of the pancreatic tumor during the respiratory gated phase. All shifts were measured along three axes, left (+)-right (-), anterior (-)-posterior (+), and superior (+)-inferior (-), and the overall interfractional tumor movement was calculated based on these values.A total of 140 fractions were analyzed. The mean absolute shift to fiducial markers after shifting to bony anatomy was 1.6 mm (95th percentile, 7 mm; range, 0-9 mm), 1.8 mm (95th percentile, 7 mm; range, 0-13 mm), and 4.1 mm (95th percentile, 12 mm; range, 0-19 mm) in the anterior-posterior, left-right, and superior-inferior directions, respectively. The mean interfractional vector shift distance was 5.5 mm (95th percentile, 14.5 mm; range, 0-19.3 mm). In 28 of 140 fractions (20%) no fiducial shift was required after alignment to bony anatomy.There is substantial residual uncertainty after alignment to bony anatomy when radiating pancreatic tumors using respiratory gating. Bony anatomy matched tumor position in only 20% of the radiation treatments. If bony alignment is used in conjunction with respiratory gating without implanted fiducials, treatment margins need to account for this uncertainty.

  View details for DOI 10.1016/j.ijrobp.2009.06.029

  View details for PubMedID 19879062

• Surgical Management of Zollinger-Ellison Syndrome; State of the Art SURGICAL CLINICS OF NORTH AMERICA Morrow, E. H., Norton, J. A. 2009; 89 (5): 1091-?

  Abstract

  Much has been learned about the diagnosis and treatment of Zollinger-Ellison Syndrome (ZES), and certain questions require further investigation. Delay in diagnosis of ZES is still a significant problem, and clinical suspicion should be elevated. The single best imaging modality for localization and staging of ZES is somatostatin receptor scintigraphy. Goals of surgical treatment for ZES differ between sporadic and MEN-1-related cases. All sporadic cases of ZES should be surgically explored (including duodenotomy) even with negative imaging results, because of the high likelihood of finding and removing a tumor for potential cure. Surgery for MEN-1-related cases should be focused on prevention of metastatic disease, with surgery being recommended when pancreatic tumors are greater than 2 cm. The role of Whipple procedure, especially for MEN-1 cases, should be explored further. Laparoscopic and endoscopic treatments are more experimental, but may have a role.

  View details for DOI 10.1016/j.suc.2009.06.018

  View details for PubMedID 19836486

• Appendiceal Mucinous Neoplasms Clinicopathologic Study of 116 Cases With Analysis of Factors Predicting Recurrence AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Beck, A. H., Norton, J. A., Longacre, T. A. 2009; 33 (10): 1425-1439

  Abstract

  The classification and nomenclature of appendiceal mucinous neoplasms are controversial. To determine the outcome for patients with appendiceal mucinous neoplasms and further evaluate whether they can be stratified into groups that provide prognostic information, the clinicopathologic features of 116 patients (66 with clinical follow-up) with appendiceal mucinous neoplasms were studied. From a wide variety of histopathologic features assessed, the important predictors that emerged on univariate statistical analysis were presence of extra-appendiceal neoplastic epithelium (P=0.01), high-grade cytology (P<0.0001), architectural complexity (P<0.001), and invasion (P<0.001). Stratification using a combination of these predictors resulted in a 4-tiered classification scheme. All 16 patients with mucinous neoplasms confined to the appendix and lacking high-grade cytology, architectural complexity, and invasion were alive with no recurrences at median 59 months follow-up (=mucinous adenoma). One of 14 patients with low-grade cytology and acellular peritoneal mucin deposits developed recurrent tumor within the peritoneum at 45 months with no patient deaths to date (median, 48-mo follow-up) (=low-grade mucinous neoplasm with low risk of recurrence). None of the 2 patients with acellular peritoneal mucinous deposits outside of the right lower quadrant developed recurrence at 163 and 206 months. Twenty-seven patients with low-grade mucinous neoplasms with extra-appendiceal neoplastic epithelium had 1-year, 3-year, 5-year, and 10-year overall survival rates of 96%, 91%, 79%, and 46%, respectively, at median 53 months follow-up (=low-grade mucinous neoplasm with high risk of recurrence). Three of the 4 patients with extra-appendiceal epithelium limited to the right lower quadrant developed full-blown peritoneal disease at 6, 41, and 99 months follow-up and 1 patient eventually died of disease. Nine patients with appendiceal neoplasms with invasion or high-grade cytology and follow-up showed 1-year, 3-year, and 5-year overall survival rates of 86%, 57%, and 28% (=mucinous adenocarcinoma). At 10 years, all patients with mucinous adenocarcinoma were either dead or lost to follow-up. Appendiceal mucinous neoplasms can be stratified into 4 distinct risk groups on the basis of a careful histopathologic assessment of cytoarchitectural features and extent of disease at presentation.

  View details for PubMedID 19641451

• Major Blood Vessel Reconstruction During Sarcoma Surgery ARCHIVES OF SURGERY Song, T. K., Harris, E. J., Raghavan, S., Norton, J. A. 2009; 144 (9): 817-822

  Abstract

  To evaluate the outcomes of major vessel reconstruction as part of surgery to remove sarcomas.Retrospective review.Tertiary academic medical center.Fourteen patients (10 female) with retroperitoneal or extremity sarcomas and major blood vessel involvement who underwent surgery to remove the tumor and had blood vessel reconstruction between 2003 and 2008. Each patient underwent computed tomography angiography.Early (<30 days) and late (>30 days) operative morbidity and mortality, freedom from disease, and graft patency.Seven patients had retroperitoneal sarcomas and 7, extremity sarcomas. Thirteen tumors were malignant (7 high grade and 6 low grade) and 1, benign (leiomyoma). Seven patients had replacement of artery and vein; 5, artery only; and 2, vein only. In all, 16 arteries were reconstructed (2 common femoral; 5 iliac; 2 superficial femoral; 1 brachial; 1 popliteal; and 2 aorta, one with implantation of both iliac arteries and the other with implantation of the left renal, superior mesenteric, and hepatic arteries). Eight patients (57%) had 9 veins reconstructed (3 external iliac, 3 superficial femoral, 2 vena cava, and 1 popliteal). Primary arterial patency was 58% and primary-assisted patency was 83%. Venous patency was 78%. Local recurrence occurred in 3 patients (21%). Five-year disease-free and overall survival were 52% and 68%, respectively. Limb salvage was achieved in 93%.Involvement of vascular structures is not a contraindication for resection of sarcomas, but appropriate planning is necessary to optimize outcome.

  View details for PubMedID 19797105

• Effect of Preoperative Intravenous Pantoprazole in Elective-Surgery Patients: A Pilot Study DIGESTIVE DISEASES AND SCIENCES Pisegna, J. R., Karlstadt, R. G., Norton, J. A., Fogel, R., Oh, D. S., Graepel, G. J., Dorr, M. B. 2009; 54 (5): 1041-1049

  Abstract

  This study evaluated the effects of intravenous pantoprazole on gastric volume and acid output in elective-surgical patients.This is a multicenter, randomized, pilot study of adult patients receiving intravenous pantoprazole: 40 mg every 24 h, 40 mg every 12 h (q12h) or 80 mg q12h. The first dose was administered 1 h before general anesthesia for surgery. All gastric fluid was aspirated through a nasogastric tube 1 h before dosing and through the postoperative period. Aspirate volume was recorded; pH and H(+) concentrations were measured.Twenty-six patients were enrolled and 21 were evaluable. Pantoprazole was well tolerated. All regimens decreased gastric acid output and volume, and increased pH within 1 h of dosing. Effects were sustained for up to 12 h following single-dose administration.Intravenous pantoprazole administered prior to anesthesia induction may be efficacious for the reduction of gastric volume and acid output, and for pulmonary aspiration prophylaxis in surgical patients.

  View details for DOI 10.1007/s10620-008-0445-1

  View details for Web of Science ID 000264810100018

  View details for PubMedID 18754096

• The value of surgery for retroperitoneal sarcoma. Sarcoma Gholami, S., Jacobs, C. D., Kapp, D. S., Parast, L. M., Norton, J. A. 2009; 2009: 605840-?

  Abstract

  Introduction. Retroperitoneal sarcomas are uncommon large malignant tumors. Methods. Forty-one consecutive patients with localized retroperitoneal sarcoma were retrospectively studied. Results. Median age was 58 years (range 20-91 years). Median tumor size was 17.5 cm (range 4-41 cm). Only 2 tumors were <5 cm. Most were liposarcoma (44%) and high-grade (59%). 59% were stage 3 and the rest was stage 1. Median followup was 10 months (range 1-106 months). Thirty-eight patients had an initial complete resection; 15 (37%) developed recurrent sarcoma and 12 (80%) had a second complete resection. Patients with an initial complete resection had a 5-year survival of 46%. For all patients, tumor grade affected overall survival (P = .006). Complete surgical resection improved overall survival for high-grade tumors (P = .03). Conclusions. Tumor grade/stage and complete surgical resection for high-grade tumors are important prognostic variables. Radiation therapy or chemotherapy had no significant impact on overall or recurrence-free survival. Complete surgical resection is the treatment of choice for patients with initial and locally recurrent retroperitoneal sarcoma.

  View details for DOI 10.1155/2009/605840

  View details for PubMedID 19826633

• INTRAOPERATIVE RADIATION THERAPY FOR LOCALLY ADVANCED AND RECURRENT SOFT-TISSUE SARCOMAS IN ADULTS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Tran, P. T., Hara, W., Su, Z., Lin, H. J., Bendapudi, P. K., Norton, J., Teng, N., King, C. R., Kapp, D. S. 2008; 72 (4): 1146-1153

  Abstract

  To analyze the outcomes of and identify prognostic factors for patients treated with surgery and intraoperative radiotherapy (IORT) for locally advanced and recurrent soft-tissue sarcoma in adults from a single institution.We retrospectively reviewed 50 consecutive patients treated with IORT to 62 sites of disease. Primary sites included retroperitoneum-pelvis (78%), extremity (8%), and other (14%). Seventy percent of patients had recurrent disease failing prior surgery (70%) and/or radiation (32%). Mean disease-free interval (DFI) before IORT was 1.9 years (range, 2 weeks-5.4 years). The IORT was delivered with orthovoltage X-rays using individually sized beveled cone applicators. Clinical characteristics were as follows: mean tumor size, 10 cm (range, 1-25 cm); high-grade histologic subtype (72%); and mean dose, 1,159 cGy (range, 600-1,600 cGy). Postoperative radiation or chemotherapy was administered to 37% of IORT Sites and 32% of patients, respectively. Outcomes measured were infield control (IFC), locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and treatment-related complications. Mean and median follow-up of alive patients were 59 and 35 months, respectively.Kaplan-Meier 5-year IFC, LRC, DMFS, and DSS probabilities for the entire group were 55%, 26%, 51%, and 25%, respectively. Prognostic factors found to be significant (p < 0.05) on multivariate analysis were prior DFI and tumor size for LRC, extremity location and leiomyosarcoma histologic subtype for DMFS, and prior DFI for DSS. Our cohort had five Grade 3/4 complications associated with treatment or a 5-year Kaplan-Meier Grade 3/4 complication-free survival rate of 85%.IORT after tumor reductive surgery is well tolerated and seems to confer IFC in carefully selected patients.

  View details for DOI 10.1016/j.ijrobp.2008.02.012

  View details for Web of Science ID 000260592600026

  View details for PubMedID 18394818

• Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Schellenberg, D., Goodman, K. A., Lee, F., Chang, S., Kuo, T., Ford, J. M., Fisher, G. A., Quon, A., Desser, T. S., Norton, J., Greco, R., Yang, G. P., Koong, A. C. 2008; 72 (3): 678-686

  Abstract

  Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy.A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT.All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13).SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.

  View details for DOI 10.1016/j.ijrobp.2008.01.051

  View details for PubMedID 18395362

• Hereditary diffuse gastric cancer - Implications of genetic testing for screening and prophylactic surgery CANCER Cisco, R. M., Ford, J. M., Norton, J. A. 2008; 113 (7): 1850-1856

  Abstract

  Approximately 10% of patients with gastric cancer show familial clustering, and 3% show autosomal dominance and high penetrance. Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant, inherited cancer syndrome in which affected individuals develop diffuse-type gastric cancer at a young age. Inactivating mutations in the E-cadherin gene CDH1 have been identified in 30% to 50% of patients. CDH1 mutation carriers have an approximately 70% lifetime risk of developing DGC, and affected women carry an additional 20% to 40% risk of developing lobular breast cancer. Because endoscopic surveillance is ineffective in identifying early HDGC, gene-directed prophylactic total gastrectomy currently is offered for CDH1 mutation carriers. In series of asymptomatic individuals undergoing total gastrectomy for CDH1 mutations, the removed stomachs usually contain small foci of early DGC, making surgery not prophylactic but curative. The authors of this review recommend consideration of total gastrectomy in CDH1 mutation carriers at an age 5 years younger than the youngest family member who developed gastric cancer. Individuals who choose not to undergo prophylactic gastrectomy should be followed with biannual chromoendoscopy, and women with CDH1 mutations also should undergo regular surveillance with magnetic resonance imaging studies of the breast. Because of the emergence of gene-directed gastrectomy for HDGC, today, a previously lethal disease is detected by molecular techniques, allowing curative surgery at an early stage.

  View details for DOI 10.1002/cncr.23650

  View details for PubMedID 18798546

• Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies CANCER Jensen, R. I., Berna, M. J., Bingham, D. B., Norton, J. A. 2008; 113 (7): 1807-1843

  Abstract

  Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed.

  View details for DOI 10.1002/cncr.23648

  View details for Web of Science ID 000259661800011

  View details for PubMedID 18798544

• Hereditary diffuse gastric cancer: surgery, surveillance and unanswered questions FUTURE ONCOLOGY Cisco, R. M., Norton, J. A. 2008; 4 (4): 553-559

  Abstract

  Hereditary diffuse gastric cancer (HDGC) is an inherited cancer-susceptibility syndrome characterized by autosomal dominance and high penetrance. In 30-50% of cases, a causative germline mutation in CDH1, the E-cadherin gene, may be identified. Female carriers of CDH1 mutations also have an increased (20-40%) risk of lobular breast cancer. Endoscopic surveillance of patients with CDH1 mutations is ineffective because early foci of HDGC are typically small and underlie normal mucosa. CDH1 mutation carriers are therefore offered the option of prophylactic gastrectomy, which commonly reveals early foci of invasive signet-ring cell cancer. We review recommendations for genetic testing, surveillance and prophylactic surgery in HDGC. Areas for future research are discussed, including development of new screening modalities, optimal timing of prophylactic gastrectomy, identification of additional causative mutations in HDGC, management of patients with CDH1 missense mutations and prevention/early detection of lobular breast cancer in CDH1 mutation carriers.

  View details for DOI 10.2217/14796694.4.4.553

  View details for PubMedID 18684065

• Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. American journal of surgical pathology Rogers, W. M., Dobo, E., Norton, J. A., Van Dam, J., Jeffrey, R. B., Huntsman, D. G., Kingham, K., Chun, N., Ford, J. M., Longacre, T. A. 2008; 32 (6): 799-809

  Abstract

  Hereditary diffuse gastric cancer is a rare autosomal dominant cancer susceptibility syndrome caused by germline E-cadherin (CDH1) mutations in 40% of cases with a high degree of penetrance. Screening endoscopy has not been useful in identifying early cancer, in part owing to conflicting data concerning site(s) of involvement in the stomach and the lack of endoscopically detectable pathology. Risk-reducing total gastrectomy specimens from 8 asymptomatic adults with germline mutations in the CDH1 gene (3 different pedigrees) were studied using a sequential serial sectioning protocol with submission of the entire stomach for histologic analysis. The presence, size, and distribution of signet ring cell clusters were determined for each section and geographic maps of the invasive foci were constructed and compared with gastrectomy specimens from patients with germline E-cadherin mutation and symptomatic gastric cancer. All but 1 of the asymptomatic patients with germline mutations in the CDH1 gene had negative endoscopic screening. All risk-reducing gastrectomy specimens were macroscopically normal. All contained multiple foci (mean, 10.9) of microscopic intramucosal signet ring cell carcinoma confined to the superficial gastric mucosa; no invasion of submucosa was identified. In situ carcinoma was present in 6/8 cases. The majority of signet ring foci were located in the proximal one third of the stomach, most within oxyntic-type mucosa. The number and size of foci were not related to age, but there was a trend toward more severe disease burden in women. Stomachs from the symptomatic group of patients with germline CDH1 mutations exhibited infiltrative foci with higher Ki-67 labeling that extended well beyond the superficial mucosa. In addition, while superficial signet ring cancer exhibited decreased or absent E-cadherin and beta-catenin protein expression in all cases studied, deeply invasive signet ring cancer showed reversion to E-cadherin and beta-catenin protein expression in a subset of mutation carriers. Our study indicates that superficial intramucosal signet ring carcinoma, although widespread, is predominantly located in the proximal one third of the stomach in patients with E-cadherin gene mutations. The observed site predilection suggests a possible role for geographically targeted endoscopic surveillance biopsy in patients who elect to delay surgical intervention.

  View details for DOI 10.1097/PAS.0b013e31815e7f1a

  View details for PubMedID 18391748

• Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): Pathologic findings with clinical implications AMERICAN JOURNAL OF SURGICAL PATHOLOGY Rogers, W. M., Dobo, E., Norton, J. A., Van Dam, J., Jeffrey, R. B., Huntsman, D. G., Kingham, K., Chun, N., Ford, J. M., Longacre, T. A. 2008; 32A (6): 799-809

  Abstract

  Hereditary diffuse gastric cancer is a rare autosomal dominant cancer susceptibility syndrome caused by germline E-cadherin (CDH1) mutations in 40% of cases with a high degree of penetrance. Screening endoscopy has not been useful in identifying early cancer, in part owing to conflicting data concerning site(s) of involvement in the stomach and the lack of endoscopically detectable pathology. Risk-reducing total gastrectomy specimens from 8 asymptomatic adults with germline mutations in the CDH1 gene (3 different pedigrees) were studied using a sequential serial sectioning protocol with submission of the entire stomach for histologic analysis. The presence, size, and distribution of signet ring cell clusters were determined for each section and geographic maps of the invasive foci were constructed and compared with gastrectomy specimens from patients with germline E-cadherin mutation and symptomatic gastric cancer. All but 1 of the asymptomatic patients with germline mutations in the CDH1 gene had negative endoscopic screening. All risk-reducing gastrectomy specimens were macroscopically normal. All contained multiple foci (mean, 10.9) of microscopic intramucosal signet ring cell carcinoma confined to the superficial gastric mucosa; no invasion of submucosa was identified. In situ carcinoma was present in 6/8 cases. The majority of signet ring foci were located in the proximal one third of the stomach, most within oxyntic-type mucosa. The number and size of foci were not related to age, but there was a trend toward more severe disease burden in women. Stomachs from the symptomatic group of patients with germline CDH1 mutations exhibited infiltrative foci with higher Ki-67 labeling that extended well beyond the superficial mucosa. In addition, while superficial signet ring cancer exhibited decreased or absent E-cadherin and beta-catenin protein expression in all cases studied, deeply invasive signet ring cancer showed reversion to E-cadherin and beta-catenin protein expression in a subset of mutation carriers. Our study indicates that superficial intramucosal signet ring carcinoma, although widespread, is predominantly located in the proximal one third of the stomach in patients with E-cadherin gene mutations. The observed site predilection suggests a possible role for geographically targeted endoscopic surveillance biopsy in patients who elect to delay surgical intervention.

  View details for Web of Science ID 000256553000001

• An update of a phase I/II study of the VEGF receptor tyrosine kinase inhibitor vatalanib and gemcitabine in patients with advanced pancreatic cancer Kuo, T., Cabebe, E. C., Koong, A., NORTON, J. A., Kunz, P. L., Ford, J. M., KAISER, H. L., Rogers, J., Sikic, B. I., Fisher, G. A. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457401374

• Identifying and preventing high-risk gastric cancer individuals with CDH1 mutations - Reply ANNALS OF SURGERY Norton, J. A., Ford, J. M. 2008; 247 (4): 715–16

  View details for DOI 10.1097/SLA.0b013e31816a5092

  View details for Web of Science ID 000254546900026

• Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome - Long-term outcome of 6 more virulent form of HPT ANNALS OF SURGERY Norton, J. A., Venzon, D. J., Berna, M. J., Alexander, H. R., Fraker, D. L., Libutti, S. K., Marx, S. J., Gibril, F., Jensen, R. T. 2008; 247 (3): 501-510

  Abstract

  Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) patients with Zollinger-Ellison syndrome (ZES) is caused by parathyroid hyperplasia. Surgery for parathyroid hyperplasia is tricky and difficult. Long-term outcome in ZES/MEN1/HPT is not well known.Eighty-four consecutive patients (49 F/35 M) with ZES/MEN1/HPT underwent initial parathyroidectomy (PTX) and were followed at 1- to 3-year intervals.Age at PTX was 36 +/- 2 years. Mean follow-up was 17 +/- 1 years. Before PTX, mean Ca = 2.8 mmol/L (normal level (nl <2.5), PTH i = 243 pg/mL (nl <65), and gastrin = 6950 pg/mL (nl < 100). Sixty-one percent had nephrolithiasis. Each patient had parathyroid hyperplasia. Fifty-eight percent of patients had 4 parathyroid glands identified. Nine of 84 (11%) had 4 glands removed with immediate autograft, 40/84 (47%) 3 to 3.5 glands, whereas 35/84 (42%) <3 glands removed. Persistent/recurrent HPT occurred in 42%/48% of patients with <3 glands, 12%/44% with 3 to 3.5 glands, and 0%/55% with 4 glands removed. Hypoparathyroidism occurred in 3%, 10%, and 22%, respectively. The disease-free interval after surgery was significantly longer if >3 glands were removed. After surgery to correct the HPT, each biochemical parameter of ZES was improved and 20% of patients no longer had laboratory evidence of ZES.HPT/MEN1/ZES is a severe form of parathyroid hyperplasia with a high rate of nephrolithiasis, persistent and recurrent HPT. Surgery to correct the hypercalcemia significantly ameliorates the ZES. Removal of less than 3.5 glands has an unacceptably high incidence of persistent HPT (42%), whereas 4-gland resection and transplant has a high rate of permanent hypoparathyroidism (22%). More than 3-gland resection has a longer disease-free interval. The surgical procedure of choice for patients with HPT/MEN1/ZES is 3.5-gland parathyroidectomy. Careful long-term follow-up is necessary as a significant proportion will develop recurrent HPT.

  View details for DOI 10.1097/SLA.0b013e31815efda5

  View details for PubMedID 18376196

• Tissue effects after stereotactic body radiotherapy using cyberknife for patients with abdominal malignancies CLINICAL ONCOLOGY Cupp, J. S., Koong, A. C., Fisher, G. A., NORTON, J. A., Goodman, K. A. 2008; 20 (1): 69-75

  Abstract

  To report the tissue effects of treatment with single fraction stereotactic body radiotherapy (SBRT) using Cyberknife on malignant tumours of the abdomen and adjacent normal organs.The data from four autopsies with unresectable pancreatic carcinoma and one lymph node excision from a case of recurrent neuroblastoma were reviewed for radiation-related tissue effects within the primary cancer and the normal organs within the radiation field.Cases of unresectable pancreatic carcinoma consistently showed radiation-induced changes in both the primary tumour and the adjacent, non-malignant colorectal tissue. An additional case of lymph nodes exposed to stereotactic radiation showed typical radiation-related changes, including lymphocyte depletion and capsular fibrosis.A myriad of radiation-related tissue effects are seen after SBRT with Cyberknife. The changes parallel those reported after conventionally fractionated radiotherapy and suggest that the pathophysiological mechanisms of radiation-induced normal tissue damage are similar for biologically equivalent single and fractionated doses of radiotherapy.

  View details for DOI 10.1016/j.clon.2007.08.009

  View details for Web of Science ID 000253281700013

  View details for PubMedID 17900882

• High predictive value of pancreatic protocol CT as the only preoperative staging in pancreatic cancer 15th Workshop on Information Technology and Systems (WITS 2005) Cisco, R. M., Jeffrey, R. B., Greco, R. S., NORTON, J. A. SPRINGER. 2008: 88–88

  View details for Web of Science ID 000252887900277

• A carrier of both MEN1 and BRCA2 mutations: case report a-lid review of the literature CANCER GENETICS AND CYTOGENETICS Ghataorhe, P., Kurian, A. W., Pickart, A., Trapane, P., Norton, J. A., Kingham, K., Ford, J. M. 2007; 179 (2): 89-92

  Abstract

  High-penetrance autosomal dominant cancer susceptibility genes such as BRCA2 and MEN1 result in specific patterns of cancers in individuals who inherit germline mutations. Their incidence in the population is relatively low, however, and it is highly unusual to identify individuals with two or more inherited cancer gene mutations. We describe a family with multiple cases of MEN1-associated cancers as well as pancreatic adenocarcinoma, ovarian cancer, and male breast cancer, in which we identified germline mutations in both MEN1 and BRCA2. To our knowledge, this is the first report of a patient with both MEN1 and BRCA2 mutations and with a personal history of hyperparathyroidism and pancreatic neuroendocrine tumors.

  View details for DOI 10.1016/j.cancergencyto.2007.08.009

  View details for Web of Science ID 000251478000001

  View details for PubMedID 18036394

• Role of surgery in Zollinger-Ellison syndrome JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Norton, J. A., Jensen, R. T. 2007; 205 (4): S34-S37

  View details for DOI 10.1016/j.jamcollsurg.2007.06.320

  View details for PubMedID 17916516

• CDH1 truncating mutations in the E-cadherin gene - An indication for total gastrectomy to treat hereditary diffuse gastric cancer ANNALS OF SURGERY Norton, J. A., Ham, C. M., Van Dam, J., Jeffrey, R. B., Longacre, T. A., Huntsman, D. G., Chun, N., Kurian, A. W., Ford, J. M. 2007; 245 (6): 873-879

  Abstract

  Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer.Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with D-2 node dissection and Roux-en-Y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically.Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51-57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality.CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.

  View details for DOI 10.1097/01.sla.0000254370.29893.e4

  View details for PubMedID 17522512

• Surgery for gastrinoma. Advances in surgery Cisco, R. M., Norton, J. A. 2007; 41: 165-176

  Abstract

  Surgery has been demonstrated to offer potential for cure in patients who have sporadic ZES and improved tumor-related survival in all patients who have ZES with gastrinomas larger than 2.5 cm. Techniques such as preoperative localization with SRS and intraoperative localization with duodenotomy have improved the effectiveness of surgical intervention for ZES. Future directions for investigation should include better defining the role of preoperative EUS and developing new, more sensitive techniques for preoperative localization. More research also is needed to define the appropriate indications for pancreaticoduodenectomy in ZES and to determine whether proximal vagotomy should be performed at the time of surgical exploration.

  View details for PubMedID 17972563

• Intraoperative radiation therapy for soft tissue sarcomas 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Hara, W., Tran, P., Su, Z., Lin, J., Norton, J., King, C., Goffinet, D., Kapp, D. S. ELSEVIER SCIENCE INC. 2007: S754–S754

  View details for Web of Science ID 000249950201666

• Surgery increases survival in patients with gastrinoma 126th Annual Meeting of the American-Surgical-Association Norton, J. A., Fraker, D. L., Alexander, H. R., Gibril, F., Liewehr, D. J., Venzon, D. J., Jensen, R. T. LIPPINCOTT WILLIAMS & WILKINS. 2006: 410–19

  Abstract

  To determine whether the routine use of surgical exploration for gastrinoma resection/cure in 160 patients with Zollinger-Ellison syndrome (ZES) altered survival compared with 35 ZES patients who did not undergo surgery.The role of routine surgical exploration for resection/cure in patients with ZES has been controversial since the original description of this disease in 1955. This controversy continues today, not only because medical therapy for acid hypersecretion is so effective, but also in large part because no studies have shown an effect of tumor resection on survival.Long-term follow-up of 160 ZES patients who underwent routine surgery for gastrinoma/resection/cure was compared with 35 patients who had similar disease but did not undergo surgery for a variety of reasons. All patients had preoperative CT, MRI, ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994 to determine resectability. At surgery, all had the same standard ZES operation. All patients were evaluated yearly with imaging studies and disease activity studies.The 35 nonsurgical patients did not differ from the 160 operated in clinical, laboratory, or tumor imaging results. The 2 groups did not differ in follow-up time since initial evaluation (range, 11.8-12 years). At surgery, 94% had a tumor removed, 51% were cured immediately, and 41% at last follow-up. Significantly more unoperated patients developed liver metastases (29% vs. 5%, P = 0.0002), died of any cause (54 vs. 21%, P = 0.0002), or died a disease-related death (23 vs. 1%, P < 0.00001). Survival plots showed operated patients had a better disease-related survival (P = 0.0012); however, there was no difference in non-disease-related survival. Fifteen-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002).These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.

  View details for DOI 10.1097/01.sla.0000234802.44320.a5

  View details for PubMedID 16926567

• Lessons from Coley's Toxin SURGICAL ONCOLOGY-OXFORD Tsung, K., Norton, J. A. 2006; 15 (1): 25-28

  Abstract

  The active molecule in Coley's Toxin is not tumor necrosis factor (TNF) or endotoxin (LPS), but interleukin-12 (IL-12). IL-12 holds the key to improved anti-tumor immuns response.

  View details for DOI 10.1016/j.suronc.2006.05.002

  View details for PubMedID 16814541

• Surgery for primary pancreatic neuroendocrine tumors 46th Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract Norton, J. A. SPRINGER. 2006: 327–31

  View details for DOI 10.1016/j.gassur.2005.08.023

  View details for PubMedID 16504877

• Surgery for gastrinoma and insulinoma in multiple endocrine neoplasia type 1. Journal of the National Comprehensive Cancer Network Norton, J. A., Fang, T. D., Jensen, R. T. 2006; 4 (2): 148-153

  Abstract

  The surgical management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1 remains controversial. Gastrinoma and insulinoma are the 2 most common functional pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. Gastrinomas cause gastric acid hypersecretion and peptic ulcer disease that are best managed using proton pump inhibitors. Surgery to remove the gastrinoma in patients with multiple endocrine neoplasia type 1 is seldom curative unless a more extensive Whipple pancreaticoduodenectomy is performed. Because the prognosis is excellent, aggressive resections such as a Whipple procedure are only indicated for large, locally metastatic, advanced tumors. Furthermore, surgery to remove imageable tumors that are 2 cm in diameter is associated with excellent outcomes and decreased probability of liver metastases. Because gastrinomas are commonly multiple and most originate in the duodenum and develop lymph node metastases, the duodenum should be opened and all tumors and lymph nodes excised. Insulinomas cause hypoglycemia that results in neuroglycopenic symptoms. Medical management of the hypoglycemia is less effective than that of the gastric acid hypersecretion. Fortunately, the insulinoma is usually clearly identified using routine pancreatic imaging studies. There is a high likelihood of cure when the insulinoma is excised surgically. However, recurrent hypoglycemia may occur, and careful follow-up is indicated.

  View details for PubMedID 16451771

• Inhibition of host signal transducer and activator of transcription factor 6 results in cure with cyclophosphamide and interleukin 12 immunotherapy ANNALS OF SURGICAL ONCOLOGY Norton, J. A., Li, M., Lee, N. C., Tsung, K. 2006; 13 (1): 118-124

  Abstract

  Interleukin (IL)-12 immunotherapy is highly effective against established immunogenic tumors. However, nonimmunogenic tumors fail to respond to IL-12 therapy. Analysis of tumor rejection of the immunogenic tumors shows that a preexisting antitumor immune response is required for an effective IL-12 response. It is not known whether this lack of a preexisting host antitumor immune response is a limiting factor for the lack of response to IL-12 therapy by nonimmunogenic tumors.Experiments were done using the spontaneously arising nonimmunogenic metastatic murine breast 4T1 carcinoma in normal and STAT6 knockout BALB/c mice.4T1 is nonimmunogenic in normal mice, and established subcutaneous tumors are resistant to immunotherapy with cyclophosphamide (Cy) plus IL-12. However, in STAT6 knockout mice, 4T1 becomes immunogenic, and established 4T1 tumors are eradicated by Cy plus IL-12. Adoptive transfer of spleen cells from normal mice into STAT6 knockout mice before tumor inoculation reduces both the immunogenicity and response to Cy plus IL-12 immunotherapy of 4T1 in the recipient mice.Cy plus IL-12 immunotherapy can eradicate nonimmunogenic tumors as long as a preexisting immunity is established in the tumor-bearing host. Furthermore, the STAT6 pathway is likely involved in the suppression of the development of host antitumor immunity.

  View details for DOI 10.1245/ASO.2006.03.514

  View details for PubMedID 16372153

• Gastrinoma CLINICAL SCENARIOS IN SURGICAL ONCOLOGY Norton, J. A., Khatri, V. P. 2006: 347–49

  View details for Web of Science ID 000267913100076

• Insulinoma CLINICAL SCENARIOS IN SURGICAL ONCOLOGY Norton, J. A., Khatri, V. P. 2006: 350–53

  View details for Web of Science ID 000267913100077

• Management of Incidental Adrenal Lesion CLINICAL SCENARIOS IN SURGICAL ONCOLOGY Norton, J. A., Khatri, V. P. 2006: 343–46

  View details for Web of Science ID 000267913100075

• Long-term functionality of cryopreserved parathyroid autografts: A 13-year prospective analysis SURGERY Cohen, M. S., Dilley, W. G., Wells, S. A., Moley, J. F., Doherty, G. M., Sicard, G. A., Skinner, M. A., NORTON, J. A., DeBenedetti, M. K., Lairmore, T. C. 2005; 138 (6): 1033-1040

  Abstract

  The functional results of cryopreserved heterotopic parathyroid autotransplantation (CHPA) are not well defined. The authors evaluated the outcomes of delayed CHPA for the treatment of surgically induced hypoparathyroidism.Since November 1991, 448 parathyroid samples from 436 patients were cryopreserved at our institution. Of these, 29 patients underwent 34 CHPA procedures, with placement of 20 to 25 pieces of parathyroid tissue (approximately 50 to 75 mg) into the forearm. Outcomes were determined based on peripheral parathyroid hormone (PTH) levels and, where available, PTH gradients between grafted and nongrafted arms. Graft function results were defined as completely functional (patients with normal PTH and calcium levels off all calcium/vitamin D supplementation), partially functional (normal PTH levels and mild hypocalcemia on calcium supplementation), or nonfunctional (low PTH levels and dependent on calcium/vitamin D supplementation).Of the 29 patients with CHPA, prospective data were available for 26 patients undergoing 30 CHPA procedures (9 patients with MEN 1, 4 with MEN 2A, 1 with MEN 2B, and 12 with sporadic hyperparathyroidism). The mean follow-up interval was 2 years. Twelve of 26 patients (46%) had completely functional grafts, 6 patients (23%) had partially functional grafts, and the remaining 8 patients (31%) had nonfunctional grafts. No patient with CHPA had graft-dependent recurrent hyperparathyroidism. Of the 14 patients (15 autografts) with MEN, 7 patients (50%) had fully functional grafts, and 2 patients (14%) had partially functional grafts. The mean cryopreservation period was 7.9 months (range, 1 week to 22 months) for functional autografts and 15.3 months (range, 2 weeks to 106 months) for nonfunctional autografts (P < .01).Based on these data and those in previous studies, approximately 60% of delayed, cryopreserved parathyroid autografts are functional. In this study 40% autografts (46% of patients) achieved full competency off supplements. Some patients have evidence of graft function with normal PTH levels but are not normocalcemic. Results were similar for patients with MEN and nonhereditary hyperparathyroidism. The duration of cryopreservation was a significant indicator of graft failure, and no functional autograft was observed beyond 22 months of preservation. CHPA is a useful treatment modality for patients with postoperative hypocalcemia after thyroid or parathyroid surgery, who do not respond to immediate parathyroid autotransplantation.

  View details for DOI 10.1016/j.surg.2005.09.029

  View details for Web of Science ID 000234319000018

  View details for PubMedID 16360388

• Surgical treatment and prognosis of gastrinoma BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY NORTON, J. A. 2005; 19 (5): 799-805

  Abstract

  Zollinger-Ellison syndrome (ZES) is a clinical syndrome with severe peptic ulcer disease and diarrhea caused by gastric acid hypersecretion secondary to a neuroendocrine tumour that secretes excessive amounts of the hormone gastrin (gastrinoma). Gastrinomas occur in a familial and a sporadic form. Patients with gastrinoma in the familial setting of Multiple Endocrine Neoplasia type 1 (MEN-1) are seldom, if ever, cured of Zollinger-Ellison syndrome by the current non-Whipple operations to remove duodenal and pancreatic gastrinoma. Surgery is currently used in these patients to deal with the malignant nature of pancreatic or duodenal neuroendocrine tumours. Malignant potential is best determined by tumour size. Tumours that are greater than 2 cm in size should be excised. In the sporadic setting, cure occurs in a significant proportion of patients (50%) by surgical resection of gastrinoma. Duodenotomy has improved both the tumour detection rate and the cure rate and should be routinely done. Whipple pancreaticoduodenectomy results in the highest probability of cure in both sporadic and MEN-1 gastrinoma patients as it removes the entire gastrinoma triangle. However, the excellent long-term survival of these patients with lesser operations and the increased operative mortality and long-term morbidity of Whipple make its current role unclear until further studies are done.

  View details for DOI 10.1016/j.bpg.2005.05.003

  View details for PubMedID 16253901

• Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Koong, A. C., Christofferson, E., Le, Q. T., Goodman, K. A., Ho, A., Kuo, T., Ford, J. M., Fisher, G. A., Greco, R., Norton, J., Yang, G. P. 2005; 63 (2): 320-323

  Abstract

  To determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by body stereotactic radiosurgery (SRS) in patients with locally advanced pancreatic cancer.In this prospective study, all patients (19) had pathologically confirmed adenocarcinoma and were uniformly staged. Our treatment protocol consisted of 45 Gy IMRT with concurrent 5-FU followed by a 25 Gy SRS boost to the primary tumor.Sixteen patients completed the planned therapy. Two patients experienced Grade 3 toxicity (none had more than Grade 3 toxicity). Fifteen of these 16 patients were free from local progression until death. Median overall survival was 33 weeks.Concurrent IMRT and 5-FU followed by SRS in patients with locally advanced pancreatic cancer results in excellent local control, but does not improve overall survival and is associated with more toxicity than SRS, alone.

  View details for DOI 10.1016/j.ijrobp.2005.07.002

  View details for PubMedID 16168826

• Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY Norton, J. A. 2005; 19 (5): 699-704

  Abstract

  It has become increasingly clear that duodenal gastrinomas are the most common cause of Zollinger-Ellison syndrome (ZES). However, attempts to find these tumors before and during surgery for ZES have had limited success until duodenotomy (opening the duodenum) was described. The routine use of duodenotomy in patients with non-familial gastrinoma increases the number of duodenal tumors found, and the immediate and long-term cure-rate. The increase in cure-rate appears to be secondary to increased detection of small, previously undetectable duodenal gastrinomas. Duodenotomy detects small tumors (<1 cm) in the proximal duodenum. It does not detect more duodenal gastrinomas per patient, nor does it detect tumors in unusual duodenal locations. Duodenotomy decreases the death-rate associated with these tumors. However, it has not affected the rate of development of liver metastases. Duodenotomy is a critical method to find duodenal gastrinomas. It should be routinely performed in all surgery to find and remove gastrinoma for cure of ZES.

  View details for DOI 10.1016/j.bpg.2005.05.001

  View details for PubMedID 16253894

• Computed tomography, endoscopic, laparoscopic, and intra-operative sonography for assessing resectability of pancreatic cancer SURGICAL ONCOLOGY-OXFORD Long, E. E., Van Dam, J., Weinstein, S., Jeffrey, B., Desser, T., Norton, J. A. 2005; 14 (2): 105-113

  Abstract

  Pancreas cancer is the fourth leading cancer killer in adults. Cure of pancreas cancer is dependent on the complete surgical removal of localized tumor. A complete surgical resection is dependent on accurate preoperative and intra-operative imaging of tumor and its relationship to vital structures. Imaging of pancreatic tumors preoperatively and intra-operatively is achieved by pancreatic protocol computed tomography (CT), endoscopic ultrasound (EUS), laparoscopic ultrasound (LUS), and intra-operative ultrasound (IOUS). Multi-detector CT with three-dimensional (3-D) reconstruction of images is the most useful preoperative modality to assess resectability. It has a sensitivity and specificity of 90 and 99%, respectively. It is not observer dependent. The images predict operative findings. EUS and LUS have sensitivities of 77 and 78%, respectively. They both have a very high specificity. Further, EUS has the ability to biopsy tumor and obtain a definitive tissue diagnosis. IOUS is a very sensitive (93%) method to assess tumor resectability during surgery. It adds little time and no morbidity to the operation. It greatly facilitates the intra-operative decision-making. In reality, each of these methods adds some information to help in determining the extent of tumor and the surgeon's ability to remove it. We rely on pancreatic protocol CT with 3-D reconstruction and either EUS or IOUS depending on the tumor location and operability of the tumor and patient. With these modern imaging modalities, it is now possible to avoid major operations that only determine an inoperable tumor. With proper preoperative selection, surgery is able to remove tumor in the majority of patients.

  View details for DOI 10.1016/j.suronc.2005.07.001

  View details for PubMedID 16125619

• Characterization of a recurrent germ line mutation of the E-cadherin gene: Implications for genetic testing and clinical management CLINICAL CANCER RESEARCH Suriano, G., Yew, S., Ferreira, P., Senz, J., Kaurah, P., Ford, J. M., Longacre, T. A., NORTON, J. A., Chun, N., Young, S., Oliveira, M. J., MacGillivray, B., Rao, A., Sears, D., Jackson, C. E., Boyd, J., Yee, C., Deters, C., Pai, G. S., Hammond, L. S., McGivern, B. J., Medgyesy, D., Sartz, D., Arun, B., Oelschlager, B. K., Upton, M. P., Neufeld-Kaiser, W., Silva, O. E., Donenberg, T. R., Kooby, D. A., Sharma, S., Jonsson, B. A., Gronberg, H., Gallinger, S., Seruca, R., Lynch, H., Huntsman, D. G. 2005; 11 (15): 5401-5409

  Abstract

  To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals.We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing.We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers.In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

  View details for Web of Science ID 000230878900012

  View details for PubMedID 16061854

• Endocrine tumours of the gastrointestinal tract. Surgical treatment of neuroendocrine metastases. Best practice & research. Clinical gastroenterology Norton, J. A. 2005; 19 (4): 577-583

  Abstract

  Neuroendocrine tumors of the intestinal tract have low malignant potential but can result in decreased survival if they spread to the liver. The estimated 5-year survival of patients with liver metastases from neuroendocrine tumor is only 20%. Further, morbidity related to the Carcinoid Syndrome and other endocrine symptoms may also greatly reduce the quality of life. Treatment options for liver neuroendocrine tumor include long-acting somatostatin receptor antagonists (LAR), inteferon-alpha, chemotherapy and hepatic artery embolisation with and without chemotherapy. Surgical resection is feasible in select patients, but it may result in major morbidity and even mortality. In our series of 18 patients with liver neuroendocrine tumors, there was no operative mortality and acceptable morbidity. All 10 patients with the Carcinoid syndrome had complete amelioration of symptoms and the 5-year actuarial survival was 80%. Aggressive major surgery for liver neuroendocrine tumor metastases can be performed safely with acceptable mortality by experienced surgeons. Results have been similar for patients with gastrinoma and pancreatic neuroendocrine tumors. Surgical resection appears to result in outstanding long-term survival and amelioration of symptoms. It should be the first-line therapy for patients with liver neuroendocrine tumors in whom the tumor can be completely removed.

  View details for PubMedID 16183528

• A national comparison of surgical versus percutaneous drainage of pancreatic pseudocysts: 1997-2001 38th Annual Meeting of the Pancreas-Club Morton, J. M., Brown, A., Galanko, J. A., NORTON, J. A., Grimm, I. S., Behrns, K. E. SPRINGER. 2005: 15–20

  Abstract

  Case series results indicate that a surgical approach is superior to percutaneous drainage of pancreatic pseudocysts. To determine if this surgical advantage is persistent, national outcomes for both approaches were compared from 1997 through 2001. The National Inpatient Sample, a 20% sample of all nonfederal hospital discharges, was searched for patients who had a pancreatic pseudocyst diagnosis, an ICD-9 diagnosis code 577.2, and an ICD-9 procedure code of 52.01 for percutaneous drainage (PD) or 52.4 and 52.96 for the surgical approaches. Variables were compared by using either t test or chi2 analysis. Confounding variables were controlled for by linear or logistic regression models. No clinically significant demographic, comorbidity, and disease-specific severity-of-illness differences existed between the two groups. Significant differences in complications, length of stay (15+/-15 versus 21+/-22 days, P<0.0001), and inpatient mortality (5.9% versus 2.8%, P<0.0001) favored the surgical approach. In addition, endoscopic retrograde cholangiopancreatography use had a protective effect on mortality (odds ratio, 0.7), whereas percutaneous drainage had an increased risk of mortality (odds ratio, 1.4). This population-based study suggests that surgical drainage of pancreatic pseudocysts, particularly when coupled with use of endoscopic retrograde cholangiopancreatography, leads to decreased complications, length of stay, and mortality in comparison with percutaneous drainage.

  View details for DOI 10.1016/j.gassur.2004.10.005

  View details for Web of Science ID 000226973200005

  View details for PubMedID 15623440

• Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment 25th Annua Meeting of the American-Association-of-Endocrine-Surgeons NORTON, J. A., Melcher, M. L., Gibril, F., Jensen, R. T. MOSBY-ELSEVIER. 2004: 1267–73

  Abstract

  Gastric carcinoid tumors occur in 15% to 50% of patients with multiple endocrine neoplasia-1/Zollinger-Ellison syndrome (MEN-1/ZES) but are thought to be benign. We report 5 patients with MEN-1/ZES with symptomatic, aggressive gastric carcinoid tumors that required surgical procedures.This was a retrospective chart review.Each patient had MEN-1/ZES. Each patient had innumerable gastric carcinoid tumors with symptoms. The fasting gastrin level was 47,000 pg/mL (normal, <200 pg/mL); the basal acid output was 79 mEq/hr (n = 3), and the age at surgical exploration was 47 +/- 6 years, with a duration of MEN-1 of 21 +/- 3 years and of ZES of 15 +/- 2 years. All patients had elevated 5-HIAA or serotonin levels. Somatostatin receptor scintigraphy showed increased stomach uptake in 4 patients (80%). Four patients had a total gastrectomy; 4 patients had lymph node metastases removed, and 3 patients had liver metastases resected. One patient who did not have a total gastrectomy had liver carcinoid metastases.These results demonstrate that gastric carcinoid tumors in patients with longstanding MEN-1/ZES may be symptomatic, aggressive, and metastasize to the liver. With increased long-term medical treatment and life expectancy, these tumors will become an important determinant of survival.

  View details for DOI 10.1016/j.surg.2004.06.057

  View details for PubMedID 15657586

• Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome ANNALS OF SURGERY Norton, J. A., Jensen, R. T. 2004; 240 (5): 757-773

  Abstract

  Highlight unresolved controversies in the management of Zollinger-Ellison syndrome (ZES).Recent studies have resolved some of the previous controversies including the surgical cure rate in patients with and without Multiple Endocrine Neoplasia-type1 (MEN1), the biological behavior of duodenal and pancreatic gastrinomas, role of imaging studies to localize tumor, and gastrectomy to manage acid output.Review of the literature based on computer searches in Index Medicus, Pubmed and Ovid.Current controversies as identified in the literature include the role of endoscopic ultrasound (EUS), surgery in ZES patients with MEN1, pancreaticoduodenectomy (Whipple procedure), lymph node primary gastrinoma, parietal cell vagotomy, reoperation and surgery for metastatic tumor, and the use of minimally invasive surgical techniques to localize and remove gastrinoma.It is hoped that future studies will focus on these issues to improve the surgical management of ZES patients.

  View details for DOI 10.1097/01.sla.0000143252.02142.3e

  View details for PubMedID 15492556

• Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? 115th Annual Session of the Southern-Surgical-Association Norton, J. A., Alexander, H. R., FRAKER, D. L., VENZON, D. J., Gibril, F., Jensen, R. T. LIPPINCOTT WILLIAMS & WILKINS. 2004: 617–25

  Abstract

  To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1.DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987.All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies).A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX.These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.

  View details for DOI 10.1097/01.sla.0000124290.05524.5e

  View details for PubMedID 15082965

• Antitumor immunity induced by dendritic cell-based vaccination is dependent on interferon-gamma and interleukin-12 JOURNAL OF SURGICAL RESEARCH Hiramoto, J. S., Tsung, K., Bedolli, M., NORTON, J. A., Hirose, R. 2004; 116 (1): 64-69

  Abstract

  This study was conducted to determine whether dendritic cells (DCs) pulsed with a tumor cell lysate can effectively vaccinate against tumor cells and to establish which cytokines are necessary.Each wild-type mouse received two subcutaneous immunizations (days 14 and 7) with either saline, tumor lysate, DCs, or tumor-lysate-pulsed DCs. Gamma-interferon (gamma-IFN), knock-out (KO), and interleukin-12 (IL-12) KO mice were also used in immunizations. A tumor challenge was given at day 0. Splenocytes were assayed for gamma-IFN production.All saline-injected mice (n = 19) and all mice injected with tumor lysate (n = 9) developed tumors. Six of nine mice immunized with DCs alone and 6/24 mice treated with lysate-pulsed DCs developed a tumor. Splenocytes from both the saline- and lysate-immunized groups produced undetectable levels of gamma-IFN, while those from mice immunized with either DCs or pulsed DCs produced high levels of gamma-IFN. Four of five gamma-IFN KO mice developed tumors after immunization with tumor-lysate-pulsed DCs. None of four IL-12 KO mice developed a tumor after immunization with wild-type pulsed DCs and 1/10 wild-type mice developed tumor after immunization with IL-12 KO pulsed DCs. Three of four IL-12 KO mice developed tumors after immunization with IL-12 KO pulsed DCs.Tumor-lysate-pulsed DCs can initiate an effective antitumor immune response. The presence of gamma-IFN in the host is essential for antitumor protection. In contrast, tumor protection is observed if IL-12 is present in either the host or the DCs.

  View details for DOI 10.1016/j.jss.2003.09.006

  View details for Web of Science ID 000188368900009

  View details for PubMedID 14732350

• Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1 24th Annual Meeting of the American-Association-of-Endocrine-Surgeons Elaraj, D. M., SKARULIS, M. C., Libutti, S. K., NORTON, J. A., Bartlett, D. L., Pingpank, J. F., Gibril, F., Weinstein, L. S., Jensen, R. T., Marx, S. J., Alexander, H. R. MOSBY-ELSEVIER. 2003: 858–64

  Abstract

  Hyperparathyroidism in patients with multiple endocrine neoplasia type 1 (MEN1) is characterized by multiglandular disease and a propensity for recurrence after parathyroidectomy (PTx). This study analyzes outcomes of a cohort of MEN1 patients undergoing initial PTx at one institution.Between April 1960 and September 2002, 92 patients with MEN1 underwent initial PTx. Outcomes were analyzed based on extent of parathyroid resection.Fourteen percent had 2.5 or fewer glands resected, 69% had subtotal PTx, and 17% had total PTx (88% with immediate autotransplantation). The initial surgical cure rate was 98%. Excluding 6 patients lost to follow-up, 33% have developed recurrent hyperparathyroidism (in 46% after < or =2.5 PTx, in 33% after subtotal, and in 23% after total PTx). Median recurrence-free survival was not statistically significantly different between subtotal versus total PTx, but it was longer for subtotal and total PTx compared with lesser resection (16.5 vs 7.0 years, respectively, P=.03). The incidence of severe hypoparathyroidism was 46% after total versus 26% after subtotal PTx.Subtotal and total PTx result in durable control of MEN1-associated hyperparathyroidism and have longer recurrence-free intervals compared with lesser resection. The high incidence of severe hypoparathyroidism after total PTx suggests that subtotal PTx is the initial operation of choice in this setting.

  View details for DOI 10.1016/S0039-6060(03)00406-9

  View details for Web of Science ID 000187389100002

  View details for PubMedID 14668715

• Aggressive surgery for metastatic liver neuroendocrine tumors 24th Annual Meeting of the American-Association-of-Endocrine-Surgeons NORTON, J. A., Warren, R. S., Kelly, M. G., Zuraek, M. B., Jensen, R. T. MOSBY-ELSEVIER. 2003: 1057–63

  Abstract

  Neuroendocrine tumors of the gastrointestinal tract (carcinoids, pancreatic endocrine tumors) have low malignant potential but can decrease survival rates if they spread to the liver (LNET).The records of 16 patients with LNET primarily from gastrointestinal carcinoids treated surgically were retrospectively reviewed.There were 12 women and 4 men. Median age was 56 years (range 25 to 75). Thirteen (81%) had a carcinoid tumor and 5 had gastrinoma. Two patients with multiple endocrine neoplasia type 1 had both a gastric carcinoid and a jejunal gastrinoma. Eight patients (50%) had the carcinoid syndrome. Each patient had all identifiable LNET either resected or ablated. Ten patients had liver wedge resections, 1 right trisegmentectomy, 5 left hepatic lobectomies, and 2 radiofrequency ablations. Thirteen (81%) patients had concomitant bowel resections. Two patients had concomitant total gastrectomies to remove stomach primaries. The final patient had an extraintestinal pelvic primary or a liver primary. There were no operative deaths, and all 8 (100%) patients with the carcinoid syndrome had amelioration of symptoms. The 5-year actuarial survival rate was 82% with a median follow-up of 32 months.This study demonstrates that liver and concomitant extrahepatic surgery can be performed safely in patients with liver metastases because of carcinoids or pancreatic endocrine tumors. It results in excellent long-term survival and amelioration of symptoms. Surgery should be the first-line therapy for patients with LNET.

  View details for DOI 10.1016/S0039-6060(03)00496-3

  View details for Web of Science ID 000187389100052

  View details for PubMedID 14668741

• Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1) SURGICAL ONCOLOGY-OXFORD NORTON, J. A., Jensen, R. T. 2003; 12 (2): 145-151

  Abstract

  The role of surgery in the management of patients with sporadic (not part of multiple endocrine neoplasia type 1) Zollinger-Ellison syndrome (ZES) is controversial. In this setting, 60-90% of gastrinomas are malignant and medical therapy can control the gastric acid hypersecretion in virtually every patient. Therefore, the progression of tumor is the major determinant of survival. Surgery will cure approximately one-third of patients with sporadic ZES. It will decrease the development of liver metastases and may improve survival. Somatostatin receptor scintigraphy is the best preoperative localization study. Its results are as good as all other imaging studies combined. Operative techniques should always include duodenotomy (opening the duodenum) and meticulous dissection of lymph nodes in the gastrinoma triangle, because duodenal primary tumors are often missed and lymph node primary tumors or metastases are common. Postoperative evaluation should include secretin test because it is the most sensitive method to document cure and detect tumor recurrence.

  View details for DOI 10.1016/S0960-7404(03)00035-5

  View details for Web of Science ID 000185260800008

  View details for PubMedID 12946485

• Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors 74th Annual Meeting of the Pacific-Coast-Surgical-Association Norton, J. A., Kivlen, M., Li, M., Schneider, D., Chuter, T., Jensen, R. T. AMER MEDICAL ASSOC. 2003: 859–65

  Abstract

  There is considerable controversy about the treatment of patients with malignant advanced neuroendocrine tumors of the pancreas and duodenum. Aggressive surgery remains a potentially efficacious antitumor therapy but is rarely performed because of its possible morbidity and mortality.Aggressive resection of advanced neuroendocrine tumors can be performed with acceptable morbidity and mortality rates and may lead to extended survival.The medical records of patients with advanced neuroendocrine tumors who underwent surgery between 1997 and 2002 by a single surgeon at the University of California, San Francisco, were reviewed in an institutional review board-approved protocol.Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates were recorded. Disease-free survival was defined as no tumor identified on radiological imaging studies and no detectable abnormal hormone levels. Proportions were compared statistically using the Fisher exact test. Kaplan-Meier curves were used to estimate survival rates.Twenty patients were identified (11 men and 9 women). Of these, 10 (50%) had gastrinoma, 1 had insulinoma, and the remainder had nonfunctional tumors; 2 had multiple endocrine neoplasia type 1, and 1 had von Hippel-Lindau disease. The mean age was 55 years (range, 34-72 years). In 10 patients (50%), tumors were thought to be unresectable according to radiological imaging studies because of multiple bilobar liver metastases (n = 6), superior mesenteric vein invasion (n = 3), and extensive nodal metastases (n = 1). Tumors were completely removed in 15 patients (75%). Surgical procedures included 8 proximal pancreatectomies (pancreatoduodenectomy or whipple procedure), 3 total pancreatectomies, 9 distal pancreatectomies, and 3 tumor enucleations from the pancreatic head. Superior mesenteric vein reconstruction was done in 3 patients. Liver resections were done in 6 patients, and an extended periaortic node dissection was performed in 1. The spleen was removed in 11 patients, and the left kidney was removed as a result of tumor metastases in 2. Eighteen patients had primary pancreatic tumors, and 2 had duodenal tumors; 2 patients with multiple endocrine neoplasia type 1 had both pancreatic and duodenal tumors. The mean tumor size was 8 cm (range, 0.5-23 cm). Of the patients, 14 (70%) had lymph node metastases and 8 (40%) had liver metastases. The mean postoperative hospital stay was 11.5 days (range, 6-26 days). Six patients (30%) had postoperative complications. There was a significantly greater incidence of pancreatic fistulas with enucleations compared with resections (P =.04). There were no operative deaths. The mean follow-up period was 19 months (range, 1-96 months); 18 patients (90%) are alive, 2 died of progressive tumor, and 12 (60%) are disease-free. The actuarial overall survival rate is 80% at 5 years, and disease-free survival rates indicate that all tumors will recur by the 7-year follow-up visit.Aggressive surgery including pancreatectomy, splenectomy, superior mesenteric vein reconstruction, and liver resection can be done with acceptable morbidity and low mortality rates for patients with advanced neuroendocrine tumors. Although survival rates following surgery are excellent, most patients will develop a recurrent tumor. These findings suggest that conventional contraindications to surgical resection, such as superior mesenteric vein invasion and nodal or distant metastases, should be reconsidered in patients with advanced neuroendocrine tumors.

  View details for Web of Science ID 000184618800011

  View details for PubMedID 12912744

• High-dose I-131-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma CANCER Rose, B., Matthay, K. K., Price, D., Huberty, J., Klencke, B., NORTON, J. A., Fitzgerald, P. A. 2003; 98 (2): 239-248

  Abstract

  131I-Metaiodobenzylguanidine (131I-MIBG) can be used systemically to treat malignant pheochromocytoma. To improve outcome, the authors used higher levels of activity of 131I-MIBG than previously reported. The authors reported the response rates and toxicity levels in patients with malignant pheochromocytoma or paraganglioma who were treated with high-dose 131I-MIBG.Following debulking surgery and stem cell harvest, 12 patients with malignant pheochromocytoma or paraganglioma were treated with 131I-MIBG. Five had received previous external beam radiation and/or chemotherapy. The median single treatment dose was 800 mCi (37 gigabecquerels; range, 386-866 mCi) or 11.5 mCi/kg (range, 5.6-18.3 mCi/kg). The median cumulative dose was 1015 mCi (range, 386-1690 mCi).Three patients had a complete response, two of whom had soft tissue and skeletal metastases. Their median follow-up was 45 months (range, 23-101 months). Seven patients had a partial response (PR), with a median follow-up 43 months (range, 6-47 months). Two patients without a response died with progressive disease (PD) and 2 patients with an initial PR died of PD at 13 and 11 months, respectively. Grade 3 thrombocytopenia occurred after 79% (15 of 19) of treatments had been administered. Grade 3 and 4 neutropenia followed 53% (10 of 19) and 19% (4 of 19) of treatments, respectively. One patient required stem cell infusion, and one developed primary ovarian failure.The single and cumulative doses of 131I-MIBG were approximately 2-3.5 times higher than those used at other centers. Unlike previous reports, two patients with both skeletal and soft tissue metastases had a complete response. Hematologic toxicity was significant but tolerable. High-dose 131I-MIBG may lead to long-term survival in patients with malignant pheochromocytoma.

  View details for DOI 10.1002/cncr.11518

  View details for Web of Science ID 000183944300005

  View details for PubMedID 12872341

• Management and outcome of patients with sporadic gastrinoma arising in the duodenum ANNALS OF SURGERY Zogakis, T. G., Gibril, F., Libutti, S. K., NORTON, J. A., White, D. E., Jensen, R. T., Alexander, H. R. 2003; 238 (1): 42-48

  Abstract

  Primary duodenal gastrinomas are now recognized as a common etiology for patients with sporadic Zollinger Ellison Syndrome (ZES); however, the clinical and pathologic features of this condition and long-term outcome after operation are not well characterized.Between November 1982 and September 2000, 63 patients diagnosed with sporadic ZES underwent resection of a primary duodenal gastrinoma and regional nodal metastases with curative intent. Data from a prospectively maintained database were reviewed for clinical and pathologic parameters relating to primary tumor size, location, frequency of lymph node metastases, and disease-specific and disease-free survival.There were 41 males and 22 females (mean age, 48.6 years). The majority of duodenal gastrinomas were in the first or second portions of the duodenum (83%). Tumor size ranged from 0.2 to 2.0 cm with 62% measuring less than 1.0 cm. Sixty percent of individuals had regional lymph node metastases identified primarily in proximity to the primary tumor. At a median 10-year follow-up, the overall disease-specific and disease-free survivals were 100% and 60%, respectively. Actuarial 10-year disease-free survival was significantly higher for patients without lymph node metastases versus those with lymph node metastases (78% versus 48%, P = 0.0137).Duodenal gastrinomas in patients with sporadic ZES are frequently small, most commonly located in the proximal duodenum, and associated with regional lymph node metastases in 60%. Disease-free survival is lower for patients with regional lymph node metastases suggesting that a more systematic lymphadenectomy to extirpate occult disease may be indicated in this group.

  View details for DOI 10.1097/01.SLA.0000074963.87688.31

  View details for Web of Science ID 000185834900006

  View details for PubMedID 12832964

• Evidence-based analysis: postoperative gastric bleeding: etiology and prevention SURGICAL ONCOLOGY-OXFORD Hiramoto, J. S., Terdiman, J. P., NORTON, J. A. 2003; 12 (1): 9-19

  Abstract

  Although the incidence of stomach hemorrhage is declining, stress-related gastric bleeding remains an important source of morbidity and mortality in cancer patients undergoing major surgical procedures to remove tumor. Prevention of stress-related bleeding is desirable; however, the optimal use of drugs to prevent gastric bleeding is unclear. Prophylaxis is recommended for surgical patients who require prolonged mechanical ventilation or have a coaguloathy. Histamine-2 receptor antagonists and sucralfate will reduce the likelihood of clinically important gastric-bleeding. Sucralfate appears to be less effective than H-2 blockers, but it is associated with fewer side effects such as nosocomial pneumonia. Preliminary studies show that proton pump inhibitors are most effective, have few side effects, but are most expensive. Intravenous proton pump inhibitors may be the drugs of choice for stress ulcer prophylaxis (SUP) in high-risk patients.

  View details for DOI 10.1016/S0960-7404(02)00073-7

  View details for Web of Science ID 000182503800002

  View details for PubMedID 12689666

• Cure of an established nonimmunogenic tumor, SCCVII with a novel interleukin 12-based immunotherapy regimen in C3H mice Annual Meeting of the American-Head-and-Neck-Society Mandpe, A. H., Tsung, K., NORTON, J. A. AMER MEDICAL ASSOC. 2003: 786–92

  Abstract

  To develop a murine model of effective treatment with immunotherapy for established head and neck squamous cell carcinoma.Prospective animal study. Subjects Female C3H mice, 8 to 12 weeks old.A subcutaneous inoculation of 2 x 10(5) SCC VII cells in C3H mice was established for 7 to 12 days. Tests for concomitant immunity were performed, with and without interleukin 12 modification. Tumors were also tested for responsiveness to interleukin 12 (5 mice) and to cyclophosphamide followed by interleukin 12 (5 mice). SCC VII tumors in 24 mice were treated with interleukin 12 followed by cyclophosphamide and interleukin 12. Five mice with tumors treated with isotonic sodium chloride solution served as controls. Tumors were measured 3 to 4 times weekly, and cure was defined as complete regression of the tumor for at least 60 days. Cured mice were rechallenged with 2 x 10(5) SCC VII cells to verify antitumor immunity. Immunohistochemistry of regressing tumors was performed for CD4+ and CD8+ T cells.Tumor-bearing mice easily developed second tumors when challenged with 2 x 10(5) tumor cells in the opposite flank. However, interleukin 12 treatment provided immunity to second tumors in 8 (100%) of 8 mice when started at day 4 and in 2 (40%) of 5 when treated from day 7. SCC VII did not respond to standard interleukin 12 or cyclophosphamide plus interleukin 12 therapy. Seventy-five percent of animals (18/24) treated with interleukin 12 followed by cyclophosphamide plus interleukin 12 were successfully cured, and all cured mice resisted subsequent challenge with SCC VII. Immunohistochemistry of regressed tumors showed an intense CD4+ and CD8+ infiltrate that was absent in the untreated and nonresponding tumors.Nonimmunogenic SCC VII is a nonimmunogenic tumor that can be converted into an immunogenic tumor with interleukin 12 treatment. Additional treatment with cyclophosphamide plus interleukin 12 leads to complete regression in 75% of mice.

  View details for Web of Science ID 000184104400018

  View details for PubMedID 12874083

• Possible primary lymph node gastrinoma: Occurrence, natural history, and predictive factors a prospective study 114th Annual Meeting of the Southern-Surgical-Association Norton, J. A., Alexander, H. R., FRAKER, D. L., VENZON, D. J., Gibril, F., Jensen, R. T. LIPPINCOTT WILLIAMS & WILKINS. 2003: 650–57

  Abstract

  To analyze the results of a prospective study of 176 patients with Zollinger-Ellison syndrome (ZES) (138 sporadic, 38 MEN1) undergoing 207 operations over a 17-year period.The existence of lymph node (LN) primary gastrinoma causing ZES is controversial.Three groups of patients were compared: LN only resected, cured, and no relapse (likely LN primary); same criteria but relapse (unlikely LN primary); and duodenal primary and LN metastases (Duo-LN).Forty-five (26%) had only LN(s) as the initial tumor found. Twenty-six of the 45 (58%) fit the definition of a likely LN primary because they were apparently cured postresection. At 10.4 +/- 1.2 years, 69% of the 26 patients with likely LN primary tumors have remained cured and have LN primaries. In the 8 of 26 with recurrent ZES, it occurred at 5 +/- 1 years, and 3 had duodenal gastrinoma that had been missed. Ten percent (13/138) of all patients with sporadic ZES and 0% (0/38) with ZES and MEN1 remained cured with only a LN tumor removed. In patients with sporadic gastrinomas no clinical, laboratory, or radiographic localization feature differed among patients with likely LN primary (n = 16) and those with unlikely LN primary (n = 6) or those with Duo-LN (n = 37). In the likely LN primary group, the largest LN was 2.2 +/- 0.2 cm, the number of LNs removed was 1.3 +/- 0.1 (25% > or =1 LN), and 78% were in the gastrinoma triangle, which also did not differ from the other 2 groups. Disease-free survival was similar in the likely LN primary group, patients with Duo-LN, and those with pancreatic primaries.These results support the conclusion that primary LN gastrinomas occur and are not rare (approximately 10% of sporadic cases). These results suggest that a proportion (25%) of these tumors are either multiple or malignant. Because no clinical, laboratory, or tumoral characteristic distinguishes patients with LN primary tumors, all patients with ZES undergoing surgery should have an extensive exploration to exclude duodenal or pancreatic tumors and routine removal of lymph nodes in the gastrinoma triangle.

  View details for Web of Science ID 000185834700012

  View details for PubMedID 12724631

• Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection CANCER RESEARCH Tsung, K., Dolan, J. P., Tsung, Y. L., NORTON, J. A. 2002; 62 (17): 5069-5075

  Abstract

  Interleukin (IL)-12 activates a T-cell-dependent antitumor immune response that is able to eradicate established large tumors in a number of immunogenic tumor models. The effector mechanisms in these dramatic antitumor responses have not yet been identified. In this report, we show that the effector mechanism of IL-12-induced rejection of established MCA207 tumors is unique in that it is not dependent on perforin, Fas/Fas ligand, and nitric oxide. Study of cyclophosphamide plus IL-12 (Cy + IL-12)-induced rejection of ascites Sa1 tumor demonstrates that macrophages are the predominant immune cell infiltration in the ascites. These macrophages possess nonspecific tumoricidal activity in vivo as immune distinct MCA207 tumor cells inoculated i.p., but not s.c., in mice bearing regressing Sa1 ascites tumors after Cy + IL-12 therapy are rejected. Furthermore, Cy + IL-12-treated Sa1 ascites cells or macrophages, but not spleen macrophages from the same mouse or inflammatory macrophages induced by thioglycollate, are able to suppress the development of immune-irrelevant s.c. tumors in a Winn assay. These macrophages kill various tumor cells in a contact-dependent manner in vitro, and the cytotoxicity is preserved after fixation with paraformaldehyde. These results demonstrate that activated macrophages function as effector cells in an IL-12-induced, T-cell-dependent eradication of established tumors through a novel contact-dependent, paraformaldehyde fixation-resistant, apoptosis-inducing mechanism.

  View details for Web of Science ID 000177897200036

  View details for PubMedID 12208763

• The role of IFN-gamma in rejection of established tumors by IL-12: Source of production and target CANCER RESEARCH Segal, J. G., Lee, N. C., Tsung, Y. L., NORTON, J. A., Tsung, K. 2002; 62 (16): 4696-4703

  Abstract

  We have demonstrated previously that established small and large murine MCA207 sarcomas can be completely eradicated by treatment with interleukin (IL) 12 alone and cyclophosphamide plus IL-12 (Cy+IL-12), respectively. The antitumor effect of IL-12/Cy+IL-12 has been found to be dependent on IFN-gamma and T cells. The role of IFN-gamma in IL-12-induced tumor rejection is unclear, because after IL-12 administration IFN-gamma is produced by multiple cell types, and it acts on most cell types because of the ubiquitous expression of its receptor. Using a T-cell-adoptive transfer model, we show that after IL-12 treatment, tumor-specific T-cell production of IFN-gamma is necessary and sufficient for rejection of established tumors. Furthermore, by testing tumors using IFN-gamma-unresponsive tumor cells, we show that tumor cell expression of MHC class I molecules in vivo is abrogated by blocking the response to IFN-gamma. However, tumor response to IFN-gamma is not essential for rejection of established small and large tumors by IL-12 and Cy+IL-12, respectively; neither is it essential for expression of tumor immunogenicity. Our results indicate that the rejection of established tumors by IL-12/Cy+IL-12 is dependent on the induction of a Th1 response producing IFN-gamma that acts on host cells.

  View details for Web of Science ID 000177496600029

  View details for PubMedID 12183428

• Multiple-gland disease in primary hyperparathyroidism - A function of operative approach? 73rd Annual Meeting of the Pacific-Coast-Surgical-Association Lee, N. C., Norton, J. A. AMER MEDICAL ASSOC. 2002: 896–99

  Abstract

  The approach to surgery for primary hyperparathyroidism (PHPT) is controversial. To determine whether routine bilateral neck exploration increases the detection of multiple-gland disease compared with a focused unilateral approach, we compared the incidence of single vs multiple-gland disease in patients undergoing surgical treatment for PHPT as a function of unilateral or bilateral exploration.From 1993 through 1997, 214 consecutive patients underwent initial bilateral neck exploration for PHPT by a single surgeon. Each patient underwent the surgical procedure without prior localizing studies. Four parathyroid glands were identified, and abnormal glands were excised. The results were compared with published studies of patients who underwent either bilateral neck exploration or focused unilateral neck exploration for PHPT.All reported studies from 1995 through 2001 in a MEDLINE search using the terms "parathyroidectomy" or "primary hyperparathyroidism and surgery" and either "bilateral" or "conventional" or "minimally invasive," "selective," or "unilateral."The studies were analyzed for numbers of patients and a final diagnosis of either a single adenoma or multiple-gland disease (double adenoma or hyperplasia). Proportions were compared statistically with a chi(2) test.In our series of 214 patients who underwent bilateral neck exploration, 79.4% had a single adenoma, and 20.6% had multiple-gland disease. Of 2166 patients in 14 studies who underwent bilateral neck exploration, 79.7% had a single adenoma, and 19.3% had multiple-gland disease. Of 2095 patients in 31 studies with a focused unilateral approach, 92.5% had a single adenoma, whereas only 5.3% had multiple-gland disease. The incidence of multiple-gland disease was significantly lower among patients treated with a focused unilateral approach compared with a bilateral approach as used in our series and the literature (P<.001).The data suggest that a focused unilateral surgical approach for PHPT may underestimate the incidence of multiple-gland disease.

  View details for Web of Science ID 000177326900004

  View details for PubMedID 12146987

• Production of interferon-gamma by tumor-sensitized T cells is essential for interleukin-12-induced complete tumor eradication 63rd Annual Meeting of the Society-of-University-Surgeons Lee, N. C., Tsung, K., NORTON, J. A. MOSBY-ELSEVIER. 2002: 365–68

  Abstract

  Interferon-gamma (IFN-gamma) is essential for eradication of established large tumors by interleukin-12 (IL-12), but the critical source of IFN-gamma has not been defined. Adoptive transfer of T cells into T cell-deficient mice allows for evaluation of the role of T cells and T cell production of IFN-gamma in the antitumor immune response.Wild-type C57BL/6, IL-12 receptor-beta1 knockout (IL-12Rbeta1 KO), IFN-gamma knockout (IFN-gamma KO), and IFN-gamma receptor-alpha knockout (IFN-gammaRalpha KO) mice were immunized and used as donors for adoptive transfer. Transfer of either splenocytes or CD90(+) T cells was performed into recipient T cell receptor-beta knockout (TCRbeta KO) and IFN-gamma/TCRbeta double knockout mice bearing 14-day subcutaneous MCA207 tumors. Half of the mice were treated with IL-12, and cure rates were compared.Transfer of either 1/4 immunized spleen equivalent or 10(7) immunized T cells into both TCRbeta KO and IFN-gamma/TCRbeta KO mice resulted in 80% to 100% cure when given with IL-12. However, transfer of 10(7) immunized T cells from IFN-gamma KO mice into TCRbeta KO mice was ineffective with or without IL-12. T cell response to IL-12, but not IFN-gamma, was required for tumor regression.Production of IFN-gamma by IL-12-responsive tumor-sensitized T cells is both necessary and sufficient for complete tumor eradication induced by IL-12. T cells are the source, but not the target, of IFN-gamma during tumor regression.

  View details for DOI 10.1067/msy.2002.125352

  View details for Web of Science ID 000177851900037

  View details for PubMedID 12219036

• Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12 JOURNAL OF IMMUNOLOGY Le, H. N., Lee, N. C., Tsung, K., NORTON, J. A. 2001; 167 (12): 6765-6772

  Abstract

  The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10-20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

  View details for Web of Science ID 000172613400010

  View details for PubMedID 11739491

• Iatrogenic pheochromocytomatosis: A previously unreported result of laparoscopic adrenalectomy 22nd Annual Meeting of the American-Association-of-Endocrine-Surgeons Li, M. L., Fitzgerald, P. A., Price, D. C., NORTON, J. A. MOSBY-ELSEVIER. 2001: 1072–77

  Abstract

  Laparoscopic adrenalectomy is now regarded as the procedure of choice for treatment of small or benign adrenal tumors, including pheochromocytoma. However, long-term outcomes have not been critically assessed. We report here 3 cases of pheochromocytomatosis recurring 3 to 4 years after laparoscopic adrenalectomy. We postulate laparoscopic-induced seeding of tumor as the mechanism of recurrence.We retrospectively reviewed the cases of 3 patients with documented biochemical and radiolabeled metaiodobenzylguanidine evidence of recurrent pheochromocytoma after prior presumed curative laparoscopic adrenalectomy.Original pheochromocytomas were 5.5 to 6.5 cm in diameter. At the time of laparoscopic adrenalectomy, tumors were not believed to be malignant, based on clinical or histopathologic data. However, on 3- to 4-year follow-up, each patient developed symptoms, elevated urinary catecholamine levels, and metaiodobenzylguanidine imaging consistent with recurrence. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of the initial laparoscopic resection. The original operative notes suggested some possible method of local seeding: tumor fragmentation and spillage or excessive tumor manipulation.Pheochromocytoma recurrence may occur as a result of local spillage of tumor during laparoscopic adrenalectomy. The relative risk of recurrence between open and laparoscopic resection needs to be assessed. Long-term follow-up will continue to be important, regardless of operative approach.

  View details for DOI 10.1067/msy.2001.118373

  View details for Web of Science ID 000173015300052

  View details for PubMedID 11742341

• Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 22nd Annual Meeting of the American-Association-of-Endocrine-Surgeons Kivlen, M. H., Bartlett, D. L., Libutti, S. F., SKARULIS, M. C., Marx, S. J., Simonds, W. F., Weinstein, L. S., Jensen, R. T., McCart, J. A., Naik, A. M., Kranda, K. C., Brennan, M. F., NORTON, J. A., FRAKER, D. L., Alexander, H. R. MOSBY-ELSEVIER. 2001: 991–98

  Abstract

  Patients with multiple endocrine neoplasia type 1 and hyperparathyroidism often undergo multiple operations because of inadequate initial surgery, presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction. Management of this patient population is complex.From January 1975 to December 2000 we performed 94 reoperative parathyroidectomies consisting of 79 neck reexplorations, 12 autograft removals, and 3 median sternotomies in 75 patients. Data were gathered by retrospective chart review and follow-up telephone interviews.Excluding autograft excision, reoperative surgery was successful (normocalcemia longer than 6 months) in 91%; autograft removal was successful in only 58%. With a median follow-up of 59 months, 64% of patients are currently free from hypercalcemia, and this outcome was not influenced by the total number of glands resected. The median time to recurrent hypercalcemia was 125 months. Thirty patients received an autograft after reoperation. The complication rate for all reoperations was 12%, including permanent recurrent laryngeal nerve injury in 2 patients (2.1%).Reoperative parathyroidectomy in patients with multiple endocrine neoplasia type 1 was safe and successful in the majority of patients; however, recurrent hyperparathyroidism is likely to develop in most individuals beyond 10 years of follow-up. The total number of glands accounted for after reoperation is not associated with successful outcome.

  View details for DOI 10.1067/msy.2001.118379

  View details for Web of Science ID 000173015300026

  View details for PubMedID 11742328

• Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome 121st Annual Scietific Session of the American-Surgical-Association NORTON, J. A., Alexander, H. R., FRAKER, D. L., VENZON, D. J., Gibril, F., Jensen, R. T. LIPPINCOTT WILLIAMS & WILKINS. 2001: 495–505

  Abstract

  To determine the role of surgery in patients with Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN1) with either limited or advanced pancreatic endocrine tumors (PETs).The role of surgery in patients with MEN1 and ZES is controversial. There have been numerous previous studies of surgery in patients with PETs; however, there are no prospective studies on the results of surgery in patients with advanced disease.Eighty-one consecutive patients with MEN1 and ZES were assigned to one of four groups depending on the results of imaging studies. Group 1 (n = 17) (all PETs smaller than 2.5 cm) and group 3 (n = 8) (diffuse liver metastases) did not undergo surgery. All patients in group 2A (n = 17; single PET 2.5-6 cm [limited disease]) and group 2B (n = 31; two or more lesions, 2.5 cm in diameter or larger, or one lesion larger than 6 cm) underwent laparotomy. Tumors were preferably removed by simple enucleation, or if not feasible resection. Patients were reevaluated yearly.Pancreatic endocrine tumors were found in all patients at surgery, with groups 2A and 2B having 1.7 +/- 0.4 and 4.8 +/- 1 PETs, respectively. Further, 35% of the patients in group 2A and 88% of the patients in group 2B had multiple PETs, 53% and 84% had a pancreatic PET, 53% and 68% had a duodenal gastrinoma, 65% and 71% had lymph node metastases, and 0% and 12% had liver metastases. Of the patients in groups 2A and 2B, 24% and 58% had a distal pancreatectomy, 0% and 13% had a hepatic resection, 0% and 6% had a Whipple operation, and 53% and 68% had a duodenal resection. No patient was cured at 5 years. There were no deaths. The early complication rate, 29%, was similar for groups 2A and 2B. Mean follow-up from surgery was 6.9 +/- 0.8 years, and during follow-up liver metastases developed in 6% of the patients in groups 2A and 2B. Groups 1, 2A, and 2B had similar 15-year survival rates (89-100%); they were significantly better than the survival rate for group 3 (52%).Almost 40% of patients with MEN1 and ZES have advanced disease without diffuse distant metastases. Despite multiple primaries and a 70% incidence of lymph node metastases, tumor can be removed with no deaths and complication rates similar to those in patients with limited disease. Further, despite previous studies showing that patients with advanced disease have decreased survival rates, in this study the patients with advanced tumor who underwent surgical resection had the same survival as patients with limited disease and patients without identifiable tumor. This suggests that surgical resection should be performed in patients with MEN1 who have ZES and advanced localized PET.

  View details for Web of Science ID 000171502900016

  View details for PubMedID 11573043

• Intraoperative ultrasound and preoperative localization detects all occult insulinomas 72nd Annual Meeting of the Pacific-Coast-Surgical-Association Hiramoto, J. S., Feldstein, V. A., LaBerg, J. M., NORTON, J. A. AMER MEDICAL ASSOC. 2001: 1020–25

  Abstract

  Preoperative invasive localization procedures with intraoperative ultrasound (IOUS) can result in successful surgical treatment of occult insulinomas when noninvasive imaging study results are equivocal or negative.Prospective study.Tertiary care university hospital.Thirty-seven consecutive patients with a biochemical diagnosis of insulinoma without multiple endocrine neoplasia (MEN).All patients underwent portal venous sampling (PVS) (n = 22) or calcium angiogram (n = 15) followed by surgery with palpation and IOUS (n = 37).Portal venous sampling, calcium angiogram, palpation, and IOUS were compared for accurate localization of insulinoma.All patients were cured of hypoglycemia after surgery. Portal venous sampling correctly localized tumors in 17 (77%) of 22 patients. Calcium angiogram was correct in 13 (87%) of 15 patients. Palpation identified 24 (65%) of 37 tumors, and IOUS found 35 (95%) of 37 tumors. The 2 tumors missed by IOUS were located in the tail of the pancreas and were resected based on regional localization alone.Intraoperative ultrasound is the single best localization study, but it will miss some tumors that regional localization can identify. Combining both modalities allowed surgical cure of all insulinomas in our study. Therefore, we recommend both IOUS and regional localization for insulinoma when preoperative imaging studies are equivocal.

  View details for Web of Science ID 000170895600012

  View details for PubMedID 11529824

• Prognostic value of initial pasting serum gastrin levels in patients with Zollinger-Ellison syndrome JOURNAL OF CLINICAL ONCOLOGY Berger, A. C., Gibril, F., VENZON, D. J., DOPPMAN, J. L., NORTON, J. A., Bartlett, D. L., Libutti, S. K., Jensen, R. T., Alexander, H. R. 2001; 19 (12): 3051-3057

  Abstract

  To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival.A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG.In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30).The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

  View details for Web of Science ID 000169303900010

  View details for PubMedID 11408501

• A high-resolution radiation hybrid map of the human genome draft sequence SCIENCE Olivier, M., Aggarwal, A., Allen, J., Almendras, A. A., Bajorek, E. S., Beasley, E. M., Brady, S. D., Bushard, J. M., Bustos, V. I., Chu, A., Chung, T. R., de Witte, A., Denys, M. E., Dominguez, R., Fang, N. Y., Foster, B. D., Freudenberg, R. W., Hadley, D., Hamilton, L. R., Jeffrey, T. J., Kelly, L., Lazzeroni, L., Levy, M. R., Lewis, S. C., Liu, X., Lopez, F. J., Louie, B., Marquis, J. P., Martinez, R. A., Matsuura, M. K., Misherghi, N. S., NORTON, J. A., Olshen, A., Perkins, S. M., Perou, A. J., Piercy, C., Piercy, M., Qin, F., Reif, T., Sheppard, K., Shokoohi, V., Smick, G. A., Sun, W. L., Stewart, E. A., Tejeda, J. F., Tran, N. M., Trejo, T., Vo, N. T., Yan, S. C., Zierten, D. L., Zhao, S. Y., Sachidanandam, R., Trask, B. J., Myers, R. M., Cox, D. R. 2001; 291 (5507): 1298-?

  Abstract

  We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

  View details for Web of Science ID 000166993400040

  View details for PubMedID 11181994

• Recent advances in carcinoid pathogenesis, diagnosis and management SURGICAL ONCOLOGY-OXFORD Ganim, R. B., NORTON, J. A. 2000; 9 (4): 173-179

  Abstract

  Carcinoid tumors usually present as diagnostic dilemmas due to obscure or nonspecific symptomatology. Advances in molecular biology are allowing the investigation of molecular markers of aggressiveness, better serum tumor markers, as well as the molecular pathogenesis of carcinoid heart disease. Somatostatin receptor scintigraphy (SRS) and whole body positron emission tomography (PET) are providing much improved sensitivity in localization of both primary and metastatic tumors. Long acting depot somatostatin analogues are combining effectiveness and ease of use for medical management of carcinoid syndrome. An additional benefit may be tumor growth suppression.

  View details for Web of Science ID 000170073800002

  View details for PubMedID 11476988

• Multiple endocrine neoplasia type 2B - genetic basis and clinical expression SURGICAL ONCOLOGY-OXFORD Lee, N. C., Norton, J. A. 2000; 9 (3): 111-118

  Abstract

  Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.

  View details for Web of Science ID 000168912100003

  View details for PubMedID 11356339

• Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1 111th Annual Meeting of the Southern-Surgical-Association Lairmore, T. C., Chen, V. Y., DeBenedetti, M. K., Gillanders, W. E., NORTON, J. A., Doherty, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2000: 909–16

  Abstract

  To review the authors' 7-year experience with a surgical approach for pancreatic and duodenal neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN 1) designed to remove all gross tumor with limited complications, preserving pancreatic function.MEN 1 is an autosomal dominant familial neoplasia syndrome characterized by the development of NETs of the duodenum and pancreas. Some tumors are clinically insignificant or follow a benign course, although a subset pursues a malignant, lethal natural history; the risk of surgical management must be appropriate to the disease course.The clinical, biochemical, genetic, and pathologic data were retrospectively reviewed for 21 consecutive MEN 1 patients undergoing pancreatic resection for NETs between 1993 and 1999 at one institution. Age at operation, presenting symptoms, results of preoperative and intraoperative localization studies, major and minor complications, and pathology, including metastases, were analyzed.The surgical approach was selected based on the location and size of the tumors. Five patients required pancreaticoduodenectomy, 11 patients underwent non-Whipple pancreatic resections, and 5 underwent simple enucleation of benign NETs. The incidence of regional lymph node metastases was 33%.Major pancreatic procedures can be performed safely in most patients with MEN 1 and NETs. Because NETs are the most common MEN 1-related cause of death in the authors' kindreds, an aggressive surgical approach, including early intervention before malignant spread and major pancreatic resection where indicated, appears justified.

  View details for Web of Science ID 000087472500031

  View details for PubMedID 10816635

• Perspective on RET proto-oncogene and thyroid cancer CANCER JOURNAL Le, H. N., NORTON, J. A. 2000; 6 (2): 50-57

  Abstract

  Much is yet to be learned about cancer and its genetic basis. The discovery of the RET proto-oncogene and its role in tumorigenesis have improved our understanding of thyroid cancer. It is clear that RET is responsible for MEN 2A, MEN 2B, FMTC, and PTC. Although the physical and genetic map of the RET proto-oncogene has been elucidated, the precise mechanism of neoplastic transformation and how it affects phenotypic variability is not completely understood. From the precise mapping of RET arose a highly reliable method of DNA analysis for presymptomatic detection of disease allele carriers. The understanding of the role of the RET proto-oncogene in MEN syndromes has led to a new paradigm in surgical practice: the recommendation for surgery based solely on genetic testing.

  View details for Web of Science ID 000088676100002

  View details for PubMedID 11069217

• Results of heterotopic parathyroid autotransplantation: A 13-year experience 20th Annual Meeting of the American-Association-of-Endocrine Surgeons Feldman, A. L., Sharaf, R. N., SKARULIS, M. C., Bartlett, D. L., Libutti, S. K., Weinstein, L. S., Marx, S. J., NORTON, J. A., FRAKER, D. L., Alexander, H. R. MOSBY-ELSEVIER. 1999: 1042–48

  Abstract

  The reported success of heterotopic parathyroid autotransplantation (HPA) in patients with primary hyperparathyroidism varies from 20% to 60%. The purpose of this study was to evaluate our results with HPA to help define its role in this patient group.Between July 1985 and June 1998, 44 patients underwent 51 HPA procedures at our institution. Twenty to 25 fragments of parathyroid tissue measuring 1 to 3 mm3 each were placed into the forearm musculature. HPA results were scored as nonfunctional (requiring calcium and vitamin D), partially functional (normocalcemia on calcium alone), fully functional (normocalcemia without supplementation), or hyperfunctional (hypercalcemia without supplementation).Follow-up data were available for 39 patients who underwent 46 autografts (20 immediate and 26 cryopreserved). With a median follow-up of 35 months, 19 autografts (41%) were nonfunctional; 9 autografts (20%) were partially functional; 15 autografts (33%) were fully functional, and 3 autografts (7%) were hyperfunctional. Full function was observed in 35% of immediate and 31% of delayed autografts.One third of parathyroid autografts develop full function, and an additional one fifth develop partial function. Recurrent hyperparathyroidism is uncommon. No benefit was observed from immediate versus delayed HPA, and the modest success rate of HPA suggests that improvements in technique are warranted.

  View details for Web of Science ID 000084064500016

  View details for PubMedID 10598186

• Surgery to cure the Zollinger-Ellison syndrome NEW ENGLAND JOURNAL OF MEDICINE NORTON, J. A., FRAKER, D. L., Alexander, H. R., VENZON, D. J., DOPPMAN, J. L., Serrano, J., Goebel, S. U., Peghini, P. L., Roy, P. K., Gibril, F., Jensen, R. T. 1999; 341 (9): 635-644

  Abstract

  The role of surgery in patients with the Zollinger-Ellison syndrome is controversial. To determine the efficacy of surgery in patients with this syndrome, we followed 151 consecutive patients who underwent laparotomy between 1981 and 1998. Of these patients, 123 had sporadic gastrinomas and 28 had multiple endocrine neoplasia type 1 with an imaged tumor of at least 3 cm in diameter. Tumor-localization studies and functional localization studies were performed routinely. All patients underwent surgery according to a similar operative protocol, and all patients who had surgery after 1986 underwent duodenotomy.The 151 patients underwent 180 exploratory operations. The mean (+/-SD) follow-up after the first operation was 8+/-4 years. Gastrinomas were found in 141 of the patients (93 percent), including all of the last 81 patients to undergo surgery. The tumors were located in the duodenum in 74 patients (49 percent) and in the pancreas in 36 patients (24 percent); however, primary tumors were found in lymph nodes in 17 patients (11 percent) and in another location in 13 patients (9 percent). The primary location was unknown in 24 patients (16 percent). Among the patients with sporadic gastrinomas, 34 percent were free of disease at 10 years, as compared with none of the patients with multiple endocrine neoplasia type 1. The overall 10-year survival rate was 94 percent.All patients with the Zollinger-Ellison syndrome who do not have multiple endocrine neoplasia type 1 or metastatic disease should be offered surgical exploration for possible cure.

  View details for Web of Science ID 000082192500002

  View details for PubMedID 10460814

• Surgical resection of intracardiac gastrinoma ANNALS OF THORACIC SURGERY Noda, S., NORTON, J. A., Jensen, R. T., Gay, W. A. 1999; 67 (2): 532-533

  Abstract

  There has been only one previous report of an intracardiac gastrinoma causing Zollinger-Ellison syndrome. In this communication we describe the successful surgical resection of a gastrinoma located in the interventricular septum using cardiopulmonary bypass, blood cardioplegia, and mild hypothermia. Preoperative evaluation and histologic examination of the resected tumor strongly suggest that this was a primary intracardiac gastrinoma.

  View details for Web of Science ID 000079337700056

  View details for PubMedID 10197684

• Analysis of factors associated with longterm (five or more years) cure in patients undergoing operation for Zollinger-Ellison syndrome 19th Annual Meeting of the American-Association-of-Endocrine-Surgeons Alexander, H. R., Bartlett, D. L., VENZON, D. J., Libutti, S. K., DOPPMAN, J. L., FRAKER, D. L., NORTON, J. A., Gibril, F., Jensen, R. T. MOSBY-ELSEVIER. 1998: 1160–66

  Abstract

  Only 30% to 40% of patients with Zollinger-Ellison syndrome (ZES) undergoing operation with curative intent have biochemical cures. The purpose of this analysis was to identify perioperative factors associated with long-term (> or = 5 years) biochemical cures.From December 1981 to September 1997, 128 patients with potentially curable ZES underwent 152 abdominal explorations with resection of all identifiable disease. Of these, 31 outcomes were identified with documented cures at > or = 5 years from operation and were compared with outcomes of 110 patients who were not cured. Univariate and multivariate statistical analyses were performed.The results of a normal immediate postoperative fasting serum gastrin and secretin stimulation test were significantly and independently correlated with 5-year cure (P2 = .005 and .0099, respectively). A diagnosis of multiple endocrine neoplasia type 1 was significantly inversely correlated with cure on univariate analysis (P2 = .027). Gender, age, duration of symptoms, results of diagnostic tests, or results of imaging studies did not correlate with outcome.All patients with sporadic potentially curable ZES should undergo exploration because outcome is not associated with preoperative tests. Only 5% of patients with ZES and multiple endocrine neoplasia type 1 were cured at 5 years. A normal fasting serum gastrin or secretin stimulation value value immediately postoperatively provides important prognostic information.

  View details for Web of Science ID 000077388700060

  View details for PubMedID 9854598

• Prospective study of the utility of somatostatin-receptor scintigraphy in the evaluation of patients with multiple endocrine neoplasia type 1 19th Annual Meeting of the American-Association-of-Endocrine-Surgeons Yim, J. H., Siegel, B. A., DeBenedetti, M. K., NORTON, J. A., Lairmore, T. C., Doherty, G. M. MOSBY-ELSEVIER. 1998: 1037–42

  Abstract

  Neuroendocrine tumors (NETs) are a potentially lethal component of multiple endocrine neoplasia type 1 (MEN 1). Somatostatin receptor scintigraphy (SRS) can be used to localize NETs and evaluate patients for extraduodenopancreatic disease; its utility in managing MEN 1 is undefined.All patients with MEN 1 evaluated by SRS from April 1994 to November 1997 are reported. SRS findings were correlated with other imaging studies and operative findings.Thirty-seven SRS studies were performed in 29 patients with MEN 1. SRS identified occult tumor in 36% (4/11) of patients with only biochemical evidence of NET; 2 patients went on to resection. SRS showed tumor in 79% (15/19) of patients with computed tomography (CT)-demonstrated tumor; 30% (6/20) of the SRS lesions were occult on CT. Conversely, 55% (16/29) of CT-identified lesions were occult on SRS. SRS found distant disease in 21% (6/29) of patients. In patients who had previous operations, SRS found tumor in 40% (4/10) of patients, again with both new positive and false-negative results compared with other imaging. SRS also had 3 important false-positive results, including 1 patient who had laparotomy with no tumor identified.SRS is useful in identifying otherwise occult NETs in patients with MEN 1 and can substantially alter management. However, SRS also has significant false-positive and false-negative results that demand correlation with other studies.

  View details for Web of Science ID 000077388700024

  View details for PubMedID 9854580

• Operative management of islet-cell tumors arising in the head of the pancreas 19th Annual Meeting of the American-Association-of-Endocrine-Surgeons Park, B. J., Alexander, H. R., Libutti, S. K., Huang, J., Royalty, D., SKARULIS, M. C., Jensen, R. T., GORDEN, P., DOPPMAN, J. L., Shawker, T. H., FRAKER, D. L., NORTON, J. A., Bartlett, D. L. MOSBY-ELSEVIER. 1998: 1056–61

  Abstract

  Pancreatic islet cell tumors (ICTs) can be treated by enucleation or pancreatic resection. We reviewed our experience with ICTs in the head of the pancreas to define indications for enucleation versus pancreaticoduodenectomy.Between January 1982 and December 1997, 48 patients underwent surgical resection for presumed ICTs of the pancreatic head. Of these, 18 were found on pathologic examination to be disease in a lymph node. Thirty patients had 32 true pancreatic head ICTs. We reviewed the operative results and postoperative courses in these patients.Mean diameter of the ICTs was 15 mm. Twenty-seven patients (90%) underwent successful enucleations. Three patients failed enucleation and underwent pancreaticoduodenectomy. There was no operative mortality. The median time to regular diet was 7 days. The median time to removal of all drains was 22 days. The most common complication was pancreatic fistula (15%). No patient required reoperation for treatment of a fistula.Most ICTs of the pancreatic head can be removed with enucleation, preserving pancreatic tissue and avoiding the morbidity of pancreaticoduodenectomy. The primary indication for pancreaticoduodenectomy is not the size of the lesion but its proximity to the pancreatic duct.

  View details for Web of Science ID 000077388700029

  View details for PubMedID 9854583

• Surgical treatment of localized gastrinoma within the liver: A prospective study 19th Annual Meeting of the American-Association-of-Endocrine-Surgeons NORTON, J. A., Doherty, G. M., FRAKER, D. L., Alexander, R., DOPPMAN, J. L., VENZON, D. J., Gibril, F., Jensen, R. T. MOSBY-ELSEVIER. 1998: 1145–52

  Abstract

  Studies demonstrate that liver metastases of gastrinoma significantly reduce survival.Since 1982 we have prospectively studied 213 patients with Zollinger-Ellison syndrome. For this report the results of surgery for localized liver gastrinoma were analyzed.Zollinger-Ellison syndrome was diagnosed biochemically in all patients and acid output was controlled with medications. Imaging studies demonstrated liver gastrinoma in 69 patients (32%). Fifty-two had diffuse unresectable disease, whereas 17 (10%) had localized disease. All patients with localized liver gastrinoma and 2 patients with diffuse disease who needed surgery are the subject of this report. Major hepatic lobectomy was performed in 10 patients and wedge resections in 9. Three patients had apparent liver primary gastrinomas and 16 had metastatic disease. Seventeen of 19 patients were able to have all identifiable gastrinoma resected. Extrahepatic tumor was also removed at the same procedure. Extirpation of liver gastrinoma required hepatic lobectomy in 10 patients and wedge resections in the others. Five-year survival was 85%. Five of 17 completely resected patients (29%) remained disease free.Resectable localized liver gastrinoma is rare. Primary liver gastrinomas can occur. Surgical resection of localized liver gastrinoma provides a cure rate similar to that of extrahepatic gastrinoma and an excellent long-term survival.

  View details for Web of Science ID 000077388700056

  View details for PubMedID 9854596

• Therapeutic controversy - The role of laparoscopic surgery in adrenal disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Wells, S. A., Merke, D. P., Cutler, G. B., NORTON, J. A., Lacroix, A. 1998; 83 (9): 3041-3043

  View details for Web of Science ID 000075840700004

  View details for PubMedID 9745398

• Prospective study of somatostatin receptor scintigraphy and its effect on operative outcome in patients with Zolinger-Ellison syndrome ANNALS OF SURGERY Alexander, H. R., FRAKER, D. L., NORTON, J. A., Bartlett, D. L., Tio, L., Benjamin, S. B., DOPPMAN, J. L., Goebel, S. U., Serrano, J., Gibril, F., Jensen, R. T. 1998; 228 (2): 228-238

  Abstract

  To determine the relative abilities of somatostatin receptor scintigraphy (SRS) and conventional imaging studies (computed tomography, magnetic resonance imaging, ultrasound, angiography) to localize gastrinomas before surgery in patients with Zollinger-Ellison syndrome (ZES) subsequently found at surgery, and to determine the effect of SRS on the disease-free rate.Recent studies demonstrate that SRS is the most sensitive imaging modality for localizing neuroendocrine tumors such as gastrinomas. Because of conflicting results in small series, it is unclear in ZES whether SRS will alter the disease-free rate, which gastrinomas are not detected, what factors contribute to failure to detect a gastrinoma, or whether the SRS result should be used to determine operability in patients without hepatic metastases, as recently recommended by some investigators.Thirty-five consecutive patients with ZES undergoing 37 exploratory laparotomies for possible cure were prospectively studied. All had SRS and conventional imaging studies before surgery. Imaging results were determined by an independent investigator depending on surgical findings. All patients underwent an identical surgical protocol (palpation after an extensive Kocher maneuver, ultrasound during surgery, duodenal transillumination, and 3 cm duodenotomy) and postoperative assessment of disease status (fasting gastrin, secretin test imaging within 2 weeks, at 3 to 6 months, and yearly), as used in pre-SRS studies previously.Gastrinomas were detected in all patients at each surgery. Seventy-four gastrinomas were found: 22 duodenal, 8 pancreatic, 3 primaries in other sites, and 41 lymph node metastases. The relative detection order on a per-patient or per-lesion basis was SRS > angiography, magnetic resonance imaging, computed tomography > ultrasound. On a per-lesion basis, SRS had greater sensitivity than all conventional studies combined. SRS missed one third of all lesions found at surgery. SRS detected 30% of gastrinomas < or =1.1 cm, 64% of those 1.1 to 2 cm, and 96% of those >2 cm and missed primarily small duodenal tumors. Tumor size correlated closely with SRS rate of detection. SRS did not increase the disease-free rate immediately after surgery or at 2 years mean follow-up.SRS is the most sensitive preoperative imaging study for extrahepatic gastrinomas in patients with ZES and should replace conventional imaging studies as the preoperative study of choice. Negative results of SRS for localizing extrahepatic gastrinomas should not be used to decide operability, because a surgical procedure will detect 33% more gastrinomas than SRS. SRS does not increase the disease-free rate. In the future, more sensitive methods to detect small gastrinomas, especially in the duodenum and in periduodenal lymph nodes, or more extensive surgery will be needed to improve the postoperative disease-free rate in ZES.

  View details for Web of Science ID 000075297600013

  View details for PubMedID 9712569

• Vaccinia virus for human gene therapy. Surgical oncology clinics of North America Peplinski, G. R., Tsung, K., NORTON, J. A. 1998; 7 (3): 575-588

  Abstract

  Recombinant vaccinia virus may be an ideal viral vector for cancer gene therapy. It has a large genome that is able to be engineered for the insertion and simultaneous expression of multiple genes. It reliably infects a large variety of tumors and expresses high levels of the gene(s) of interest. Although naturally cytopathic, it can be engineered to be noncytopathic but still infectious. Recently, it has been used in preclinical trials of animals and patients with cancer.

  View details for PubMedID 9624218

• Lethality of multiple endocrine neoplasia type I International-Association-of-Endocrine-Surgeons International Surgical Week Doherty, G. M., Olson, J. A., Frisella, M. M., Lairmore, T. C., Wells, S. A., NORTON, J. A. SPRINGER. 1998: 581–87

  Abstract

  The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years, p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years, p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n = 12), ulcer disease (n = 6), hypercalcemia/uremia (n = 3), carcinoid tumor (n = 6), and nonendocrine malignancies (n = 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

  View details for Web of Science ID 000073528400013

  View details for PubMedID 9597932

• Immune response against large tumors eradicated by treatment with cyclophosphamide and IL-12 JOURNAL OF IMMUNOLOGY Tsung, K., Meko, J. B., Tsung, Y. L., Peplinski, G. R., NORTON, J. A. 1998; 160 (3): 1369-1377

  Abstract

  Previous studies have demonstrated eradication of small (4-8 mm) established murine MCA207 sarcomas by treatment with systemic IL-12. Analysis of the mechanism has revealed a cellular and molecular immune response at the tumor typical of a Th1 cell-mediated, macrophage-effected, delayed-type hypersensitivity (DTH) response. In the current study we investigate the immune response against long term established, large MCA207 tumors induced by combined treatment with IL-12 and cyclophosphamide (Cy), an agent known to potentiate the DTH response. Our results demonstrate that s.c. large MCA207 tumors (15-20 mm) that are refractory to treatment by either IL-12 or Cy alone can be completely eradicated by the combination of Cy and IL-12. IL-12 is apparently the only cytokine capable of mediating tumor eradication, and the effect is dependent on IFN-gamma. The contribution of Cy is probably due to immunopotentiation of DTH rather than to direct cytotoxicity to the tumor. The regression of these large tumors takes >4 wk and, in many cases, is self-sustained, in that little or no additional IL-12 is needed beyond the initial week of administration. Analysis of the cellular and molecular events at the tumor site suggests that the mechanism is a Th1-mediated antitumor immune response.

  View details for Web of Science ID 000071915400041

  View details for PubMedID 9570556

• A prospective analysis of the frequency, location, and curability of ectopic (nonpancreaticoduodenal, nonnodal) gastrinoma 18th Annual Meeting of the American-Association-of-Endocrine-Surgeons Wu, P. C., Alexander, H. R., Bartlett, D. L., DOPPMAN, J. L., FRAKER, D. L., NORTON, J. A., Gibril, F., Fogt, F., Jensen, R. T. MOSBY-ELSEVIER. 1997: 1176–82

  Abstract

  Extrapancreatic, extraduodenal and extralymphatic (ectopic) gastrinomas have been reported only rarely. The frequency, locations, and surgical outcome of these lesions are unknown.From 1982 to 1997, 215 patients with Zollinger-Ellison syndrome were evaluated prospectively at the National Institutes of Health and 142 patients (66%) underwent standardized surgical exploration and resection. Eight patients (5.6%) (six men and two women; mean age, 41 years) had primary gastrinoma located in ectopic sites. Long-term follow-up was derived from a prospective database.Ectopic gastrinoma tissue was identified and resected in the liver (three patients), common bile duct (one patient), jejunum (one patient), omentum (one patient), pylorus (one patient), and ovary (one patient). Seven patients (88%) were cured biochemically after resection and five patients (63%) have sustained cures, with a mean follow-up of 7.5 years (range, 0.4 to 11.7 years). One patient with a jejunal primary gastrinoma had a biochemical recurrence at 2 years, and another with a primary hepatic gastrinoma had a recurrence 6 years after resection. A patient with a pyloric primary gastrinoma was not cured.Extraduodenal, extrapancreatic, and extranodal gastrinomas are encountered in 5.6% of patients who undergo exploration with curative intent. If no gastrinoma is found in the usual locations, other ectopic sites should be examined carefully. Resection of these primary ectopic tumors can lead to durable biochemical cures.

  View details for Web of Science ID 000071089200049

  View details for PubMedID 9426435

• Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 18th Annual Meeting of the American-Association-of-Endocrine-Surgeons Mutch, M. G., Frisella, M. M., DeBenedetti, M. K., Doherty, G. M., NORTON, J. A., Wells, S. A., Lairmore, T. C. MOSBY-ELSEVIER. 1997: 1012–19

  Abstract

  The usefulness of human pancreatic polypeptide (hPP) as a plasma marker for islet cell neoplasms is controversial. We sought to determine the relation between fasting plasma hPP levels and radiographically detectable pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 (MEN 1).Fasting plasma hPP levels were measured prospectively in 202 individuals from 31 independent kindreds with MEN 1. Plasma levels greater than 3.0 times the normal age-specific values were defined as elevated. Patients with elevated plasma hPP levels were evaluated with computed tomographic scanning and magnetic resonance imaging, octreotide scanning, or selective angiography.Twenty-two patients had elevated fasting plasma hPP levels, and 20 of these patients were evaluated radiographically. Pancreatic lesions were detected in 19 patients. A group of eight patients with normal basal fasting plasma hPP levels were evaluated with computed tomography, magnetic resonance imaging, octreotide scanning, or selective angiography based on clinical presentation. One patient in this group had an imaging study that was positive for a pancreatic lesion.The presence of a markedly elevated fasting plasma hPP level in patients with MEN 1 is 95% sensitive and 88% specific for the presence of radiographically detectable pancreatic islet cell tumors.

  View details for Web of Science ID 000071089200008

  View details for PubMedID 9426414

• Prospective study of provocative angiograms to localize functional islet cell tumors of the pancreas 18th Annual Meeting of the American-Association-of-Endocrine-Surgeons Cohen, M. S., Picus, D., Lairmore, T. C., Strasberg, S. M., Doherty, G. M., NORTON, J. A. MOSBY-ELSEVIER. 1997: 1091–1100

  Abstract

  Controversy exists concerning the use of preoperative imaging studies in patients with islet cell tumors. Since 1993 we have evaluated the use of provocative angiography in patients with insulinoma or Zollinger-Ellison syndrome (ZES).Twelve patients with a working diagnosis of insulinoma (n = 4) or ZES (n = 8) were studied. Of the eight patients with ZES, four were known to have multiple endocrine neoplasia type 1. All patients underwent conventional imaging studies followed by provocative angiography. Angiograms were graded based on the ability to detect tumor and regionalize it within the pancreas.Of the three patients with a working diagnosis of ZES but equivocal results of biochemical studies, none had arteriographic imaging of an islet cell tumor or a positive provocative study result (true negative result). Of the nine patients with documented islet cell tumor, seven (78%) underwent arteriographic imaging of the tumor and eight (89%) had correct regional localization by provocative angiography. Sensitivity and specificity for imaging were 78% and 100%, respectively, and for regional localization 89% and 100%, respectively.Provocative angiography is the localization study of choice for both gastrinoma and insulinoma. Having few false-negative results, it can be used to corroborate the diagnosis and, having few false-positive results, it detects tumor and biochemically confirms localization in nearly every patient.

  View details for Web of Science ID 000071089200028

  View details for PubMedID 9426424

• Artificial antigen-presenting cells engineered by recombinant vaccinia viruses expressing antigen, MHC class II, and costimulatory molecules elicit proliferation of CD4(+) lymphocytes in vitro CLINICAL AND EXPERIMENTAL IMMUNOLOGY Oertli, D., Marti, W. R., NORTON, J. A., Tsung, K. 1997; 110 (1): 144-149

  Abstract

  The current study was designed to test the ability of recombinant Vaccinia virus (rVV) encoding essential components of an artificial antigen-presenting cell to activate antigen-specific T cells in vitro. We have constructed a set of rVV encoding separately or in combination a CD4+ T cell-specific epitope (the 133-145 peptide of chicken conalbumin), the MHC class II molecule I-Ak, and costimulatory molecules (mB7-1 and mB7-2). Cultured cells infected with rVV encoding both the antigen and the presenting MHC, but not either one alone, could activate cloned CD4+ T cells specific for the virus-encoded epitope. Additional co-expression of mB7-1 and mB7-2 resulted in further enhancement of T cell response. Thus, our rVV vector expressing four different foreign gene products elicited the highest proliferation rates of antigen-specific cloned T cells.

  View details for Web of Science ID A1997YA90400023

  View details for PubMedID 9353162

• Staging laparoscopy with laparoscopic ultrasonography: Optimizing resectability in hepatobiliary and pancreatic malignancy JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Callery, M. P., Strasberg, S. M., Doherty, G. M., Soper, N. J., NORTON, J. A. 1997; 185 (1): 33-39

  Abstract

  Open laparotomy has traditionally been required to stage hepatobiliary and pancreatic (HBP) cancers accurately. For unresectable patients, costs and morbidity have been high. Today, laparoscopy alone or combined with laparoscopic ultrasonography (LUS) is being examined for its value in defining the extent of malignancy.We have analyzed the effect of routine implementation of this new staging technique in our HBP center. Staging laparoscopy (SL) with LUS was performed in 50 consecutive patients with HBP malignancies. All patients were considered to have resectable tumors as determined by traditional preoperative staging modalities. Primary tumors were located in the liver (n = 7), biliary tract (n = 11), or pancreas (n = 32). An average of 2.7 preoperative studies per patient were performed prior to SL-LUS.Staging laparoscopy with laparoscopic ultrasonography predicted resectable tumors in 28 patients (56%). At laparotomy, 26 of 28 were actually resectable: the false-negative rate was 4%. Staging laparoscopy with laparoscopic ultrasonography indicated unresectability in 22 patients (44%). Staging laparoscopy alone demonstrated previously unrecognized occult metastases in 11 patients (22%). In 11 other patients (22%) in whom SL alone was negative, LUS established unresectability from vascular invasion (n = 5), lymph node metastases (n = 5), or intraparenchymal hepatic tumor (n = 1). All cases of unresectability due to vascular invasion were validated by laparotomy. Five of six lymph node or hepatic metastases were proved histologically by LUS-guided needle biopsy rather than laparotomy.Unnecessary laparotomy can be safely avoided by SL-LUS in many patients with HPB malignancies, reducing costs and morbidity.

  View details for Web of Science ID A1997XG41900006

  View details for PubMedID 9208958

• Underlying pathology in mammary Paget's disease ANNALS OF SURGICAL ONCOLOGY Yim, J. H., WICK, M. R., PHILPOTT, G. W., NORTON, J. A., Doherty, G. M. 1997; 4 (4): 287-292

  Abstract

  Management of patients with mammary Paget's disease is controversial; recent recommendations range from primary radiotherapy to modified radical mastectomy. This review correlates associated breast findings with disease stage and outcome to help guide evaluation and treatment.Retrospective review of clinical, mammographic and pathologic data from 38 women with mammary Paget's disease treated between 1979 and 1995 was performed. Mastectomies were performed on all but two patients with the entire breast and lymph nodes evaluated for histopathologic evidence of carcinoma.Underlying carcinoma (ductal carcinoma in situ and/or invasive ductal cancer) was found in most patients (92%) even when no palpable mass was evident (85%); this carcinoma is often multifocal (73%). Mammography fails to identify the underlying disease in many patients with no palpable mass and multifocal underlying disease (64%). Patients with Paget's disease and a palpable mass have a much greater incidence of invasive cancer, multifocal lesions, and positive lymph nodes, and have worse survival.Although some patients with Paget's disease might be well treated by breast conservation therapy, many patients have underlying multifocal carcinoma (including invasive cancer), which can be inapparent by examination and mammography. Selecting candidates with disease amenable to complete excision without mastectomy is problematic.

  View details for Web of Science ID A1997XB70400002

  View details for PubMedID 9181226

• IL-12 induces T helper 1-directed antitumor response JOURNAL OF IMMUNOLOGY Tsung, K., Meko, J. B., Peplinski, G. R., Tsung, Y. L., NORTON, J. A. 1997; 158 (7): 3359-3365

  Abstract

  Although IL-12 possesses the most potent single-cytokine antitumor efficacy, the mechanism by which IL-12 exerts its antitumor activities remains unclear. Using a complete tumor regression model induced by IL-12 treatment, we demonstrate that the antitumor response induced by IL-12 is mediated by a Th1 cell-directed process, with the macrophage as the effector cell and nitric oxide produced by the activated macrophage as the effector molecule. The induction of the Th1 response by IL-12 depends on the existence of a host T cell response to the tumor before IL-12 administration. IL-12 treatment causes the complete regression of 10-day established s.c. tumors (4-8 mm). Associated with the induction of tumor necrosis, activated macrophages expressing high levels of inducible nitric oxide synthase were found surrounding the tumor. The importance of nitric oxide as the effector molecule was further confirmed by the delay and loss of tumor regression in the presence of a nitric oxide synthase inhibitor in vivo. Examination of tumor-associated T cells indicates that IL-12 induces production of the Th1 cytokine IFN-gamma and suppresses production of IL-2, IL-4, and IL-10 at the tumor site, where these are found to be the predominant cytokines produced by tumor-associated T cells before IL-12 treatment. These findings demonstrate that IL-12 plays an essential role in the induction of an effective Th1 type of cell-mediated immune response against established tumors.

  View details for Web of Science ID A1997WQ64300041

  View details for PubMedID 9120294

• Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy 43rd Annual International Congress of the British-Association-of-Paediatric-Surgeons Skinner, M. A., NORTON, J. A., Moley, J. F., DeBenedetti, M. K., Wells, S. A. W B SAUNDERS CO-ELSEVIER INC. 1997: 510–13

  Abstract

  The purpose of this study was to examine the efficacy of parathyroid autotransplantation in children undergoing total thyroidectomy.We have prospectively evaluated 32 cases of total thyroidectomy in children. The ages ranged from 1 year to 15.7 years, and the mean was 8.9 years. In 31 cases, the indication for surgery was a diagnosis of MEN2A or 2B based on direct DNA testing. One child had suspected sporadic medullary thyroid carcinoma. All of the patients underwent heterotopic autotransplantation of parathyroid gland tissue. In 26 cases, the parathyroid tissue was placed in the nondominant forearm, while in 6 children it was autotransplanted into the sternocleidomastoid muscle.In 31 of 32 children (97%), the serum calcium level transiently decreased in the immediate postoperative period. All of the patients were placed on oral calcium carbonate and vitamin D supplementation, and the serum calcium levels became normal within several days. The supplemental medications were then weaned as tolerated. Within 3 months of their procedure, 30 patients (94%) had adequate parathyroid tissue engraftment, and the calcium and vitamin D medications were discontinued. One child required 9 months of calcium and vitamin D medications before she could be weaned from the medications. One child has been treated more recently, and is currently being weaned from supplemental calcium and vitamin D. Serum PTH levels in 22 patients who had placement of the tissue into their forearms were measured, and in each there was increased PTH in the grafted arm compared with the nongrafted arm. In five children who had parathyroid tissue grafted into the sternocleidomastoid muscle, the peripheral serum PTH levels were in the normal range.The heterotopic autotransplantation of resected parathyroid tissue is safe and effective in preventing permanent hypoparathyroidism.

  View details for Web of Science ID A1997WP14100033

  View details for PubMedID 9094030

• IFN regulatory factor-1 gene transfer into an aggressive, nonimmunogenic sarcoma suppresses the malignant phenotype and enhances immunogenicity in syngeneic mice JOURNAL OF IMMUNOLOGY Yim, J. H., Wu, S. J., Casey, M. J., NORTON, J. A., Doherty, G. M. 1997; 158 (3): 1284-1292

  Abstract

  IFN-gamma has a direct antitumor effect on many tumor cell lines mediated through the IFN-gammaR. One effect of IFN-gamma is to induce the nuclear transcription factor IFN regulatory factor-1 (IRF-1), which may function as a tumor suppressor. In this study, mouse IRF-1 cDNA under a high constitutive expression promoter was transfected into the highly aggressive, nonimmunogenic MCA 101 murine sarcoma. Clones were obtained by G418 selection and screened for IRF-1 mRNA expression by reverse transcriptase-PCR (RT-PCR). High expression clones had high levels of two MHC class I proteins (H-2Kb and H-2Db) on the cell surface that correlated with increased levels of class I mRNA by RT-PCR. Furthermore, these clones also had increased levels of MHC class II protein (I-Ab), which correlated with increased levels of one subunit of class II mRNA by RT-PCR. IRF-1-expressing clones had markedly diminished cell growth in vitro and decreased anchorage-independent growth in a soft agar assay. These clones also demonstrated markedly prolonged tumor latency and slowed growth in syngeneic C57BL/6 mice. IRF-1 gene-transfected cells had shortened tumor latency and formed faster growing tumors in gamma-irradiated immunodeficient mice compared with results in immunocompetent mice. Mice immunized with IRF-1-transfected cells were protected against subsequent challenge with IRF-1 transfected cells and also demonstrated greater tumor latency and slower tumor growth against subsequent challenge with untransfected cells compared with mice immunized with empty vector-transfected cells. These studies demonstrate a tumor suppressor effect of IRF-1, which acts in vivo through both partial reversion of the malignant phenotype and enhanced immune recognition and may play a role in the antitumor effects of IFN-gamma.

  View details for Web of Science ID A1997WE02000033

  View details for PubMedID 9013971

• Induction of antigen-presenting capacity in tumor cells upon infection with non-replicating recombinant vaccinia virus encoding murine MHC class II and costimulatory molecules JOURNAL OF IMMUNOLOGICAL METHODS Marti, W. R., Oertli, D., Meko, J. B., NORTON, J. A., Tsung, K. 1997; 200 (1-2): 191-198

  Abstract

  The possibility of inducing antigen-presenting capacity in cells normally lacking such capacity, currently represents a major goal in vaccine research. To address this issue we attempted to generate 'artificial' APC able to stimulate CD4+ T cell responses when tumor cells were infected with a single, recombinant, vaccinia virus (rVV) containing the two genes encoding murine MHC class II I-Ak and a third gene encoding the murine B7-1 (mB7-1) costimulatory molecule. To minimize the cytopathic effect and to improve safety, in view of possible in vivo applications, we made this rVV replication incompetent by Psoralen and long wave UV treatment. Tumor cells infected with rVV encoding I-Ak alone, pulsed with hen egg white lysozyme peptide (HEL46-61), induced IL-2 secretion by an antigen-specific T hybridoma. Tumor cells infected with the rVV encoding mB7-1 provided costimulation for activating resting CD4+ T cells in the presence of ConA. Tumor cells infected with the rVV encoding I-Ak and mB7-1, and pulsed with chicken ovotransferrin peptide (conalbumin133-145), induced a significantly higher response in a specific Th2 cell clone (D10.G4.1) as compared to cells infected with rVV encoding I-Ak molecules only. Thus, this replication incompetent rVV represents a safe, multiple gene, vector system able to confer in one single infection step effective APC capacity to non-professional APCs.

  View details for Web of Science ID A1997WD49800020

  View details for PubMedID 9005958

• Bilateral adrenalectomy for Cushing's syndrome - Anterior versus posterior surgical approach ANNALS OF SURGERY Buell, J. F., Alexander, H. R., NORTON, J. A., Yu, K. C., FRAKER, D. L. 1997; 225 (1): 63-68

  Abstract

  This study evaluates the intraoperative and postoperative complications in patients with Cushing's syndrome who underwent bilateral adrenalectomy comparing the posterior or anterior operative approach.The posterior approach for bilateral adrenalectomy has been advocated over the anterior approach because of rapid recovery and decreased morbidity, but the long-term complications associated with each procedure are not well described.The intraoperative profiles and morbidity in 48 patients undergoing bilateral adrenalectomy for Cushing's disease through either the anterior or posterior approach from 1985 to the present were reviewed comparing the intraoperative complication and early and late postoperative complication rate and morbidity.Twenty-seven patients underwent an anterior transabdominal procedure, whereas 21 underwent a posterior retroperitoneal procedure via bilateral incisions. Age, weight, and diagnostic categories of Cushing's syndrome were similar between the two groups as well as serum cortisol and 24-hour urinary cortisol levels. Operative time, estimated blood loss, and transfusion requirements were not different between the groups, even though adrenal glands excised through the anterior approach were significantly larger. Acute morbidity was similar between the groups. However, 17 (81%) of 21 patients who underwent posterior bilateral adrenalectomy suffered from chronic back pain, compared with 2 (7%) of 27 via the anterior approach. Five of these patients in the posterior group considered the pain incapacitating, and the mean time to return to work was significantly longer in the posterior group because of back pain.The anterior approach to bilateral adrenalectomy has comparable intraoperative complications and early morbidity compared to the posterior approach. The posterior approach has a very high incidence of chronic incision-related back pain. The anterior approach is the preferred open surgical technique in most patients undergoing bilateral adrenalectomy for Cushing's syndrome without other contraindications for undergoing laparotomy.

  View details for Web of Science ID A1997WB87900009

  View details for PubMedID 8998121

• Advances in molecular genetics AMERICAN JOURNAL OF SURGERY Lairmore, T. C., NORTON, J. A. 1997; 173 (1): 37-41

  Abstract

  The three known mechanisms of cellular transformation and oncogenesis include mutations in proto-oncogenes, inactivation of both copies of a tumor suppressor gene, and defects in DNA mismatch repair genes. Examples of each are included to substantiate the importance of understanding these mechanisms. RET is a proto-oncogene that is fundamental to the pathogenesis, and in the current era, molecular diagnosis of MEN 2 syndromes. TP53 is a tumor suppressor gene that is mutated in individuals with Li-Fraumeni syndrome. CDKN2 is a tumor suppressor gene that is mutated in pancreatic cancers and is associated with a poorer prognosis and the development of melanoma. MSH2 is a mismatch repair gene that is important in the pathogenesis of HNPCC and Muir-Torre syndrome. Altered gene function such as loss of DCC in colon cancers may affect cell adhesion properties and promote metastases. As we begin to better define and understand the mechanisms of neoplasia, we will be able to improve current diagnosis and treatment.

  View details for Web of Science ID A1997WJ12700013

  View details for PubMedID 9046882

• Is reoperation for gastrinoma excision indicated in Zollinger-Ellison syndrome? 17th Annual Meeting of the American-Association-of-Endocrine-Surgeons Jaskowiak, N. T., FRAKER, D. L., Alexander, H. R., NORTON, J. A., DOPPMAN, J. L., Jensen, R. T. MOSBY-ELSEVIER. 1996: 1055–62

  Abstract

  Surgical excision of gastrinomas in patients with Zollinger-Ellison syndrome (ZES) decreases the incidence of hepatic metastases, but long-term biochemical cures are achieved in fewer than 30% of cases. A growing number of patients have persistent or recurrent disease after initial operation. The effect of reoperation in these patients has not been previously reported.From December 1982 to August 1995, 120 patients with ZES underwent operation for gastrinoma resection. Seventy-eight patients had recurrent or persistent ZES after operation; 17 patients underwent 18 reoperations. After initial operation all patients underwent yearly functional and imaging studies. If a tumor was unequivocally imaged, reexploration was done.Five patients, all with sporadic disease, were disease free after operation, with a median follow-up of 28 months. Tumor was found in all 18 reoperations and resected in 17. In patients with continuing disease-free intervals, locations of gastrinomas included pancreatic head lymph nodes (three), liver metastasis (one), and pancreatic tail lymph node (one). There were no deaths in the cured group; two patients in the group with persistent disease have died (median follow-up, 34 months).Reoperation for gastrinoma excision resulted in elimination of disease in 30% of patients and should be considered for patients with imageable disease.

  View details for Web of Science ID A1996VW99200046

  View details for PubMedID 8957495

• Non-replicating recombinant vaccinia virus encoding murine B-7 molecules elicits effective costimulation of naive CD4(+) splenocytes in vitro JOURNAL OF GENERAL VIROLOGY Oertli, D., Marti, W. R., NORTON, J. A., Tsung, K. 1996; 77: 3121-3125

  Abstract

  Using a series of new insertion/expression vectors, we constructed a set of recombinant vaccinia viruses (recVV) encoding the murine T cell costimulatory molecules mB7-1 or mB7-2, or both together in the same construct. On infection with replication incompetent and non-cytopathic recVV, several tumour cell lines expressed the respective molecules and bound to CTLA-4. The highest binding capacity was found when both mB7 molecules were co-expressed. Mouse B16.F10 melanoma cells expressing mB7-1 or mB7-2 provided effective costimulation for proliferation of resting CD4+ T cells in the presence of concanavalin A and plate-bound anti-T cell receptor antibodies, respectively. If mB7-1 and mB7-2 were delivered together on the same cell, the proliferative response of CD4+ T cells increased further. The costimulatory effect could be blocked with CTLA-4, the soluble ligand for B7 molecules. The possibility of engineering tumour cells using recVV holds implications for the future design of vaccination strategies.

  View details for Web of Science ID A1996WB25100027

  View details for PubMedID 9000106

• Evaluation of somatostatin-receptor scintigraphy for detecting neuroendocrine tumors 17th Annual Meeting of the American-Association-of-Endocrine-Surgeons Meko, J. B., Doherty, G. M., Siegel, B. A., NORTON, J. A. MOSBY-ELSEVIER. 1996: 975–83

  Abstract

  Somatostatin-receptor scintigraphy (SRS) has gained attention as an imaging modality for neuroendocrine tumors (NETs). The purpose of this study was to present one of the first American series evaluating the ability of SRS to detect local and distant disease caused by NETs.Medical records were reviewed from 35 patients who underwent a total of 38 studies using 111In-pentetreotide between 1993 and 1995. Twenty-two patients had islet cell tumors, seven had carcinoid tumors, and six had other NETs.The overall sensitivity of SRS was 74% for detecting local disease (primary tumor +/- regional lymph node metastases) in all NETs, excluding insulinoma, 75% in gastrinoma, 0% in insulinoma, 78% in other islet cell tumors, and 50% in carcinoids. For detecting distant disease, the overall sensitivity of SRS was 67% for all NETs, excluding insulinoma, 100% for gastrinoma, 50% for other islet cell tumors, and 80% for carcinoids. Specificity and positive predictive value were 100% for all tumors. Negative predictive value ranged from 33% to 100%.A positive SRS study strongly predicts the presence of tumor (100% positive predictive value in our study). However, unlike the European reports of very high sensitivity (80% to 88%), we found that SRS had a lower sensitivity (67% for all NETs excluding insulinoma and 71% for noninsulinoma gastroenteropancreatic NETs). Thus negative SRS in patients with NETs must be viewed cautiously, because the false-negative rate is high, and this limits the use of this method in the most difficult patients.

  View details for Web of Science ID A1996VW99200022

  View details for PubMedID 8957483

• Parathyroid adenomas in the aortopulmonary window RADIOLOGY DOPPMAN, J. L., SKARULIS, M. C., Chen, C. C., Chang, R., PASS, H. I., FRAKER, D. L., Alexander, H. R., Niederle, B., Marx, S. J., NORTON, J. A., Wells, S. A., Spiegel, A. M. 1996; 201 (2): 456-462

  Abstract

  To describe localization studies in nine patients with ectopic parathyroid adenomas in the aortopulmonary window.Nine patients with ectopic parathyroid tissue (eight adenomas, one hyperplastic gland) in the aortopulmonary window were examined with ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, and scintigraphy. Diagnostic arteriography (n = 4) and venous sampling (n = 3) were performed in the first four patients; arteriography for the purpose of staining was attempted in the last five patients.The results of CT and MR imaging studies were positive in eight of nine patients (89%) and five of eight patients (63%), respectively. The results of thallium/technetium scintigraphy were negative in three patients scanned (0%), but the results of a repeat study in one patient were positive (33%). Sestamibi scans were positive in six of six patients (100%). Single photon emission CT was performed in all six patients and enabled distinction between adenomas in the aortopulmonary window and those in the thymus.Ectopic parathyroid glands in the aortopulmonary window are usually detected at sestamibi scintigraphy, and SPECT is helpful in distinguishing these adenomas from more common adenomas in the anterior mediastinum. CT and MR imaging studies can also enable this distinction, but imaging must extend below the aortic arch.

  View details for Web of Science ID A1996VP38900028

  View details for PubMedID 8888240

• Expression of secreted platelet-derived growth factor-B by recombinant nonreplicating and noncytopathic vaccinia virus 116th Annual Meeting of the American-Surgical-Association NORTON, J. A., Peplinski, G. R., Tsung, K. LIPPINCOTT-RAVEN PUBL. 1996: 555–60

  Abstract

  The purpose of this study was to develop a noncytopathic vector for transient delivery of biologically active platelet-derived growth factor (PDGF) to wounds.Topical application of the protein PDGF-B has improved wound healing in experimental studies of healing-impaired wounds. However, use of PDGF-B has been limited by availability of recombinant protein, short half-life, and inability to reliably apply to the wounded area. One approach to supply local PDGF-B is through transient gene transfer and expression.Treatment of vaccinia virus with psoralen and long-wave ultraviolet irradiation makes it noncytopathic and nonreplicative. The authors inserted various transgenes encoding different forms of PDGF into recombinant vaccinia virus at the hemaglutinin locus by homologous recombination. Because the PDGF-B expressed from full length cDNA is not secreted because of the membrane retention sequence at the C-terminal end of the polypeptide, the authors inserted a 3'-truncated form of human PDGF-B cDNA in recombinant vaccinia virus to achieve secretion. To avoid interference in bioassays by a virally encoded epidermal growth factor homologue called vaccinia growth factor (VGF) in wild type vaccinia virus (CR-19), we used a VGF-negative strain to express PDGF-B (vSC20PDGF-B). Biologic activity of PDGF was tested by measuring proliferation of a 3T3 fibroblast cell line.Supernatant from CR-19-infected cells (VGF+) and from truncated vSC20PDGF infected cells caused mild and marked proliferation of 3T3 cells, respectively, whereas supernatant from full-length vSC20PDGF virally infected cells did not. Furthermore, in vitro infection of a confluent 3T3 monolayer with noncytopathic and nonreplicative vaccinia encoding either VGF or truncated PDGF also caused similar proliferation.These results provide important preliminary evidence for the ability to treat nonhealing wounds with nonreplicating and noncytopathic recombinant vaccinia viruses encoding cytokine growth factors.

  View details for Web of Science ID A1996VL76000080

  View details for PubMedID 8857859

• A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma 116th Annual Scientific Session of the American-Surgical-Association Jaskowiak, N., NORTON, J. A., Alexander, H. R., DOPPMAN, J. L., Shawker, T., Skarulis, M., Marx, S., Spiegel, A., FRAKER, D. L. LIPPINCOTT-RAVEN PUBL. 1996: 308–20

  Abstract

  The authors evaluate the results of preoperative imaging protocols and surgical re-exploration in a series of patients with missed parathyroid adenomas after failed procedures for primary hyperparathyroidism.The success rate is lower and the complication rate is increased in patients undergoing reoperation for primary hyperparathyroidism compared with initial procedures. Scarring and distortion of tissue planes plus the potential for ectopic gland location leads to this worsened outcome.Two hundred eighty-eight consecutive patients with persistent/recurrent hyperparathyroidism were treated at a single institution after a failed procedure or procedures at outside institutions. Two hundred twenty-two of these patients (77%) were believed to have a missed single adenoma, and these patients underwent 228 operations and 227 preoperative work-ups. Preoperative evaluation consisted of a combination of four noninvasive imaging studies--neck ultrasound, nuclear medicine scan, neck and mediastinal computed tomography scan, and neck and mediastinal magnetic resonance imaging. Based on the noninvasive testing alone, 27% patients underwent surgery whereas the other patients underwent invasive studies, including selective angiography (58%), selective venous sampling for parathyroid hormone (43%), or percutaneous aspiration of suspicious lesions (15%).Abnormal parathyroid adenomas were found in 209 of 222 initial procedures and 6 of 6 second procedures, with an overall success rate in terms of resolution of hypercalcemia in 97% (215/222) of patients. The single most common site of missed adenoma glands was in the tracheal-esophageal groove in the posterior superior mediastinum (27%). The most common ectopic sites for parathyroid adenomas are thymus (17%), intrathyroidal (10%), undescended glands (8.6%), carotid sheath (3.6%), and the retroesophageal space (3.2%). The most sensitive and specific noninvasive imaging test is the sestamibi subtraction scan, with 67% true-positive and no false-positive results. The rate of true-positive and false-positive results for ultrasound, computed tomography, magnetic resonance imaging, and technetium thallium scans were 48%/21%, 52%/16%, 48%/14% and 42%/8%, respectively. The incidence of injury to the recurrent laryngeal nerve was 1.3%.A single missed parathyroid adenoma is the most common cause for a failed initial parathyroid operation. Appropriate use of preoperative imaging tests and knowledge of the potential location or parathyroid adenomas can lead to very high cure rates with minimal morbidity.

  View details for Web of Science ID A1996VG49400012

  View details for PubMedID 8813259

• Cytokine production and antitumor effect of a nonreplicating, noncytopathic recombinant vaccinia virus expressing interleukin-12 57th Annual Meeting of the Society-of-University-Surgeons Meko, J. B., Tsung, K., NORTON, J. A. MOSBY-ELSEVIER. 1996: 274–83

  Abstract

  Cancer gene therapy with interleukin-12 (IL-12) has generated much interest because of the potent antitumor effects of this cytokine. The purpose of this study was to construct a nonreplicating, noncytopathic recombinant vaccinia virus (irecVV) encoding murine IL-12 (ivKT0327mIL-12) and to assess its biologic activity and antitumor effects.ivKT0327mIL-12 was constructed by inserting the genes encoding mIL-12 into the VV genome by homologous recombination. Psoralen and long-wave ultraviolet light were used to render the virus incapable of replication or cell lysis. Cytokine production was assessed by infecting tumor cell lines and measuring mIL-12 in the culture supernatants by using a bioassay. C57BL/6 mice were injected subcutaneously in a randomized, blinded fashion with 5 x 10(5) MCA 101 fibrosarcoma cells or 5 x 10(5) PAN 02 pancreatic tumor cells infected in vitro with either ivKT0327mIL-12 or ivKT033, a control irecVV containing no cytokine genes. Emergence of tumor and tumor size were measured.Tumor cells infected with ivKT0327mIL-12 produced large amounts of biologically active mIL-12 (up to 793 ng/10(6) cells/24 hr) but continued to proliferate in vitro with no cytopathic effect. Mice injected with MCA 101 infected with ivKT0327mIL-12 had significantly delayed tumor emergence (p < 0.03) and decreased tumor size (p < 0.003) compared with mice injected with ivKT033-infected MCA 101. Tumor growth was also significantly smaller in a similar experiment with PAN 02 (p < 0.01).Tumor cells infected with irecVV encoding mIL-12 express high levels of biologically active mIL-12 in vitro and exhibit delayed tumor establishment, significant tumor growth inhibition, or both, in vivo.

  View details for Web of Science ID A1996VK88600021

  View details for PubMedID 8751593

• Endogenous interferon-gamma acts directly on tumor cells in vivo to suppress growth JOURNAL OF SURGICAL RESEARCH Doherty, G. M., Tsung, K., McCluskey, B., NORTON, J. A. 1996; 64 (1): 68-74

  Abstract

  Recent evidence implicates endogenous interferon-gamma (IFN-gamma) in the host response to an immunogenic tumor (MCA105); antibody blockade of host IFN-gamma increased tumor growth rate (Doherty et al., Ann. Surg. Oncol. 3: 198-203, 1996). Those experiments did not attempt to determine the site of IFN-gamma activity (the host, the tumor, or both).MCA101 murine tumor cells were transfected with a plasmid expression vector containing an antisense construct to the IFN-gamma receptor (IFN-gamma R) or a control construct. Clones were isolated and tested for IFN-gamma stimulation of MHC I expression, sensitivity to IFN-gamma growth effects in vitro, and specific [125I]IFN-gamma binding.The antisense strategy was successful in decreasing the number of cell-surface IFN-gamma binding sites and in vitro response to IFN-gamma. Finally, in vivo experiments demonstrated significantly increased untransfected tumor growth rate in animals after blockade of endogenous IFN-gamma by a single dose of anti-IFN-gamma antibody and more rapid growth of the IFN-gamma R-deficient cells compared to controls.endogenous IFN-gamma has a direct effect on this less immunogenic tumor in vivo, which serves to slow growth and which is, at least partially, mediated through interferon-gamma receptors on the tumor cell.

  View details for Web of Science ID A1996VC18000012

  View details for PubMedID 8806476

• Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Brunt, L. R., Doherty, G. M., NORTON, J. A., Soper, N. J., Quasebarth, M. A., Moley, J. F. 1996; 183 (1): 1-10

  Abstract

  Laparoscopic adrenalectomy has recently been used for removing a variety of adrenal neoplasms. The purpose of the present study was to compare results and outcomes in patients who underwent either laparoscopic or open adrenalectomy at our institution from 1988 to the present.The records of 66 consecutive patients with benign adrenal neoplasms who underwent adrenalectomy from 1988 through 1995 were retrospectively reviewed. Patients were divided into three groups based on the operative approach: group I (n = 25), open anterior transabdominal approach; group II (n = 17), open posterior retroperitoneal approach; and group III (n = 24), laparoscopic transabdominal flank approach. Various parameters were compared and statistical analyses were performed.The three groups were similar in age, gender, American Society of Anesthesiologists class, and distribution of unilateral compared with bilateral adrenalectomy. Mean tumor size was slightly larger in group I (3.4 +/- 1.4 cm) than in group II (2.4 +/- 1.4 cm) or group III (2.7 +/- 1.4 cm) (p = NS). Mean operative times for unilateral adrenalectomy were 142 +/- 38 minutes in group I, 136 +/- 34 minutes in group II, and 183 +/- 35 minutes in group III (p < 0.001, groups I and II compared with group III). For bilateral adrenalectomy, mean operative times were 205 +/- 71 minutes (group I), 328 +/- 11 minutes (group II), and 422 +/- 77 minutes (group III). Patients who underwent laparoscopic adrenalectomy had significantly less operative blood loss (mean, 104 mL compared to 408 mL in group I and 366 mL in group II, p < 0.001) and a lower incidence of perioperative blood transfusion. Laparoscopic adrenalectomy was also associated with significantly reduced parenteral pain medication requirements (p < or = 0.001) and more rapid resumption of a regular diet (p < or = 0.01) compared to open adrenalectomy. Postoperative length of stay was significantly longer in group I (8.7 +/- 4.5 days) and in group II (6.2 +/- 3.9 days) after open adrenalectomy than after laparoscopic adrenalectomy (3.2 +/- 0.9 days) (p < 0.01). Total hospital charges were similar for groups II and III but somewhat higher for group I. Patients were able to resume 100 percent activity an average of 10.6 +/- 4.9 days after laparoscopic adrenalectomy and returned to work a mean of 16.0 +/- 6.1 days postoperatively.Laparoscopic adrenalectomy is a safe and effective procedure and has several advantages over open adrenalectomy. Laparoscopic adrenalectomy should become the preferred operative approach for the treatment of patients with small, benign adrenal neoplasms.

  View details for Web of Science ID A1996UV69700001

  View details for PubMedID 8673301

• Mammographically detected breast cancer - Benefits of stereotactic core versus wire localization biopsy 107th Annual Scientific Session of the Southern-Surgical-Association Yim, J. H., Barton, P., Weber, B., Radford, D., Levy, J., Monsees, B., Flanagan, F., NORTON, J. A., Doherty, G. M. LIPPINCOTT-RAVEN PUBL. 1996: 688–97

  Abstract

  The authors evaluated the differences between stereotactic core needle biopsy (SCNBx) and needle localization surgical biopsy (NLBx) in cost and treatment course for patients with mammographically detected breast cancer.Stereotactic core needle breast biopsy is a reproducible and reliable alternative to surgical biopsy for histologic diagnosis of mammographic lesions.Records from 52 consecutive patients with invasive breast cancer diagnosed by SCNBx (n = 21) or NLBx (n = 31) over 2 years were reviewed. Episode-of-care costs were extracted from the Barnes Hospital billing system database.At the time of excision, surgical margins were statistically more frequently positive in patients treated with NLBx (55%) than patients treated with SCNBx (0%, p < 0.0001). Furthermore, patients in the NLBx group undergoing breast conservation surgery required re-excision more frequently (74%) than those in the SCNBx group (0%, p = 0.001). There were no complications in either group after the diagnostic procedure. All SCNBx results were correct in the diagnosis of invasive breast cancer. The median cost of SCNBx was approximately $1000 less than the median cost of NLBx. This cost difference was carried through the definitive procedure, whether it was breast conservation or mastectomy.This study shows the advantage of SCNBx to diagnose breast cancer and definitive operative care at a single procedure. The preoperative diagnosis of breast cancer eliminated positive operative margins and procedures to re-excise breast tissue. The use of SCNBx also saved approximately $1000 per patient compared with the use of NLBx. Our data suggest that SCNBx is the diagnostic procedure of choice for mammographically detected cancers.

  View details for Web of Science ID A1996UQ46900013

  View details for PubMedID 8645042

• Reduced survival in patients with ductal pancreatic adenocarcinoma associated with CDKN2 mutation JOURNAL OF THE NATIONAL CANCER INSTITUTE Bartsch, D., Shevlin, D. W., Callery, M. P., NORTON, J. A., Wells, S. A., Goodfellow, P. J. 1996; 88 (10): 680-682

  View details for Web of Science ID A1996UK18600014

  View details for PubMedID 8627645

• Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy ANNALS OF SURGICAL ONCOLOGY Doherty, G. M., Alexander, H. R., MERINO, M. J., VENZON, D. J., NORTON, J. A. 1996; 3 (2): 198-203

  Abstract

  The anticancer role of tumor necrosis factor-alpha (TNF-alpha) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-gamma) activity to abrogate TNF-alpha toxicity.C57B1/6 mice bearing MCA 105 tumor were treated with TNF-alpha and anti-IFN-gamma antibody (Ab) to evaluate the effect on the acute lethality of TNF-alpha and their efficacy as evaluated by tumor growth rate, tumor histology, and survival.Anti-IFN-gamma Ab decreased TNF-alpha lethality. Anti-IFN-gamma Ab alone increased tumor growth significantly more than did nonimmune IgG (p2 < 0.0001). Tumor-bearing mice that received nonimmune IgG and TNF-alpha had slower tumor growth (p2 < 0.02) and a trend toward improved survival (p = 0.07) compared with saline-treated controls. Anti-IFN-gamma Ab abrogated the antitumor effect of TNF-alpha, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN-gamma Ab and high-dose TNF-alpha were comparable with those in mice that received a lower, equitoxic dose of TNF-alpha alone.Blocking endogenous IFN-gamma accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF-alpha equally. This suggests that blocking endogenous IFN-gamma activity is not a useful strategy for limiting TNF-alpha treatment toxicity.

  View details for Web of Science ID A1996TX81500015

  View details for PubMedID 8646522

• Prevention of murine breast cancer by vaccination with tumor cells modified by cytokine-producing recombinant vaccinia viruses ANNALS OF SURGICAL ONCOLOGY Peplinski, G. R., Tsung, K., Meko, J. B., NORTON, J. A. 1996; 3 (1): 15-23

  Abstract

  Cancer gene therapy expressing specific levels of multiple genes has not been adequately tested. This study investigates the antitumor effects of recombinant vaccinia viruses (recVVs) that express predictable levels of single and multiple cytokines in a passive immunization murine breast cancer (C3HBA) model.Seventeen recVVs encoding different cytokine combinations under weak and strong VV promoters were constructed. Cytokine production was measured in vitro by enzyme-linked immunosorbent assay. Mice were immunized with infected C3HBA cells and rechallenged 10 days later with 10(6) parental tumor cells. Controls were treated with saline or recVVs not expressing cytokines. Tumors were measured for 24 days. Data were analyzed using Fisher's exact test and the Breslow-Gehan-Wilcoxon test.recVVs encoding multiple cytokines induced secretion of each cytokine at predictable levels corresponding to VV promoter strength. Ten of 10 controls developed tumors by day 11 after rechallenge. recVVs producing large but not small amounts of murine granulocyte-macrophage colony-stimulating factor (GM-CSF) alone resulted in complete protection in all immunized mice (p = 0.0003) for 24 days and disease-free survival (DFS) was significantly prolonged versus controls (p < 0.001). GM-CSF under a weak promoter was also effective in combination with human interleukin-1 beta (hIL-1 beta; p = 0.0220; DFS, p = 0.031) or interferon-gamma (IFN-gamma; p = 0.0037; DFS, p = 0.003). Effectiveness of hIL-1 beta and IFN-gamma vaccines depended on cytokine combinations and not the amount of cytokine produced. IL-2 or tumor necrosis factor-alpha vaccines had no significant antitumor effect.(a) recVVs can simultaneously express controllable levels of two cytokines; (b) tumor cells modified by recVVs generate systemic antitumor immunity; and (c) strength of immunity appears to be related to the amounts and specific cytokine(s) produced.

  View details for Web of Science ID A1996TP42500003

  View details for PubMedID 8770297

• Infrequent CDKN2 mutation in human differentiated thyroid cancers MOLECULAR CARCINOGENESIS Tung, W. S., Shevlin, D. W., Bartsch, D., NORTON, J. A., Wells, S. A., Goodfellow, P. J. 1996; 15 (1): 5-10

  Abstract

  We examined the frequency of cyclin-dependent kinase (CDK) N2 alterations in differentiated and anaplastic thyroid cancers to assess the involvement of CDKN2 in the development of these cancers. The CDKN2 gene, which encodes the cell-cycle regulator p16, was recently shown to be mutated or deleted in many tumor cell lines. Its role in the genesis of primary tumors is uncertain, however. Tumor and corresponding normal DNAs were prepared by microdissection of paraffin-embedded tissue blocks or from frozen surgical specimens of 15 papillary, 15 follicular, and five anaplastic thyroid carcinomas. The entire CDKN2 coding region was screened by single-strand conformational variant analysis and direct sequencing of variants. The presence of homozygous deletions was evaluated by multiplex polymerase chain reaction (PCR) analysis. Loss of heterozygosity (LOH) in the CDKN2 region was assessed by using flanking polymorphic markers. Two somatic missense mutations were found among the 35 thyroid cancers, one in a follicular tumor and one in an anaplastic tumor. Multiplex PCR suggested the presence of homozygous deletion in one anaplastic tumor and hemizygous deletions in four tumors. LOH studies revealed loss of 9p sequences in four follicular (27%) and two anaplastic (50%) cancers. Our data suggest that alterations in CDKN2 played a role in a minority of thyroid cancers (three of 35). LOH in the region of CDKN2 is seen in a significant proportion of follicular and anaplastic but not papillary cancers. Loss of 9p sequences suggests a role for a tumor suppressor gene in the development of follicular and anaplastic thyroid cancers.

  View details for Web of Science ID A1996TR17600002

  View details for PubMedID 8561866

• Gastrointestinal endocrine cancers and nodal metastasis: biologic significance and therapeutic implications. Surgical oncology clinics of North America Peplinski, G. R., NORTON, J. A. 1996; 5 (1): 159-171

  Abstract

  Gastrointestinal endocrine tumors consist of pancreatic endocrine neoplasms and carcinoid tumors. Except for insulinoma, a majority of gastrointestinal endocrine tumors are malignant. With improved medical treatment of syndromes of hormonal excess, growth of the primary tumor and metastatic spread has increasingly become an important determinant of long-term survival. Although few randomized, prospective data are available given the rare occurrence of malignant gastrointestinal endocrine tumors, surgery appears to be the only potentially curative treatment for malignant endocrine tumors, and complete resection of localized or regional nodal metastases provides the highest probability of cure. Surgery may also be the most effective treatment for hepatic metastases if most or all of the tumor can be resected, and patients with solitary, localized metastatic disease appear to benefit most. Symptoms from extensive metastases may respond to chemotherapy or octreotide. Gastrointestinal endocrine tumors are generally indolent, slow-growing neoplasms, and when symptoms are adequately controlled, patients can live comfortably and productively for many years with metastatic disease.

  View details for PubMedID 8789500

• Gene expression and cytopathic effect of vaccinia virus inactivated by psoralen and long-wave UV light JOURNAL OF VIROLOGY TSUNG, K. L., Yim, J. H., Marti, W., Buller, R. M., NORTON, J. A. 1996; 70 (1): 165-171

  Abstract

  Induction of the cytopathic effect (CPE) in cells infected with poxvirus seems ubiquitous in that it has been associated with all different strains and preparations of poxviruses, regardless of the replicating status of these viruses. The study of the mechanisms by which CPE is induced by nonreplicating poxviruses is hampered by the lack of any noncytopathic mutant strains and preparations. In this paper, we report on the patterns of gene expression and induction of CPE by vaccinia viruses treated by limited cross-linking with psoralen and long-wave UV light (PLWUV). We show that treatment of cell-free virus with PLWUV could inactivate viral replication without abolishing the ability of the virus to infect cells. Viral transcription as indicated by reporter genes was generally enhanced and prolonged under early viral promoters and abolished under late promoters. Furthermore, increasing the levels of cross-linking with PLWUV resulted in a decrease and abolishment of viral expression of a large reporter gene and a concomitant loss of the induction of CPE. Cells infected with such a virus were able to express the reporter genes and proliferate. The generation of nonreplicating and noncytopathic recombinant vaccinia viruses may help in studies of the mechanisms of CPE induction by poxvirus and may facilitate the use of poxviral vectors in broader areas of research and clinical applications.

  View details for Web of Science ID A1996TJ65000022

  View details for PubMedID 8523521

• In vivo murine tumor gene delivery and expression by systemic recombinant vaccinia virus encoding interleukin-1beta. cancer journal from Scientific American Peplinski, G. R., Tsung, A. K., Casey, M. J., Meko, J. B., Fredrickson, T. N., Buller, R. M., NORTON, J. A. 1996; 2 (1): 21-27

  Abstract

  This study investigates the feasibility of systemic gene delivery in a tumor-bearing host using a vaccinia virus-based in vivo gene delivery and expression system.A recombinant vaccinia virus encoding human interleukin-1beta (hIL-1beta) was constructed with a strong synthetic vaccinia virus late promoter driving hIL-1beta gene expression. C57BL/6 mice bearing established subcutaneous pancreatic tumors were injected intravenously in a blinded, randomized fashion with different doses of either the recombinant vaccinia virus(vMJ601hIL-Ibeta), control vaccinia (wild-type or TK-deficient), or saline. Toxicity was assessed, serial tumor sizes were measured, and viral titers and the amount of hIL-1beta in tumor, liver, and spleen were determined.High viral titers (10(6) PFU/g) were detected in tumors for all three viruses on postinjection day 3, and tumor viral titers persisted at high levels until day 9. In contrast, viral titers were initially 104-fold lower in nontumor tissues and decreased to undetectable levels by day 9. vMJ60hIL-1beta was rapidly cleared from liver and spleen by day 3 (titer levels < 100 PFU/g), while tumor titer levels persisted at 8.5 x 10(6) PFU/g. hIL-1beta was measurable in three of three tumors from vMJ601hIL-1beta treated mice on postinjection day 3, one of three on day 6, and one of three on day 9; no hIL-1beta was detected in any other tumors or normal tissues. Wild-type vaccinia had no antitumor effects. Treatment with two different doses of vMJ601hIL-1beta resulted in a consistent and significant decrease in tumor size in repeatable experiments as compared to controls. Histologic analysis revealed tumor cell necrosis with a surrounding neutrophil infiltrate in the vMJ601hIL-1beta treated tumor.These data show that recombinant vaccinia virus encoding hIL-1beta given intravenously preferentially localizes and amplifies in tumor tissue, is rapidly cleared from liver and spleen, produces measurable hIL-1beta in tumor but not normal tissues, and inhibits growth of established solid tumors in mice. Recombinant vaccinia virus encoding therapeutic genes may be a practical, efficient vehicle for direct in vivo gene transfer and expression in the treatment of cancer.

  View details for PubMedID 9166494

• Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B 26th Annual Meeting of the American-Pediatric-Surgical-Association Skinner, M. A., DeBenedetti, M. K., Moley, J. F., NORTON, J. A., Wells, S. A. W B SAUNDERS CO-ELSEVIER INC. 1996: 177–82

  Abstract

  Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only 3 (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.

  View details for Web of Science ID A1996TR13500034

  View details for PubMedID 8632274

• ROLE OF SURGERY IN MANAGEMENT OF ADRENOCORTICOTROPIC HORMONE-PRODUCING ISLET-CELL TUMORS OF THE PANCREAS 16th Annual Meeting of the American-Association-of-Endocrine-Surgeons Amikura, K., Alexander, H. R., NORTON, J. A., DOPPMAN, J. L., Jensen, R. T., Nieman, L., Cutler, G., Chrousos, G., FRAKER, D. L. MOSBY-YEAR BOOK INC. 1995: 1125–30

  Abstract

  Ectopic adrenocorticotropic hormone-producing islet cell tumors of the pancreas (ACTH-ICT) are a rare cause of Cushing's syndrome with a severe and rapidly progressive clinical course.Charts were reviewed on all patients evaluated and treated for proven Cushing's syndrome caused by ACTH-ICT (n = 12), specifically for the role of surgery in the management of this disease.Ten (83%) of twelve patients with ACTH-ICT had liver metastases at the time of diagnosis (eight of eight with Zollinger-Ellison syndrome, two of four without Zollinger-Ellison syndrome). Surgical management of the primary tumor included three patients who underwent distal pancreatectomy combined with hepatic resection and one patient who underwent laparoscopic enucleation of a tumor from the pancreatic tail. Eight of twelve patients underwent bilateral adrenalectomy to control symptoms of Cushing's syndrome, including three patients who underwent concurrent distal pancreatectomy and hepatic resection. Six of twelve patients died of the disease within 2 1/2 years of diagnosis, four are alive with progressive hepatic metastases, and one has biochemical evidence of disease.ACTH-ICT of the pancreas is an aggressive tumor, particularly when there is coproduction of gastrin. The benefit of aggressive surgical resection of primary or metastatic ACTH-ICT has not been established. However, palliative bilateral adrenalectomy is justified, because no patients had biochemical cures after aggressive surgical resection in this series.

  View details for Web of Science ID A1995TH94700030

  View details for PubMedID 7491532

• LARGE CYSTIC SOLID THYROID-NODULES - A POTENTIAL FALSE-NEGATIVE FINE-NEEDLE ASPIRATION 16th Annual Meeting of the American-Association-of-Endocrine-Surgeons Meko, J. B., NORTON, J. A. MOSBY-YEAR BOOK INC. 1995: 996–1004

  Abstract

  False-negative fine-needle aspiration (FNA) biopsy results of thyroid nodules are of particular concern because they imply missed malignant lesions. The purpose of this study was to identify characteristics of thyroid nodules that may lead to false-negative cytologic interpretation after FNA.We reviewed 90 consecutive patients who underwent preoperative FNA of thyroid nodules followed by thyroid surgery during a period of 27 months, including their clinical data, type and size of thyroid nodule, FNA cytology results, and final pathology report of the surgical specimen.Thyroid nodules that had the highest probability of malignancy were those that were large (3 cm or larger), cystic/solid, or large and cystic/solid. The overall false-negative rate for preoperative FNA was 11%. Large, cystic/solid, and thyroid nodules with both characteristics had false-negative rates of 17%, 25%, and 30%, respectively, compared with 0%, 9%, and 17% for small (less than 3 cm), solid, and solid nodules 3 cm or larger, respectively.Because of the high prevalence of malignancy in thyroid nodules that are large (3 cm or larger), cystic/solid, or large and cystic/solid and the high false-negative rate of FNA in diagnosing these lesions, thyroid lobectomy for diagnosis should be strongly considered in these patients even when FNA cytologic finding is interpreted as benign.

  View details for Web of Science ID A1995TH94700012

  View details for PubMedID 7491545

• PROSPECTIVE-STUDY OF SURGICAL RESECTION OF DUODENAL AND PANCREATIC GASTRINOMAS IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-1 16th Annual Meeting of the American-Association-of-Endocrine-Surgeons MacFarlane, M. P., FRAKER, D. L., Alexander, H. R., NORTON, J. A., Lubensky, I., Jensen, R. T. MOSBY-YEAR BOOK INC. 1995: 973–80

  Abstract

  The role of surgical resection of gastrinoma in multiple endocrine neoplasia type 1 (MEN 1) is controversial because of low biochemical cure rates, but with adequate duodenal exploration higher cure rates may be possible.We have prospectively evaluated this proposal in ten consecutive patients with MEN 1 and Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection including a detailed evaluation of the duodenum by palpation, intraoperative endoscopy with transillumination, and duodenotomy.Duodenal tumors were present in seven patients. Six of seven patients had metastatic deposits in lymph nodes, and two of seven had synchronous pancreatic tumors. Three patients had a single duodenal tumor, one patient had two tumors, and three patients had more than 20 duodenal tumors. Positive gastrin staining by use of immunohistochemistry was seen in all duodenal tumors. None of these seven patients were biochemically cured. Of three patients with negative duodenal explorations, two had single pancreatic tumors removed and one had only lymph node gastrinoma. No patients were biochemically cured.Not all patients with MEN 1 and Zollinger-Ellison syndrome have duodenal gastrinomas. In the 70% of patients with duodenal tumors, even extensive duodenal exploration with removal of positive lymph nodes does not result in cures because 86% of tumors had metastasized to lymph nodes and 43% of patients had large numbers of tumors.

  View details for Web of Science ID A1995TH94700009

  View details for PubMedID 7491542

• ADRENOCORTICOTROPIC HORMONE-SECRETING PHEOCHROMOCYTOMAS - THE EXCEPTION TO THE RULE 16th Annual Meeting of the American-Association-of-Endocrine-Surgeons Chen, H., DOPPMAN, J. L., Chrousos, G. P., NORTON, J. A., NIEMAN, L. K., Udelsman, R. MOSBY-YEAR BOOK INC. 1995: 988–95

  Abstract

  Operative management of pheochromocytomas dictates resection of the involved adrenal and exploration-resection of the contralateral gland if enlarged. We describe an exception to this rule.We report the largest series of patients with adrenocorticotropic hormone (ACTH)-secreting pheochromocytomas and review the world literature.Four patients presented with findings of adrenocorticoid and catecholamine excess, as well as elevated levels of plasma ACTH, urinary metanephrines, and urinary free cortisol. Abdominal computed tomography scans revealed bilateral adrenal hyperplasia, and magnetic resonance imaging scans showed a unilateral adrenal mass with a bright T2 signal suggesting a pheochromocytoma. Two patients underwent adrenal venous sampling localizing ACTH secretion to the pheochromocytoma. All underwent unilateral adrenalectomy for a benign tumor without morbidity or death, leaving the contralateral hyperplastic adrenal in situ. After operation all patients experienced normalization of their levels of plasma ACTH, urinary metanephrines, and urinary free cortisol with resolution of symptoms. Combining our series with previously reported cases of ACTH-secreting pheochromocytomas, almost all are benign (20 of 21), in contrast to most ACTH-secreting tumors.ACTH-secreting pheochromocytomas are the exception to the rule; unilateral adrenalectomy is curative and the contralateral hyperplastic adrenal can be preserved. This approach results in resolution of both syndromes of hormone excess and preserves long-term adrenal function.

  View details for Web of Science ID A1995TH94700011

  View details for PubMedID 7491544

• ROLE OF PREOPERATIVE IODOCHOLESTEROL SCINTISCANNING IN PATIENTS UNDERGOING ADRENALECTOMY FOR CUSHINGS-SYNDROME 16th Annual Meeting of the American-Association-of-Endocrine-Surgeons Yu, K. C., Alexander, H. R., ZIESSMAN, H. A., NORTON, J. A., DOPPMAN, J. L., Buell, J. F., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., FRAKER, D. L. MOSBY-YEAR BOOK INC. 1995: 981–87

  Abstract

  Iodocholesterol scintiscanning (IS) is a noninvasive, functional diagnostic test. We report our experience with IS as an adjunct for adrenal surgery for Cushing's syndrome.Between April 1983 and October 1994, 23 patients with Cushing's syndrome from benign primary adrenal disease underwent IS and computed tomography (CT) and/or magnetic resonance imaging (MRI). Twelve patients had unilateral adrenal involvement with a solitary adenoma (n = 11) or unilateral multinodular disease (n = 1), and 11 patients had bilateral adrenal disease.In patients with Cushing's syndrome caused by unilateral adrenal disease, IS was 100% specific and 100% sensitive, whereas in two cases CT/MRI incorrectly showed bilateral disease. In patients with Cushing's syndrome with bilateral adrenal involvement, IS had one false-negative result with nonvisualization. CT/MRI showed unilateral disease in four cases and no abnormalities in two. All patients in this series were cured of Cushing's syndrome after unilateral adrenalectomy in 11 cases and bilateral adrenalectomy in 12 cases.IS is a highly sensitive and specific imaging modality and is an essential adjunct to biochemical testing in planning adrenal resections for Cushing's syndrome caused by primary adrenal disease.

  View details for Web of Science ID A1995TH94700010

  View details for PubMedID 7491543

• PLASMA PROINSULIN-LIKE COMPONENT IN INSULINOMA - A 25-YEAR EXPERIENCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM GORDEN, P., SKARULIS, M. C., Roach, P., Comi, R. J., FRAKER, D. L., NORTON, J. A., Alexander, H. R., DOPPMAN, J. L. 1995; 80 (10): 2884-2887

  View details for Web of Science ID A1995RZ37700010

  View details for PubMedID 7559869

• LOCALIZATION OF INSULINOMAS TO REGIONS OF THE PANCREAS BY INTRAARTERIAL STIMULATION WITH CALCIUM ANNALS OF INTERNAL MEDICINE DOPPMAN, J. L., Chang, R., FRAKER, D. L., NORTON, J. A., Alexander, H. R., MILLER, D. L., COLLIER, E., SKARULIS, M. C., GORDEN, P. 1995; 123 (4): 269-273

  Abstract

  To determine the sensitivity of calcium injected into pancreatic arteries in localizing insulin-secreting tumors to regions of the pancreas.To stimulate the release of insulin, 25 patients with surgically proven insulinomas (average diameter, 15 mm) had calcium gluconate (0.025 mEq Ca++/kg body weight) injected before surgery into the arteries supplying the pancreatic head (gastroduodenal and superior mesenteric arteries) and the body and tail (splenic artery) of the pancreas.Tertiary referral hospital.Insulin levels were measured in samples taken from the right and left hepatic veins before and 30, 60, and 120 seconds after calcium injection. A twofold increase in insulin level in the sample taken from the right hepatic vein 30 or 60 seconds after injection localized the insulinoma to the segment of the pancreas supplied by the selectively injected artery. Localization done using calcium stimulation was compared with localization done using transcutaneous ultrasonography (n = 22), computed tomography (n = 23), magnetic resonance imaging (n = 21), arteriography (n = 25), and portal venous sampling (n = 9).Calcium stimulation localized 22 of 25 insulinomas (sensitivity, 88% [95% CI, 68% to 97%]) to the correct region of the pancreas. The sensitivities of the other imaging methods were 9% for ultrasonography (CI, 1% to 23%), 17% for computed tomography (CI, 5% to 39%), 43% for magnetic resonance imaging (CI, 22% to 66%), 36% for arteriography (CI, 18% to 57%), and 67% for portal venous sampling (CI, 30% to 93%). Calcium stimulation added only a few minutes to the time needed for pancreatic arteriography and caused no morbid conditions.Intra-arterial calcium stimulation with right hepatic vein sampling for insulin gradients is the most sensitive preoperative test for localizing insulinomas.

  View details for Web of Science ID A1995RN66500004

  View details for PubMedID 7611592

• IN-VIVO GENE-THERAPY OF A MURINE PANCREAS TUMOR WITH RECOMBINANT VACCINIA VIRUS ENCODING HUMAN INTERLEUKIN-1BETA 56th Annual Meeting of the Society-of-University-Surgeons Peplinski, G. R., Tsung, K., Meko, J. B., NORTON, J. A. MOSBY-ELSEVIER. 1995: 185–91

  Abstract

  Recombinant vaccinia virus (VV) encoding human interleukin-1 beta (vMJ601hIL-1 beta) given intravenously persists in tumor tissue and expresses hIL-1 beta for at least 9 days after treatment and is associated with significant retardation of tumor growth. To document the significance of this approach and to further elucidate the mechanism, this study compares the antitumor effect of vMJ601hIL-1 beta administered either intravenously or intratumorally and intravenous recombinant hIL-1 beta protein.C57BL/6 mice with established subcutaneous pancreatic tumors were randomized to treatment with intravenous or intratumoral vMJ601hIL-1 beta, wild-type VV, saline solution, or intravenous recombinant hIL-1 beta protein in a blinded fashion. Toxicity and tumor size were measured. Data were analyzed with the Kruskal-Wallis and Wilcoxon tests.Treatment with intratumoral vMJ601hIL-1 beta repeatedly resulted in significant reduction in tumor size as compared with saline treated controls (p < 0.001). Tumor growth inhibition was consistently similar after intravenous or intratumoral vMJ601hIL-1 beta administration (p > 0.52). Wild-type VV given intratumorally or intravenously had no antitumor effect versus saline controls (p > 0.30). No significant toxicity or deaths resulted from vMJ601hIL-1 beta treatment. Recombinant hIL-1 beta protein administered intravenously caused severe toxicity (median lethal dose approximately 100 micrograms/kg), and no significant antitumor effect was observed at sublethal doses versus saline controls (p = 0.19).Direct, in vivo hIL-1 beta gene delivery and expression by recombinant VV given intravenously or intratumorally results in significant tumor growth inhibition, which appears to be a consequence of local, intratumoral vaccinia infection and production of hIL-1 beta.

  View details for Web of Science ID A1995RM96500009

  View details for PubMedID 7638732

• PALLIATIVE OPERATIONS FOR PATIENTS WITH UNRESECTABLE ENDOCRINE NEOPLASIA SURGICAL CLINICS OF NORTH AMERICA Zogakis, T. G., NORTON, J. A. 1995; 75 (3): 525-538

  Abstract

  No good randomized studies exist for many types of endocrine tumors to prove that surgery increases the survival of patients with these tumors. However, many case reports and our own experience suggest that it does. Therefore, surgery may be performed to potentially increase the survival of patients with metastatic and localized malignant endocrine tumors. Subsequently, these tumors may still recur locally or distantly. Therefore, surgery is usually a palliative procedure but is occasionally curative. Because endocrine tumors secrete hormonal substances resulting in particular syndromes, debulking surgery may be necessary to control hormonal syndromes. The location of a tumor may cause mass symptoms that can also be relieved by surgery. Thus, many patients with malignant endocrine neoplasia benefit from aggressive surgery. The surgeon must determine the resectability of the tumor as well as the operative morbidity and benefit to the patient before proceeding.

  View details for Web of Science ID A1995QY63500014

  View details for PubMedID 7538230

• DETERMINANTS OF METASTATIC RATE AND SURVIVAL IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME - A PROSPECTIVE LONG-TERM STUDY GASTROENTEROLOGY Weber, H. C., VENZON, D. J., Lin, J. T., FISHBEIN, V. A., ORBUCH, M., Strader, D. B., Gibril, F., Metz, D. C., FRAKER, D. L., NORTON, J. A., Jensen, R. T. 1995; 108 (6): 1637-1649

  Abstract

  It is unclear whether tumor location, size, or the presence of multiple endocrine neoplasia type 1 (MEN-1) alters metastatic rate and survival in patients with pancreatic endocrine tumors. The purpose of this study was to determine the prognostic factors of survival and metastatic rate in patients with Zollinger-Ellison syndrome (ZES).Data were analyzed from 185 consecutive patients with ZES who were followed up prospectively.Liver metastases were present in 24% of patients and correlated with the size of the primary tumor. Duodenal tumors were smaller than pancreatic tumors. Liver metastases occurred more often (P < 0.00001) with pancreatic than duodenal tumors, whereas the metastatic rate to lymph nodes was not different. Survival of patients with liver but not lymph node metastases was shortened. In patients with sporadic ZES, liver metastases were more common during the initial evaluation and survival was decreased compared with patients with MEN-1; however, during follow-up, an equal percentage of patients with and without MEN-1 developed liver metastases.Survival was primarily determined by the presence of liver metastases. The frequency of liver metastases depends on the size and location of the primary tumor and on the presence of MEN-1 at the initial presentation. Metastases to the lymph nodes do not depend on these factors. A benign and malignant form of ZES exists.

  View details for Web of Science ID A1995RA37800005

  View details for PubMedID 7768367

• PROLONGATION OF SKIN ALLOGRAFTS BY RECOMBINANT TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 106th Annual Session of the Southern-Surgical-Association Parenteau, G. L., Doherty, G. M., Peplinski, G. R., Tsung, K., NORTON, J. A. LIPPINCOTT-RAVEN PUBL. 1995: 572–78

  Abstract

  The hypothesis is that systemic administration of recombinant tumor necrosis factor-alpha (TNF-alpha) and/or recombinant interleukin-1 alpha (IL-1 alpha) can decrease the rejection of a skin allograft.Tumor necrosis factor and IL-1 are pluripotent cytokine hormones that are central to the host immunologic response to foreign substances. Cytokine effects and toxicity may be reduced by systemic administration of recombinant cytokines. The authors previously have demonstrated that pretreatment with cytokines such as IL-1 or TNF can reduce the lethality of endotoxin (lipopolysaccharide), gram-negative sepsis, cancer cachexia, and oxygen toxicity.Skin grafts from the tails of Balb/c mice were placed on the backs of C57Bl/6 mice. Mice were treated with daily intraperitoneal saline, recombinant m-TNF (Genentech, South San Francisco, CA) or h-IL-1 (Hoffman LaRoche, Nutley, NJ) from postgraft day 1 to postgraft day 28. Tumor necrosis factor and IL-1 high doses were chosen because they protected mice from the lethality of lipopolysaccharide. Animals were examined daily for toxicity and graft rejection. Graft survival was plotted in a Kaplan-Meier plot and analyzed by the log-rank test. Comparison of proportions was done using the Fisher's exact test.Either TNF or IL-1 alone significantly prolonged skin graft survival compared with saline control. Furthermore, the combination of TNF and IL-1 prolonged skin graft survival longer than either cytokine alone. Mice on the highest dose TNF and IL-1 combination did not reject skin grafts during the 28-day treatment period. Significant toxicity was associated with cytokine treatment. Similar significant proportions of death occurred with IL-1 alone and the highest combination of TNF and IL-1.Both TNF and IL-1 can be effective as suppressors of skin allograft rejection in mice.

  View details for Web of Science ID A1995QX81000015

  View details for PubMedID 7748039

• CONSTRUCTION AND EXPRESSION IN TUMOR-CELLS OF A RECOMBINANT VACCINIA VIRUS ENCODING HUMAN INTERLEUKIN-1-BETA 47th Annual Meeting of the Society-of-Surgical-Oncology Peplinski, G. R., Tsung, K., Whitman, E. D., Meko, J. B., NORTON, J. A. LIPPINCOTT-RAVEN PUBL. 1995: 151–59

  Abstract

  Human interleukin-1 beta (hIL-1 beta) injected intratumorally has demonstrated growth inhibition of transplanted subcutaneous tumors in mice, regression of metastatic lesions, resistance to tumor rechallenge, and increased survival. Vaccinia virus (VV) can be genetically engineered to produce cytokines and may be an effective vector for gene therapy of cancer. This study was designed to (a) construct a VV expressing hIL-1 beta, (b) assess tumor cell infection in vitro with this construct, (c) measure hIL-1 beta production, and (d) assess the bioactivity of the secreted cytokine.The hIL-1 beta gene was amplified from a plasmid clone using polymerase chain reaction (PCR) and then cloned into a homologous recombination (HR) and expression vector, which was used to insert the hIL-1 beta gene into the VV genome. Selection of the recombinant VV (vMJ601hIL-1 beta) was based on inactivation of viral TK and expression of beta-galactosidase. vMJ601hIL-1 beta infectivity and cytokine production was assessed by infecting tumor cell lines and analyzing culture supernatants for hIL-1 beta. Bioactivity of the hIL-1 beta produced was demonstrated using an IL-1 dependent T helper cell line.The hIL-1 beta gene was successfully cloned into the VV genome by HR, which was confirmed by PCR. vMJ601hIL-1 beta efficiently infected tumor cells, as shown by increased hIL-1 beta secretion (0 to > 500 ng/ml) and morphologic evidence of viral cytopathic effect. vMJ601hIL-1 beta-infected cells secreted large amounts of hIL-1 beta (mean 772 ng/10(6) cells/24 h). The secreted hIL-1 beta was bioactive (mean bioactivity 6.8 x 10(8) U/mg of hIL-1 beta).(a) hIL-1 beta can be cloned into VV, (b) vMJ601hIL-1 beta retains its infectivity, (c) a large amount of hIL-1 beta is secreted, and (d) the secreted hIL-1 beta is bioactive. Recombinant VV may allow in situ cytokine gene delivery and expression in established tumors.

  View details for Web of Science ID A1995QH86800011

  View details for PubMedID 7728569

• MANAGEMENT OF PATIENTS WITH ZOLLINGER-ELLISON SYNDROME ANNUAL REVIEW OF MEDICINE Meko, J. B., NORTON, J. A. 1995; 46: 395-411

  Abstract

  Zollinger-Ellison syndrome (ZES) is caused by gastrin-secreting tumors called gastrinomas. Patients commonly present with peptic ulcer disease and may have recurrent, multiple, and atypically located ulcers, e.g. in the jejunum. Alternatively, severe diarrhea may be the only presenting symptom. Patients with multiple endocrine neoplasia Type I (MEN-I) and ZES become symptomatic at an earlier age than patients with sporadic ZES. Patients with ZES have elevated fasting serum gastrin concentrations (> 100 pg/ml) and basal gastric acid hypersecretion (> 15 mEq/h). The secretin stimulation test is the best test to distinguish ZES from other conditions resulting in elevated gastrin levels. Gastric acid hypersecretion can be controlled in virtually all patients with H2-receptor antagonists or omeprazole, thus rendering total gastrectomy unnecessary. Computed tomography (CT), magnetic resonance imaging (MRI), radionuclide octreotide scanning, endoscopic ultrasound, and the selective arterial secretin injection test are the recommended imaging studies for localization of gastrinoma; nevertheless, 50% of gastrinomas are not evident on preoperative imaging studies. All patients with sporadic gastrinoma who do not have unresectable metastatic disease should undergo exploratory laparotomy for potential curative resection. With increased awareness of duodenal tumors, gastrinoma can be found in 80-90% of patients. Surgery may be the most effective treatment for metastatic gastrinoma if most or all of the tumor can be resected. The management of patients with MEN-I and ZES remains controversial. Some clinicians advocate an aggressive surgical approach, whereas others have had little success in rendering patients eugastrinemic.

  View details for Web of Science ID A1995QT17500035

  View details for PubMedID 7598474

• DEGENERATION OF SERTOLI AND SPERMATOGENIC CELLS IN HOMOZYGOUS AND HETEROZYGOUS WEAVER MICE JOURNAL OF NEUROGENETICS Verina, T., Tang, X., Fitzpatrick, L., Norton, J., Vogelweid, C., Ghetti, B. 1995; 9 (4): 251-265

  Abstract

  In the neurological mutant mouse weaver (wv/wv), the majority of males are infertile due to hypospermatogenesis. Heterozygous weaver mice (wv/+) cease mating successfully when males reach an average age of 3.5 months. The contents of epididymal fluid were scored for the number of sperm and sperm motility in wv/wv, wv/+ and controls. Testes were examined in mice of the three genotypes at various ages using light and electron microscopy. In wv/+ males, sperm counts were significantly lower than in controls and were significantly higher than in wv/wv. The seminiferous epithelium in weaver mice appears depleted soon after puberty and a wide range of degenerative changes was identified in both germ cells and Sertoli cells. Analogous cellular aberrations were detected in heterozygous males, but they appeared at an older age and were not as severe as in wv/wv. We hypothesize that in weaver homo- and heterozygosity the damage of Sertoli cells may induce degeneration of germinal cells and particularly affect the most advanced spermatogenic cells.

  View details for Web of Science ID A1995QH61300005

  View details for PubMedID 7760215

• LOCALIZATION AND OPERATIVE MANAGEMENT OF UNDESCENDED PARATHYROID ADENOMAS IN PATIENTS WITH PERSISTENT PRIMARY HYPERPARATHYROIDISM 15th Annual Meeting of the American-Association-of-Endocrine-Surgeons Billingsley, K. G., FRAKER, D. L., DOPPMAN, J. L., NORTON, J. A., Shawker, T. H., SKARULIS, M. C., Marx, S. J., Spiegel, A. M., Alexander, H. R. MOSBY-YEAR BOOK INC. 1994: 982–90

  Abstract

  Between 5% and 10% of patients who undergo cervical exploration for primary hyperparathyroidism will have persistent or recurrent hyperparathyroidism. Many of these patients have parathyroid tumors in unusual locations. One such site of ectopic parathyroid tissue is an undescended parathyroid adenoma at or superior to the carotid bifurcation. We describe our experience with the preoperative localization and surgical management of undescended parathyroid adenomas.From 1982 to 1993 a consecutive series of 255 patients have undergone localization studies and surgical exploration for persistent or recurrent hyperparathyroidism at the Clinical Center of the National Institutes of Health. Operative strategy was determined by review of the patient's surgical history, disease reports, and data from localizing studies. Patients with an undescended parathyroid adenoma identified before the operation were examined with a direct approach high in the neck. Patients who did not have definitive preoperative localization were explored with the previous transverse cervical incision.Seventeen undescended parathyroid adenomas were identified in 255 patients. Thirteen (76%) of 17 patients had an undescended parathyroid adenoma precisely localized before the operation and were examined via a limited, oblique incision high in the neck anterior to the sternocleidomastoid muscle. In the 13 patients who had undergone accurate localization before the operation, the median operative time was 75 minutes compared with 235 minutes for four patients who did not have an undescended parathyroid adenoma identified before the operation and were examined via a previous transverse cervical incision. All patients were cured of their hyperparathyroidism.Undescended parathyroid adenomas were the cause of failed cervical exploration in 17 (7%) of 255 patients. Accurate preoperative localization of these lesions is possible in most cases with a combination of noninvasive and invasive modalities. Successful preoperative localization can convert a prolonged exploration of the neck and mediastinum into a brief, curative procedure with minimal morbidity.

  View details for Web of Science ID A1994PW09000006

  View details for PubMedID 7985106

• APPARENT LYMPH-NODE PRIMARY GASTRINOMA 15th Annual Meeting of the American-Association-of-Endocrine-Surgeons Arnold, W. S., FRAKER, D. L., Alexander, H. R., Weber, H. C., NORTON, J. A., Jensen, R. T. MOSBY-YEAR BOOK INC. 1994: 1123–30

  Abstract

  The existence of lymph node (LN) primary gastrinoma as a cause of Zollinger-Ellison syndrome is controversial. We reviewed our experience with patients in whom gastrinomas were identified and excised only from LNs.From 1982 to 1992, 110 patients with ZES underwent exploration for gastrinoma and 21 (19%) had disease limited to one or more LNs. Standardized exploration included intraoperative ultrasonography, intraoperative endoscopy with transillumination and exploratory duodenotomy in 86%, 67%, and 24% of patients, respectively. Each patient underwent yearly biochemical and radiologic follow-up.Thirteen patients (62%) with a median follow-up period of 5.8 years had an initial biochemical cure, whereas eight patients (38%) with a median follow-up period of 3.6 years had persistent disease. Of the 13 patients whose condition initially returned to normal, four have had biochemical recurrence, with a median time to recurrence of 4.2 years and a median follow-up period of 7.4 years. Nine patients (43%) remain biochemically cured, with a median follow-up period of 5.3 years.Resection of apparent LN primary gastrinoma is warranted, because 43% of those who underwent resection had no evidence of disease, with a median follow-up period of 5.3 years.

  View details for Web of Science ID A1994PW09000027

  View details for PubMedID 7985097

• COST OF UNSUCCESSFUL SURGERY FOR PRIMARY HYPERPARATHYROIDISM 15th Annual Meeting of the American-Association-of-Endocrine-Surgeons Doherty, G. M., Weber, B., NORTON, J. A. MOSBY-YEAR BOOK INC. 1994: 954–58

  Abstract

  Surgery for primary hyperparathyroidism demands skill and experience. The monetary and personal costs of unsuccessful surgery are investigated here.We reviewed 47 consecutive patients operated on by one surgeon during a period of 16 months, including their clinical data and medical costs of their treatment.All 39 patients without previous operation were normocalcemic after operation, with no recurrent nerve injury nor hypoparathyroidism. Of the eight who had undergone previous operation elsewhere, seven had abnormal glands that should have been resected at the initial operation, and hypoparathyroidism developed in two patients. Total costs of reoperative parathyroid surgery were more than twice the cost of an initial operation (median, $8383 versus $3948, p < 0.001) because of the cost of radiologic studies (median, $3378 versus $43, p < 0.001).(1) An experienced parathyroid surgeon can consistently cure hyperparathyroidism at the initial operation. (2) The majority of patients referred for hyperparathyroidism not cured by previous operation have glands in usual anatomic locations. (3) The cost to the patient of an inadequate initial operation includes the physical effects of remaining hyperparathyroid, additional time off work, potentially invasive localization testing, reoperative surgery with increased risk of complications, and substantial expense. Initial parathyroid surgery should be performed by surgeons experienced and proficient in its practice.

  View details for Web of Science ID A1994PW09000002

  View details for PubMedID 7985102

• THE PREDICTIVE VALUE OF DIAGNOSTIC-TESTS FOR PHEOCHROMOCYTOMA 15th Annual Meeting of the American-Association-of-Endocrine-Surgeons Peplinski, G. R., NORTON, J. A. MOSBY-YEAR BOOK INC. 1994: 1101–10

  Abstract

  Ascertaining or excluding a pheochromocytoma may be difficult. The purpose of this study is to identify preoperative tests that are good predictors of a pheochromocytoma.Patients presumptively diagnosed with a pheochromocytoma based on clinical assessment, plasma or urinary catecholamines, computed tomography, or magnetic resonance imaging were analyzed. The sensitivity, specificity, positive, and negative predictive values were determined for each test based on the pathologic finding of a pheochromocytoma. Data were analyzed with Student's t test or Fisher's exact test.Of 14 patients, seven had pathologically proven pheochromocytomas, whereas three had cortical adenomas. In four patients, a pheochromocytoma was excluded by repeat testing. The 24-hour urinary mean metanephrine levels were significantly different between patients with and without pheochromocytomas (5.8 micrograms vs 0.5 micrograms, p = 0.05) and had the best positive predictive value (83%) and negative predictive value (100%) of the biochemical tests. T2-weighted magnetic resonance imaging had a 100% positive and negative predictive value. Age, sex, symptoms, blood pressure, tumor location, tumor size, and plasma catecholamine levels could not accurately predict or exclude a pheochromocytoma.T2-weighted magnetic resonance imaging is the imaging study of choice for predicting a pheochromocytoma. The 24-hour urinary metanephrine level is the single best biochemical indicator of a pheochromocytoma. Plasma catecholamine levels and computed tomography are not helpful in diagnosing or excluding a pheochromocytoma.

  View details for Web of Science ID A1994PW09000024

  View details for PubMedID 7985094

• SURGERY IN ZOLLINGER-ELLISON SYNDROME ALTERS THE NATURAL-HISTORY OF GASTRINOMA 114th Annual Scientific-Session of the American-Surgical-Association FRAKER, D. L., NORTON, J. A., Alexander, H. R., VENZON, D. J., Jensen, R. T. LIPPINCOTT WILLIAMS & WILKINS. 1994: 320–30

  Abstract

  The authors assessed the impact of gastrinoma resection on the subsequent development of hepatic metastases in Zollinger-Ellison syndrome.The symptoms of acid hypersecretion can be controlled medically in Zollinger-Ellison syndrome with high-dose pharmacologic therapy. The current role of surgery is curative excision of the gastrinoma. Because biochemical cure is obtained only in a portion of the patients and the neoplastic disease may be indolent in this syndrome, the ability of surgical resection of gastrinoma to alter or improve the subsequent development of hepatic metastases and mortality has not been defined.One hundred twenty-four patients with the biochemical diagnosis of Zollinger-Ellison syndrome and no hepatic metastases on initial imaging studies were evaluated. Ninety-eight patients underwent surgical exploration for curative gastrinoma resections while 26 patients were managed medically. Long-term follow-up regarding development of hepatic metastases and survival were evaluated.Surgical exploration with gastrinoma excision resulted in a significantly decreased incidence of hepatic metastases 3% (3/98) compared with patients managed medically 23% (6/26) with comparable follow-up (p < 0.003). Two deaths due to metastatic gastrinoma occurred in the nonoperative group compared with no disease-specific deaths in the surgical group (p = 0.085).For the patient with Zollinger-Ellison syndrome without metastatic disease, surgical exploration with attempted curative gastrinoma resection is recommended because it may alter the natural history of this syndrome.

  View details for Web of Science ID A1994PH67000008

  View details for PubMedID 7916560

• PREDICTIVE DNA TESTING AND PROPHYLACTIC THYROIDECTOMY IN PATIENTS AT RISK FOR MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A 114th Annual Scientific-Session of the American-Surgical-Association Wells, S. A., Chi, D. D., Toshima, K., DEHNER, L. P., Coffin, C. M., DOWTON, B., Ivanovich, J. L., DeBenedetti, M. K., Dilley, W. G., Moley, J. F., NORTON, J. A., DONISKELLER, H. LIPPINCOTT WILLIAMS & WILKINS. 1994: 237–50

  Abstract

  Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy.A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing.Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal.The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

  View details for Web of Science ID A1994PH67000002

  View details for PubMedID 7916559

• IN-VITRO AND IN-VIVO KINETICS OF RECOMBINANT VACCINIA VIRUS CANCER-GENE THERAPY 55th Annual Meeting of the Society-of-University-Surgeons Whitman, E. D., Tsung, K., Paxson, J., NORTON, J. A. MOSBY-ELSEVIER. 1994: 183–88

  Abstract

  Gene therapy of cancer is a promising therapeutic modality. Recombinant vaccinia viruses (RecVV), engineered to produce cytokines, may be effective in this area. This study's purpose was to investigate the kinetics of RecVV infection, measuring protein production and in vivo viral growth pattern.RecVV were constructed by homologous recombination, encoding murine interleukin-2 (mIL-2). After tumor cell infection, mIL-2 production was measured in vitro. Tumor-bearing and naive hosts were inoculated with RecVV and wild type vaccinia. Livers, spleens, and (where applicable) tumors were sequentially harvested, and tissue viral levels were measured.Infected tumor cells made high levels of mIL-2 after infection with RecVV encoding for this cytokine. Naive mice were able to clear recombinant but not wild type VV from their livers and spleens by days 3 and 5, respectively. Tumor-bearing animals had persistent RecVV titers in the tumor tissue at day 8.RecVV can infect tumor cells, causing the production of a large amount of foreign protein but are attenuated relative to wild type virus in the murine host.

  View details for Web of Science ID A1994PA54400009

  View details for PubMedID 8047984

• ENDOCRINE SURGICAL DISEASES OF ELDERLY PATIENTS SURGICAL CLINICS OF NORTH AMERICA Whitman, E. D., NORTON, J. A. 1994; 74 (1): 127-144

  Abstract

  The causes, evaluation, and preoperative and postoperative care of primary hyperparathyroidism and thyroid nodules in the elderly patient population have been described. Primary hyperparathyroidism is easily diagnosed and is almost always curable by surgery. Elderly patients with asymptomatic disease are candidates for nonoperative, expectant management. If they become symptomatic, surgery should be performed. Postoperative care of the elderly patient who has undergone parathyroid exploration is potentially complicated by the patient's other medical problems, including cardiac and pulmonary difficulties, variable severity of symptoms of hypocalcemia, and sensitivity to medications. Thyroid nodules in the elderly may present later than in younger patients and are more likely to contain malignant tissue. Tissue diagnosis preoperatively, usually by FNA testing, is mandatory. Anaplastic thyroid carcinoma and thyroid lymphoma are both treated nonoperatively. Thyroid surgery in the elderly is usually well tolerated, although other medical conditions, as mentioned above, may complicate postoperative care. Thyroid carcinoma in the elderly carries a worse prognosis than in younger patients and should always be treated with postoperative adjuvant (radioablative) therapy. Although this does not affect survival (from the thyroid cancer), it does extend the disease-free interval. As the number of elderly patients increases, the frequency with which these disorders are encountered will also rise. It is important to realize that almost all elderly patients can both tolerate and benefit from surgical correction of these two disorders, if appropriate preoperative evaluation is coupled with excellent intraoperative and postoperative care.

  View details for Web of Science ID A1994MX78300009

  View details for PubMedID 8108764

• ADRENOCORTICOTROPIC HORMONE - SECRETING ISLET-CELL TUMORS - ARE THEY ALWAYS MALIGNANT RADIOLOGY DOPPMAN, J. L., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., FRAKER, D. L., NORTON, J. A., Jensen, R. T. 1994; 190 (1): 59-64

  Abstract

  To evaluate the frequency with which benign occult islet cell tumors cause ectopic adrenocorticotropic hormone (ACTH) syndrome.Ten patients with Cushing syndrome due to the production of ACTH by a pancreatic islet cell tumor were studied. In addition, 53 cases of ACTH-secreting islet cell tumors in the English-language literature were reviewed.All 10 of the authors' patients had malignant islet cell tumors. Liver metastases were present in all 10 patients at presentation. Five patients are dead, four patients are alive with liver metastases, and one patient is alive without gross evidence of residual tumor after distal pancreatectomy and right hepatectomy. Eight of the 10 islet cell carcinomas produced gastrin in addition to ACTH. In the 53 reported cases of ectopic ACTH production, there was only one benign adenoma with a prolonged follow-up.When ectopic ACTH production is caused by an islet cell tumor, the tumor is large and malignant and has usually metastasized to the liver by the time Cushing syndrome is diagnosed. No occult ACTH-producing islet cell tumor was encountered in the authors' experience or in a review of the literature.

  View details for Web of Science ID A1994MW25300014

  View details for PubMedID 8259429

• Endocrine tumors of the pancreas. Current opinion in general surgery Meko, J. B., NORTON, J. A. 1994: 186-194

  Abstract

  Pancreatic endocrine tumors are rare, yet can cause significant morbidity due to excessive secretion of hormones. Octreotide is effective in reducing the plasma concentrations of many of these hormones. The availability of potent H2-receptor antagonists and omeprazole has altered the emphasis in patients with Zollinger-Ellison syndrome away from total gastrectomy and towards resection of the gastrinoma for potential cure. Fifty percent of insulinomas and gastrinomas are not evident on preoperative imaging studies, despite their sophistication. Calcium angiography, endoscopic ultrasonography, isotope-labeled octreotide scanning, and injection of methylene blue during secretin angiography are recent imaging modalities that have shown promise in the localization of these tumors. Intraoperative ultrasound has emerged as the best method for operative detection of insulinomas. Duodenotomy and intraoperative endoscopic transillumination are especially important in the surgical management of Zollinger-Ellison syndrome because 30% to 40% of gastrinomas are located in the duodenum. The management of patients with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome continues to be controversial. Some advocate an aggressive surgical approach, whereas others have had little success in rendering patients eugastrinemic.

  View details for PubMedID 7583963

• PROSPECTIVE EVALUATION OF SELECTIVE VENOUS SAMPLING FOR PARATHYROID-HORMONE CONCENTRATION IN PATIENTS UNDERGOING REOPERATIONS FOR PRIMARY HYPERPARATHYROIDISM 14th Annual Meeting of the American-Association-of-Endocrine-Surgeons Sugg, S. L., FRAKER, D. L., Alexander, H. R., DOPPMAN, J. L., MILLER, D. L., Chang, R., SKARULIS, M. C., Marx, S. J., Spiegel, A. M., NORTON, J. A., Cohn, K., Clark, O. H., Thompson, N. W. MOSBY-YEAR BOOK INC. 1993: 1004–10

  Abstract

  The utility of standard radiologic imaging studies in guiding reoperative parathyroid surgery for primary hyperparathyroidism is widely known and accepted. The additional information gained by selective venous sampling in that patient population has not been well defined. We report the results of our experience with this method.Between 1982 and 1992, 223 consecutive patients underwent reoperations for persistent or recurrent primary hyperparathyroidism after a prospectively determined series of imaging studies. Patients underwent noninvasive testing consisting of ultrasonography, computed tomography, technetium thallium scanning, and magnetic resonance imaging. Patients with negative, equivocal, or discordant results on the noninvasive studies proceeded to angiography. If angiography was negative, selective venous sampling was performed.Eighty-six patients (39%) with negative or equivocal noninvasive test and angiogram results underwent selective venous sampling. Seventy-six patients (88%) had a significant gradient in levels of parathyroid hormone from veins draining the left side of the neck (n = 25), the right side of the neck (n = 33), both sides of the neck (n = 7), and the thymus (n = 11). Correlation of these findings with operative findings revealed a sensitivity of 88% and a specificity of 86%. In the subgroup of patients who underwent venous sampling and had completely negative results of standard radiologic studies (35 of 86; 40%), 28 patients (80%) had venous gradients and seven patients (20%) had no gradient. Of those 28 patients in whom the venous sampling gradients were the only positive localization study, the venous samplings were helpful in 23 patients (true positive gradients), and the operative success rate was 93%. In the seven patients with no positive preoperative localizing studies including venous sampling, there were two operative failures (operative success, 71%).Our results show that selective venous sampling is a highly sensitive and specific method to regionally localize abnormal parathyroid glands not imaged by standard noninvasive and invasive radiologic techniques. Venous sampling is the study of choice in guiding reoperative procedures for occult abnormal parathyroid glands that are undetected despite the use of all available imaging studies.

  View details for Web of Science ID A1993MK90000003

  View details for PubMedID 8256203

• FINE-NEEDLE ASPIRATION BIOPSY OF ADRENAL MASSES IN PATIENTS WITH EXTRAADRENAL MALIGNANCY SURGERY Candel, A. G., Gattuso, P., Reyes, C. V., Prinz, R. A., Castelli, M. J., Cohn, H. E., Hunt, T. K., NORTON, J. A., McLeod, M. K., Allo, M., DOPPMANN, J. L., Thompson, N. W. 1993; 114 (6): 1132-1137

  Abstract

  Reports evaluating the efficacy of fine needle aspiration (FNA) of the adrenal gland have suggested a possible correlation between size of an adrenal mass and the presence of a primary or metastatic malignancy. These studies have focused on FNAs of all adrenal gland masses regardless of clinical history. This study investigates this relationship in a subpopulation of patients with a known history of primary extraadrenal malignancy.All patients who have undergone computed tomographic-guided FNA biopsy of an adrenal mass at Loyola University Medical Center and Hines Veterans Administration Hospital, from 1985 to 1991, were reviewed.If size was assumed to be an independent predictor for presence of metastases, the highest efficiency was obtained with a cutoff value of 3 cm. This value divided the group into 15 (42%) "low-risk" (< or = 3 cm) and 21 (58%) "high-risk" (> 3 cm) subjects. In the "low-risk" group, 87% of the masses (13 of 15) were benign and 13% (2 of 15) were malignant. Within the "high-risk" group, more than 95% of the masses (20 of 21) were malignant, with a single (5%) benign case (p < 0.05).There is a significant correlation between the size of an adrenal nodule and the presence of metastases in patients with a known primary extraadrenal malignancy. Nodules greater than 3 cm have a very high probability of involvement by metastatic tumor. Nodules 3 cm or smaller are usually benign, but metastatic tumor can still be found in up to 13%. FNA biopsy is useful in evaluating adrenal masses in this setting.

  View details for Web of Science ID A1993MK90000022

  View details for PubMedID 8256219

• EFFECTIVE REVERSIBILITY OF THE SIGNS AND SYMPTOMS OF HYPERCORTISOLISM BY BILATERAL ADRENALECTOMY 14th Annual Meeting of the American-Association-of-Endocrine-Surgeons ZEIGER, M. A., FRAKER, D. L., PASS, H. I., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., NORTON, J. A., Merrell, R. C., Pasieka, J. L., Kaplan, E., Clark, O. H., Andersen, D., Thompson, N. W. MOSBY-YEAR BOOK INC. 1993: 1138–43

  Abstract

  The long-term outcome of bilateral adrenalectomy in the management of patients with Cushing's syndrome has not been previously well studied.We reviewed our long-term results in 34 patients treated with bilateral adrenalectomy between 1983 and the present. Fourteen presented with occult or metastatic ectopic adrenocorticotropic hormone (ACTH) syndrome, 10 with failed treatment of Cushing's disease, five with primary micronodular and four with massive macronodular adrenocortical disease and one with indeterminate cause of Cushing's syndrome.All patients underwent bilateral adrenalectomy. Of 19 patients who required antihypertensive medications before operation, 15 (79%) had significant improvement and were either off all antihypertensive medication or required less medication after operation. Of 7 patients who required medications for diabetes mellitus, after operation 6 (86%) required no medication or changed from injections to oral hypoglycemic agents. Of 9 patients with mood changes or depression, the symptoms of 8 (88%) resolved. Of 29 patients with documented weight gain, 23 (79%) showed marked weight loss. Of 13 hirsute patients, 10 (77%) had resolutions of symptoms. Of 21 patients with complaints of fatigue, the symptoms of 16 (76%) resolved. Of 8 women with amenorrhea, 6 (75%) had resolution of symptoms. Each patient in the primary adrenocortical disease group, except one with residual fatigue, had complete resolution of his or her symptoms. There was no difference in resolution of symptoms between the ectopic ACTH and Cushing's disease groups. Six patients died: in the ectopic ACTH group one died of suicide at 1 month, and four of metastatic tumor at 9, 24, 25, and 48 months, and the patient with macronodular adrenocortical hyperplasia died of a myocardial infarction at 30 months. The remainder of the patients have been followed for a mean of 32 months (3 to 67 months). None of the patients had any evidence of recurrent hypercortisolism.We conclude that bilateral adrenalectomy is a safe, effective, and long-lasting method to ameliorate the devastating signs and symptoms of hypercortisolism in patients with Cushing's syndrome.

  View details for Web of Science ID A1993MK90000023

  View details for PubMedID 8256220

• PREVALENCE OF PHEOCHROMOCYTOMA AND HYPERPARATHYROIDISM IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A - RESULTS OF LONG-TERM FOLLOW-UP 14th Annual Meeting of the American-Association-of-Endocrine-Surgeons Howe, J. R., NORTON, J. A., Wells, S. A., Proye, C., Talpos, G. B., Carty, S. E. MOSBY-YEAR BOOK INC. 1993: 1070–77

  Abstract

  Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant condition in which virtually all affected kindred members have medullary thyroid carcinoma (MTC). However, the penetrance of pheochromocytoma and hyperparathyroidism in affected kindred members is variable, and the true prevalence of these neoplasms is unclear from previous studies.Members of MEN 2A kindreds with more than 10 years of follow-up screening for MTC, pheochromocytoma, or hyperparathyroidism were studied. The diagnosis of pheochromocytoma was based on histologic examination and hyperparathyroidism on both parathyroid hyperplasia plus preoperative elevation of serum calcium levels.Eighty-six patients operated on for MTC from 12 different MEN 2A kindreds were studied, with a mean follow-up of 12.9 years of screening for pheochromocytoma (79 patients) and 15.0 years for hyperparathyroidism (78 patients). Pheochromocytomas developed in 42% of patients with MTC, with a range of 6% to 100% in different kindreds. The prevalence of hyperparathyroidism was 35%, ranging from 0% to 53% between kindreds. The average age at diagnosis of MTC, pheochromocytoma, and hyperparathyroidism was 29, 37, and 36 years, respectively.We conclude that the penetrance of pheochromocytoma and hyperparathyroidism is variable in different kindreds with MEN 2A but that the overall prevalence of pheochromocytoma approximates 40% and that of hyperparathyroidism 35%.

  View details for Web of Science ID A1993MK90000012

  View details for PubMedID 7903003

• EXPRESSION OF PAPILLARY THYROID-CARCINOMA IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A 14th Annual Meeting of the American-Association-of-Endocrine-Surgeons Decker, R. A., Numann, P. J., NORTON, J. A., Moley, J. F., Talpos, G. B. MOSBY-YEAR BOOK INC. 1993: 1059–63

  Abstract

  The ret protooncogene (RET), shown to be rearranged in human papillary thyroid cancers (PTC), has been mapped by in situ hybridization to 10q11.2 near the predisposition locus for the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). To date PTC has not been an observed characteristic of MEN 2; however, linkage studies in affected families have shown no meiotic recombinants between the MEN 2A gene and RET suggesting tight linkage between loci. Furthermore, RET appears to be expressed in medullary thyroid carcinoma (MTC) and pheochromocytoma and for these reasons has emerged as a candidate gene for MEN 2.Two patients from a single kindred with MEN 2A (18 affected) are presented in which expression of PTC appeared to cosegregate with the MEN2 gene. In both patients the diagnosis of occult C-cell disease was suspected by an elevation in the basal and pentagastrin-stimulated peak calcitonin levels. Histologic examination of the thyroid gland after operation for MTC revealed tumor nodules consistent with PTC. There was no history of radiation exposure. Characteristics of MEN 2A syndrome in the kindred in addition to MTC and PTC include hyperparathyroidism and Hirschsprung's disease in three and two patients, respectively.Two-point linkage analysis with a new highly polymorphic DNA marker, LGfd01, derived from a cosmid clone mapping to 10q11.2 assigns the MEN 2 predisposition locus in this kindred to chromosome 10q11.2 (0 = 0.00; maximum LOD, 4.78). Recombination between MEN 2A and a polymorphic microsatellite from the RET locus could not be shown among informative meioses.The observed association of MEN 2A and PTC is intriguing and suggests that the variation in expression of the syndrome may be due to the presence of a structural alteration affecting several contiguous genes spanning the putative MEN 2 region.

  View details for Web of Science ID A1993MK90000010

  View details for PubMedID 7903002

• REOPERATION FOR RECURRENT OR PERSISTENT MEDULLARY-THYROID CANCER 14th Annual Meeting of the American-Association-of-Endocrine-Surgeons Moley, J. F., Wells, S. A., Dilley, W. G., Tisell, L. E., NORTON, J. A., Grant, C., Pasieka, J. L., Merrell, R. C., Talpos, G. B., Rosen, I. B., Carty, S. E. MOSBY-YEAR BOOK INC. 1993: 1090–96

  Abstract

  Initial operations for medullary thyroid cancer (MTC) frequently do not eradicate all disease, as evidenced by persistently elevated levels of stimulated plasma calcitonin.Thirty-two patients with MTC and elevated stimulated plasma calcitonin levels after thyroidectomy were studied between 1990 and 1993. Thirty-five repeat neck explorations and microdissections were performed. Four patients also underwent a median sternotomy and mediastinal dissection.In nine patients (group 1), stimulated plasma calcitonin levels were undetectable after reoperation, whereas in 13 cases (group 2) the calcitonin levels decreased by 40% or more. In 10 cases (group 3) the CT levels did not decrease. Primary tumors that exhibited invasive features (invasion of adjacent structures or extranodal or extracapsular spread) were found more often in patients from group 3 than in patients from groups 1 or 2 (p < 0.05, Fisher's exact test).Reoperation resulted in normalization of calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The data also suggest that patients whose primary MTC has invaded tissues beyond the thyroid gland or a lymph node capsule are less likely to benefit from repeat operation.

  View details for Web of Science ID A1993MK90000015

  View details for PubMedID 8256212

• AN EVALUATION OF HUMAN RECOMBINANT ALPHA-INTERFERON IN PATIENTS WITH METASTATIC GASTRINOMA GASTROENTEROLOGY Pisegna, J. R., SLIMAK, G. G., DOPPMAN, J. L., Strader, D. B., Metz, D. C., Benya, R. V., ORBUCH, M., FISHBEYN, V. A., FRAKER, D. L., NORTON, J. A., Maton, P. N., Jensen, R. T. 1993; 105 (4): 1179-1183

  Abstract

  Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is < 20%. Chemotherapeutic regimens are of limited benefit. The aim of this study was to evaluate the use of interferon in these patients because a preliminary report suggested it might be effective.The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant alpha interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained.No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly.These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.

  View details for Web of Science ID A1993LZ24600029

  View details for PubMedID 8405864

• PARENTERAL CONTROL OF GASTRIC-ACID HYPERSECRETION IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME DIGESTIVE DISEASES AND SCIENCES Vinayek, R., Hahne, W. F., Euler, A. R., NORTON, J. A., Jensen, R. T. 1993; 38 (10): 1857-1865

  Abstract

  Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome is increasingly required; however, existing methods of determining the required dose are cumbersome and not applicable in all centers. A previous study suggested that the required parenteral dose of histamine H2-receptor antagonists correlated with the previous oral dose. In the present study, in 31 patients with Zollinger-Ellison syndrome we evaluated the hypothesis that an effective parenteral histamine H2-receptor antagonist dose could be predicted from the previous oral dose. Twenty-three patients were taking oral ranitidine (mean 1.3 g/day), six patients famotidine (152 mg/day), and two patients cimetidine (1.8 g/day). Each patient was treated with a continuous intravenous infusion of the equivalent dose of ranitidine (mean dose 1 mg/kg/hr with 35% requiring 0.5 mg/kg/hr, 49% 1 mg/kg/hr, 3% 1.5 mg/kg/hr, 10% 2 mg/kg/hr, and 3% 2.5 mg/kg/hr. This dose of ranitidine acutely controlled acid secretion (< 10 meq/hr) in all patients. To evaluate long-term efficacy and safety, 20 patients were maintained on this dose through the peri- and postoperative periods. Mean duration was 7.1 days with 25% treated 3-5 days, 40% 6-8 days, 30% 8-10 days, and 5% > 10 days. The predicted dose continued to control acid secretion in 95% of patients with one patient requiring one dose adjustment. No biochemical, clinical, or hematological toxicity was seen, although ranitidine was stopped in one patient because of skin rash. These results demonstrate that the parenteral dose of ranitidine required to control acid secretion in patients with Zollinger-Ellison syndrome can be predicted from the oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993MB72700014

  View details for PubMedID 8104773

• CONTROVERSIES IN SURGICAL THERAPY FOR APUDOMAS SEMINARS IN SURGICAL ONCOLOGY FRAKER, D. L., NORTON, J. A. 1993; 9 (5): 437-442

  Abstract

  Location of gastrinomas by means of portal venous sampling is a technique in which venous blood from various sites in the portal system around the pancreas and duodenum is obtained and assayed for gastrin levels. A gradient of 50% or greater compared to systemic gastrin levels from a given location regionally identifies the site of gastrin overproduction, thereby locating the tumor. The only area in which venous sampling may help, in the authors' opinion, is in the small subset of patients who have occult gastrinoma not imaged with any other modality, in the body or tail of the pancreas that cannot be found with intraoperative ultrasound or palpation. It is considered that a secretin angiogram is equally effective and is a simpler procedure. Similarly, in insulinoma regional location of the tumor by means of a calcium angiogram has eliminated the usefulness of portal venous sampling. Controversial areas of surgical treatment of APUDomas often reflect a balance between the risks and benefits of aggressive surgery, as data to support an aggressive surgical approach to obtain improved survival often do not exist. For example, if patients with occult MTC can undergo cervical reexploration with minimal or no morbidity the potential benefit of removing malignant disease, warrants this approach. Similarly, if patients with MEN-1 can be explored safely with resection of pancreatic and duodenal tumors, then this position can be defended. On the other hand, if a subgroup of patients with MEN-2 and pheochromocytomas can be spared bilateral adrenalectomy without compromising their long-term outcome in terms of disease-free survival, then this conservative approach is warranted.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993LZ54500010

  View details for PubMedID 7902610

• GSALPHA - IDENTIFICATION OF A GENE HIGHLY EXPRESSED BY INSULINOMA AND OTHER ENDOCRINE TUMORS 54TH ANNUAL MEETING OF THE SOC OF UNIVERSITY SURGEONS ZEIGER, M. A., NORTON, J. A. MOSBY-YEAR BOOK INC. 1993: 458–63

  Abstract

  The isolation of mRNA molecules that are either uniquely or more highly expressed by tumor and not normal tissue is a powerful tool in the study of cell regulation and growth. To this end we constructed a complementary DNA (cDNA) library from messenger RNA (mRNA) isolated from a human insulinoma and, by differential hybridization with cDNA from both normal pancreas and insulinoma, isolated clones more highly expressed by insulinoma.Total RNA was isolated from human insulinoma and normal pancreas and purified to mRNA by oligo (dT) column. An insulinoma cDNA library was constructed and screened with 32P-labeled cDNA from pancreas and insulinoma. Northern blots from insulinoma, pancreas, carcinomas, normal endocrine tissues, and endocrine tumors were then probed with the 32P-labeled inserts.Two clones that consistently hybridized with 32P cDNA from insulinoma and not pancreas proved to represent mRNAs for insulin and the alpha subunit of the Gs protein. There was a markedly higher expression (30-fold) of the gene for Gs alpha in mRNA from insulinoma compared with normal pancreas by Northern blot analysis. We found Gs alpha to be more highly expressed by a pheochromocytoma, a corticotropin-producing islet cell tumor of the pancreas, and a corticotropin-producing thymic carcinoid (up to 35-fold) compared with normal pancreas, whereas normal endocrine tissues, a parathyroid adenoma, thyroid follicular adenoma, gastrinoma, and several carcinomas showed no expression.This study showed that Gs alpha is highly expressed in insulinoma and certain endocrine tumors. It is not expressed in several cancers or normal endocrine tissues. Others have implicated mutated Gs proteins in the tumorigenesis of pituitary and thyroid tumors. G proteins are also known to mediate hormonal transmembrane signaling. Its overexpression in four of seven endocrine tumors tested suggests that it may have a role in the unregulated hormone secretion and/or a role in the tumorigenesis of differentiated endocrine tumors.

  View details for Web of Science ID A1993LQ38400042

  View details for PubMedID 8342148

• ASSESSMENT AND PREDICTION OF LONG-TERM CURE IN PATIENTS WITH THE ZOLLINGER-ELLISON SYNDROME - THE BEST APPROACH ANNALS OF INTERNAL MEDICINE FISHBEYN, V. A., NORTON, J. A., Benya, R. V., Pisegna, J. R., VENZON, D. J., Metz, D. C., Jensen, R. T. 1993; 119 (3): 199-206

  Abstract

  To identify the best method for determining freedom from disease after gastrinoma resection and for predicting long-term disease-free status in patients with the Zollinger-Ellison syndrome.Prospective study in consecutive patients.Referral-based clinical research center.Eighty-one consecutive patients with the Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection.Patients were evaluated after gastrinoma resection, before discharge, 3 to 6 months after surgery, and yearly thereafter. Evaluation included secretin provocative testing and fasting serum gastrin determinations. Follow-up examinations after the initial postoperative evaluations included a clinical assessment, acid secretion studies, a calcium provocative test, and various imaging studies.Most patients (96%) had gastrinomas. Freedom from disease was defined by improved symptoms, reduced acid output and antisecretory drug requirements, and a normal gastrin level, normal imaging studies, and negative gastrin provocative studies. Fifty-two percent of patients (n = 42) were disease-free immediately after surgery, 44% at 3 to 6 months, 42% at 1 year, and 35% by 5 years (mean follow-up, 39 months). The secretin provocative test was the first test to become positive in 45% of patients with a recurrence, the serum gastrin determination was the first test to become positive in 36%, and both tests became positive at the same time in 18%. No recurrence was first detected by imaging studies or by calcium provocative testing. Fasting serum gastrin levels and secretin provocative test results at different postoperative times can be used to predict the probability of a patient remaining disease free at 3 years. Patients with a normal gastrin level and a normal secretin provocative test immediately after surgery had a 3-year disease-free probability of 75%, and normal results on both tests at 6 months, 1 year, and 2 years yielded respective probabilities of 88%, 95%, and 100%.Both the secretin provocative test and fasting serum gastrin determination are necessary for the early diagnosis of cases of recurrent disease after gastrinoma resection. The calcium provocative test and imaging studies do not detect any recurrences first. Fasting serum gastrin determinations and secretin provocative testing at different postoperative times can be used to predict the probability of a patient remaining disease free at 3 years.

  View details for Web of Science ID A1993LU90300004

  View details for PubMedID 8323088

• T-CELL RECOGNITION OF OVARIAN-CANCER 54TH ANNUAL MEETING OF THE SOC OF UNIVERSITY SURGEONS Peoples, G. E., Schoof, D. D., ANDREWS, J. V., NORTON, J. A., Kim, B., Alexander, H. R., Goedegebuure, P. S., Eberlein, T. J. MOSBY-YEAR BOOK INC. 1993: 227–34

  Abstract

  The existence of a tumor-specific T-cell immune response to human malignant melanoma has been well documented. In contrast, the existence of tumor-specific cytotoxic T lymphocyte to ovarian cancer remains controversial despite the abundant lymphocytic infiltrates in the malignant ascites and solid tumor of these patients.Tumor-associated lymphocytes (TAL) from the malignant ascites and tumor-infiltrating lymphocytes (TIL) from the solid tumors were isolated from six untreated patients with ovarian cancer. TAL and TIL were grown with initial anti-cluster of differentiation of T cells (CD3), low-dose interleukin-2, and tumor stimulation. T-cell lines were analyzed in functional studies.At 5 weeks, TAL and TIL from five of six patients were > 50% CD8+, and one of six was > 70% CD4+. In all five pairs of CD8 positive cultures, both TAL and TIL exhibited high levels of tumor-specific cytotoxicity for ascite and solid tumor, respectively. T-cell recognition of tumor was mediated through the T-cell receptor-CD3 complex and was human leukocyte antigen class I restricted. TAL and TIL lysed autologous ascitic tumor equally well; however, TAL-mediated tumoricidal activity against autologous solid tumor was consistently and significantly poorer than TIL-mediated killing.Tumor-specific cytotoxic T lymphocytes can be expanded from both TAL and TIL. However, TAL do not kill solid tumor as efficiently as TIL. This suggests the requirement of TIL, or a combination of TIL and TAL, for effective immunotherapy.

  View details for Web of Science ID A1993LQ38400013

  View details for PubMedID 8342128

• A PROSPECTIVE-STUDY OF INTRAOPERATIVE METHODS TO DIAGNOSE AND RESECT DUODENAL GASTRINOMAS ANNALS OF SURGERY Sugg, S. L., NORTON, J. A., FRAKER, D. L., Metz, D. C., Pisegna, J. R., FISHBEYN, V., Benya, R. V., Shawker, T. H., DOPPMAN, J. L., Jensen, R. T. 1993; 218 (2): 138-144

  Abstract

  This study determined, prospectively, whether duodenotomy (DX) should be routinely performed in explorations for patients with Zollinger-Ellison syndrome (ZES).Duodenal gastrinomas are now being found with increasing frequency in patients with Zollinger-Ellison syndrome. The surgical approach used to detect these tumors is controversial. Some recommend intraoperative endoscopy with transillumination (IOE) at surgery, while others recommend routine DX.Beginning in 1989, the authors prospectively compared the ability of palpation, intraoperative ultrasound (IOUS), IOE, and DX (in that sequence) to detect gastrinomas in 35 consecutive patients with ZES. Each patient also underwent preoperative localization studies.Thirty-three of 35 patients (94%) had tumor detected and excised; duodenal gastrinomas were excised in 27 patients (77%). The average size of the duodenal tumors was 0.8 cm, significantly smaller (p < 0.005) than the pancreatic and lymph node tumors in this series. Standard palpation after a Kocher maneuver identified 19 of the 31 duodenal tumors (61%) in the 27 patients. IOUS revealed only eight duodenal tumors (26%) and no new lesions. IOE identified 20 duodenal gastrinomas (64%) and 6 new lesions. DX identified 31 duodenal tumors (100%) and 5 additional tumors. The morbidity rate was 17%. One patient had a duodenal fistula after operation (2.8%) and subsequently recovered. No patient died.These results demonstrate that the duodenum is the most common location for gastrinoma in patients with ZES (77%) and that DX to detect and remove duodenal gastrinomas should be routinely performed in all explorations for patients with ZES.

  View details for Web of Science ID A1993LR02200005

  View details for PubMedID 8342993

• USE OF INTRAOPERATIVE ULTRASONOGRAPHY TO LOCALIZE ISLET-CELL TUMORS WORLD JOURNAL OF SURGERY ZEIGER, M. A., Shawker, T. H., NORTON, J. A. 1993; 17 (4): 448-454

  Abstract

  Because approximately 50% of insulinomas and a similar proportion of gastrinomas are not evident on preoperative imaging studies, precise intraoperative localization of these small tumors is imperative. Recently the use of high-resolution real-time B-mode ultrasonography has dramatically facilitated the operative detection of pancreatic islet cell tumors. The tumor appears sonolucent compared to the more echo-dense surrounding pancreas. This operative technique has been especially useful in patients with insulinoma because these tumors are generally located within the pancreas. In fact, it is so helpful during explorations for insulinoma some suggest that extensive preoperative localization studies are no longer indicated--that the patient can simply be explored with intraoperative ultrasonography (IOUS). It has not been as useful for gastrinomas because of their common extrapancreatic location. Accumulating evidence suggests that IOUS is an effective tool to aid in the operative localization and resection of pancreatic islet cell tumors. Not only can it precisely localize the tumor, it can accurately document the relation of the tumor to other vital pancreatic structures including ducts, veins, and arteries.

  View details for Web of Science ID A1993LP53500006

  View details for PubMedID 8395749

• PROSPECTIVE COMPARATIVE-STUDY OF ABILITY OF MR-IMAGING AND OTHER IMAGING MODALITIES TO LOCALIZE TUMORS IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME DIGESTIVE DISEASES AND SCIENCES Pisegna, J. R., DOPPMAN, J. L., NORTON, J. A., Metz, D. C., Jensen, R. T. 1993; 38 (7): 1318-1328

  Abstract

  The role of magnetic resonance (MR) imaging in patients with pancreatic endocrine tumors such as Zollinger-Ellison syndrome (ZES) is controversial. In the present study we have examined the ability of current MR imaging compared with other imaging modalities, to localize gastrinomas in 43 patients with ZES. All results were subsequently assessed at exploratory laparotomy (N = 34) or by liver biopsy (N = 9). For the 18 patients with metastatic gastrinoma in the liver, MR imaging had a sensitivity of 83%, ultrasound 50%, CT 56%, and angiography 61%. The combination of MR imaging, ultrasound, and CT were the same as MR imaging alone. For MR imaging, both T1 and STIR sequences had equal sensitivity, although tumors were more easily seen with STIR sequences. Specificity of MR imaging was slightly lower (88%) than the other modalities (96-100%) because MR imaging incorrectly identified small hemangiomas as possible tumors in four patients. MR imaging was better than CT in identifying metastatic lesions in the liver. For the localization of primary gastrinoma, assessed in 32 patients, MR imaging had a sensitivity of 25%, ultrasound 19%, CT 28%, all three together 38%, and angiography 59%. Localization of metastatic gastrinoma in the liver or primary gastrinomas in 16 patients was assessed before and after gadolinium-DTPA (0.1 mmol/kg). The sensitivity and specificity of MR imaging was unchanged but bolus injection and rapid MR acquisition techniques were not used. These results indicate that recent advances in MR imaging have greatly improved its sensitivity for the detection and assessment of the extent of metastatic gastrinoma. MR imaging is now the imaging study of choice to assess metastatic pancreatic endocrine tumors in the liver. In contrast, the detection of primary tumors by MR imaging has not improved; therefore, angiography remains the study of choice.

  View details for Web of Science ID A1993LN12900022

  View details for PubMedID 8325191

• INTRAARTERIAL CALCIUM STIMULATION TEST FOR DETECTION OF INSULINOMAS WORLD JOURNAL OF SURGERY DOPPMAN, J. L., MILLER, D. L., Chang, R., GORDEN, P., Eastman, R. C., NORTON, J. A. 1993; 17 (4): 439-443

  Abstract

  Occult insulinomas are adenomas not visualized by routine preoperative imaging studies, including ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and arteriography. Reliance for detecting occult insulinomas has been placed on portal venous sampling (PVS), a sensitive (> 75%) but invasive procedure that requires considerable experience to enable sampling of small veins about the pancreatic head. For the past 2 years we have attempted to localize insulinomas by stimulating the release of insulin with a selective intraarterial injection of calcium gluconate and sampling for insulin gradients in the hepatic veins. This study replaces PVS by indicating the region of the pancreas within which the tumor lies, although, like PVS, it does not directly visualize the tumor. Our experience in 9 patients with surgically proved insulinomas is reviewed, comparing the results with PVS as well as with US, CT, MRI, and arteriography.

  View details for Web of Science ID A1993LP53500004

  View details for PubMedID 8362527

• PROSPECTIVE-STUDY OF THE NEED FOR LONG-TERM ANTISECRETORY THERAPY IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME FOLLOWING SUCCESSFUL CURATIVE GASTRINOMA RESECTION ALIMENTARY PHARMACOLOGY & THERAPEUTICS Metz, D. C., Benya, R. V., FISHBEYN, V. A., Pisegna, J. R., ORBUCH, M., Strader, D. B., NORTON, J. A., Jensen, R. T. 1993; 7 (3): 247-257

  Abstract

  A long-term cure is now possible in more than 30% of selected patients with Zollinger-Ellison syndrome who undergo gastrinoma resection. The need, however, for continued gastric acid antisecretory therapy in these patients remains controversial. The current study was designed to determine whether post-operative antisecretory therapy is needed in patients who have undergone successful gastrinoma resection and, if so, to attempt to define criteria with which to identify patients who require therapy. Twenty-eight consecutive patients who had previously undergone curative gastrinoma resection were prospectively studied. When antisecretory therapy was discontinued, 43% (12/28) of these patients developed gastro-oesophageal reflux, diarrhoea, acid-peptic symptoms or endoscopic evidence of acid-peptic disease within 2 weeks and were deemed to have failed a trial of antisecretory drug withdrawal. The remaining 57% (16/28) of patients who successfully discontinued antisecretory therapy were followed for a mean time of 31 months after withdrawal of therapy. Analysis of acid output studies pre-operatively, as well as at the time of drug withdrawal, demonstrated that patients who were unable to discontinue antisecretory therapy exhibited higher pre-operative maximal acid output values and higher basal acid output values at the time of attempted drug withdrawal than patients who were able to discontinue therapy. Despite these findings, there was significant overlap in acid output values between groups so that it was not possible to define specific acid output criteria for successful drug withdrawal. Pre-operative clinical characteristics, such as the presence or absence of gastro-esophageal reflux or acid-peptic disease, or post-operative laboratory values, such as the fasting serum gastrin level, did not correlate with the ability to discontinue antisecretory therapy. We conclude that following successful curative gastrinoma resection, 40% of patients still require antisecretory therapy and that both symptom evaluation as well as upper endoscopy should be used to guide attempted drug withdrawal. Although patients who are not able to discontinue therapy have significantly higher acid output measurements than those who are able to discontinue therapy, neither acid output criteria nor any other laboratory or clinical characteristics are able to predict the need for continued antisecretory therapy in these patients.

  View details for Web of Science ID A1993LJ38800002

  View details for PubMedID 8364130

• IL-1 RECEPTOR ANTAGONIST (IL-1RA) AUGMENTS IL-2-INDUCED PULMONARY VASCULAR LEAK 1992 Annual Meeting of the Association-for-Academic-Surgery THOM, A. K., FRAKER, D. L., NORTON, J. A. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1993: 336–41

  Abstract

  Interleukin-2 (IL-2) therapy is dose limited by a severe vascular leak with resulting systemic and pulmonary toxicity. Although recognized as a mediator of septic shock and vascular leak, the relative role of IL-1 in IL-2 toxicity is unclear. We evaluated the effect of IL-1 receptor antagonist (IL-1ra) on IL-2 lethality, pulmonary vascular leak, and treatment of pulmonary metastases in a murine model. In vivo induction of mRNA for IL-1 alpha was evaluated in liver by Northern blots after 0, 5, 8, and 11 doses of IL-2 in C3H/HEN mice. The expression index for the IL-1 alpha gene increased from 0.16 to 0.74 after 5 doses of IL-2, and further increased to 1.04 after 11 doses of IL-2. C3H/HEN mice (n = 56) were randomized to receive phosphate-buffered saline (PBS), IL-1ra high dose (HD), or IL-1ra low dose (LD) by continuous subcutaneous infusion via Alzet mini-pumps. The biologic effectiveness of the dose and administration of IL-1ra was determined by the ability to block IL-1-induced IL-6 production in vivo. Mean serum IL-6 levels 3 hr after intraperitoneal IL-1 alpha (10 micrograms/kg) were: PBS, 3730 +/- 526 (mean +/- SEM pg/ml); IL-1ra (LD), 1156 +/- 398; and IL-1ra (HD), 594 +/- 30 (P < 0.01, IL-1ra HD or LD vs PBS). Pulmonary vascular leak was measured by iv I125 albumin after 8 doses of IL-2 (100,000 U ip q 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993LM66700013

  View details for PubMedID 8331927

• INTERLEUKIN-1 RECEPTOR ANTIBODY (IL-1RAB) PROTECTION AND TREATMENT AGAINST LETHAL ENDOTOXEMIA IN MICE 1992 Annual Meeting of the Association-for-Academic-Surgery McNamara, M. J., NORTON, J. A., Nauta, R. J., Alexander, H. R. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1993: 316–21

  Abstract

  Interleukin-1 (IL-1) is a mediator of endotoxin shock and IL-1 receptor blockade has been shown to have therapeutic efficacy against endotoxic shock and sepsis in laboratory models. The current studies were designed to characterize the efficacy of a murine monoclonal IL-1 receptor antibody (IL-1rab) against endotoxin (LPS) lethality and to investigate whether combined anticytokine therapy using the IL-1rab and a highly specific polyclonal rabbit anti-mouse TNF antibody (TNF Ab) could provide additive or synergistic efficacy against LPS lethality in C57B1/6 female mice. A single intraperitoneal (ip) dose of IL-1rab, 0.1 or 0.2 mg, significantly reduced lethality from LPS, 30 to 40 mg/kg ip, compared to nonimmune IgG, 0.1 or 0.2 mg, in control mice (P2 < 0.05). Treatment with IL-1rab was effective when administered from 6 hr before to 1 hr after LPS. After LPS, circulating levels of IL-6 were significantly lower in IL-1rab-treated mice [IL-6 (ng/ml) 2 h after LPS: IgG, 100 +/- 25, IL-1rab, 41 +/- 8; 4 h after LPS: IgG, 46 +/- 13, IL-1rab, 8 +/- 1; P2 < 0.05 and 0.03, respectively]. Northern blot analysis showed that IL-1rab markedly lowered IL-6 gene expression after LPS. Combined treatment with IL-1rab and TNF Ab did not result in any improvement in survival after LPS compared to either agent alone. These results indicate that an IL-1 receptor antibody has therapeutic efficacy against LPS and significantly decreases IL-6 production.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993LM66700009

  View details for PubMedID 8331925

• IODINE-131-METAIODOBENZYLGUANIDINE SCINTIGRAPHY IN PREOPERATIVE AND POSTOPERATIVE EVALUATION OF PARAGANGLIOMAS - COMPARISON WITH CT AND MRI JOURNAL OF NUCLEAR MEDICINE MAUREA, S., CUOCOLO, A., Reynolds, J. C., Tumeh, S. S., BEGLEY, M. G., Linehan, W. M., NORTON, J. A., Walther, M. M., Keiser, H. R., Neumann, R. D. 1993; 34 (2): 173-179

  Abstract

  Iodine-131-metaiodobenzylguanidine (MIBG) scintigraphy, transmission computed tomography and magnetic resonance imaging were used to evaluate 36 patients with clinically suspected functioning paragangliomas. The patients were divided into two groups. In Group 1 (n = 21), studied before surgery, patients mainly had benign adrenal disease. In Group 2 (n = 15), studied after surgery, patients frequently had malignant or extra-adrenal tumors. In Group 1, transmission computed tomography and magnetic resonance imaging were more sensitive (100% for both) than MIBG scintigraphy (82%), which, however, was the most specific (100%). In Group 2, MIBG scintigraphy and magnetic resonance imaging were more sensitive (83% for both) than transmission computed tomography (75%), but MIBG was again the most specific (100%). Thus, all three were complementary modalities for localizing paragangliomas both preoperatively and postoperatively. MIBG imaging is indicated for both groups but it is especially recommended for postsurgical patients with recurrence because the disease is often malignant or extra-adrenal.

  View details for Web of Science ID A1993KK92600005

  View details for PubMedID 8381474

• THE ROLE OF TUMOR-NECROSIS-FACTOR IN THE TOXICITY AND THE ANTINEOPLASTIC ACTIVITY OF INTERLEUKIN-2 IMMUNOTHERAPY 4TH INTERNATIONAL CONF ON TUMOUR NECROSIS FACTOR AND RELATED CYTOKINES FRAKER, D. L., NORTON, J. A. KARGER. 1993: 221–225

  View details for Web of Science ID A1993BY26K00031

• ULTRASTRUCTURAL HISTOLOGY CORRELATES WITH RESULTS OF THALLIUM-201/TECHNETIUM-99M PARATHYROID SUBTRACTION SCINTIGRAPHY JOURNAL OF NUCLEAR MEDICINE Sandrock, D., MERINO, M. J., NORTON, J. A., Neumann, R. D. 1993; 34 (1): 24-29

  Abstract

  Specimens from 15 scintigraphically true-positive adenomas (golden standard: histology), 15 false-negative adenomas, 15 true-positive hyperplasias, 15 false-negative hyperplasias, 15 true-negative normal glands from patients with hyperparathyroidism, and 15 normal glands from patients without hyperparathyroidism, all selected randomly, were studied. After fixation, sectioning and H and E staining, in all 90 tissues the number of oxyphil, chief, and clear cells was counted in five randomly selected squares (103 x 103 microns). In 30 tissues, the number of mitochondria per cell was counted in five randomly selected cells from each lesion in transmission electron photomicrographs. Total cell counts in each group and number of chief cells showed no correlation with lesion detectability by scintigraphy. However, true-positive lesions had a significantly higher number of oxyphil cells than false-negative or normal glands. Twenty-one of 30 true-positive lesions had a oxyphil-to-clear cell ratio > 1; in contrast to only two of 30 false-negative lesions and 0 of 30 normal glands (p < 0.0005). The number of mitochondria per cell was higher in oxyphil cells in true-positive lesions (adenomas: 155 +/- 58, hyperplasias: 55 +/- 18) than in chief or clear cells in false-negative or normal lesions (30 +/- 15, p < 0.001). Our data suggest that the detectability of abnormal parathyroid glands by 201TI/99mTc subtraction scintigraphy is in part dependent upon the presence of mitochondria-rich oxyphil cells.

  View details for Web of Science ID A1993KE71500009

  View details for PubMedID 8418265

• ALLELIC LOSS FROM CHROMOSOME-11 IN PARATHYROID TUMORS CANCER RESEARCH FRIEDMAN, E., DeMarco, L., GEJMAN, P. V., NORTON, J. A., Bale, A. E., AURBACH, G. D., Spiegel, A. M., Marx, S. J. 1992; 52 (24): 6804-6809

  Abstract

  Parathyroid tumors may occur in a sporadic fashion or, more rarely, as part of a familial syndrome (such as familial multiple endocrine neoplasia type I). The MENI gene has been mapped by linkage analysis to chromosome 11 at band q11-q13, and presumably acts as a tumor suppressor gene. In the present study, which is an extension of our previous studies, we examined 41 parathyroid tumors from patients with familial multiple endocrine neoplasia type I and 61 sporadic parathyroid tumors with markers on chromosome 11, to assess the extent of allelic loss in those tumors. Twenty-four of the MENI-associated tumors (58%) and 16 of the sporadic parathyroid tumors (26%) displayed allelic loss from chromosome 11. The region of overlap of the allelic losses in the MENI-associated tumors enables us to place the MENI gene between PGA centromerically and INT2 telomerically, a region spanning about 7.5 cM. Taken together with locus ordering by linkage analysis, this clearly localizes the MENI gene telomeric to the PGA locus. Our inability to detect allelic loss on chromosome 11 in some parathyroid tumors suggests the existence of other genes involved in the development and/or progression of this subgroup of presumably monoclonal tumors; or that localized events involving the 11q tumor suppressor gene have occurred in some parathyroid tumors whose detection is beyond the sensitivity of our analysis; or that at least some of the specimens analyzed were in fact primarily hyperplastic parathyroid tissue.

  View details for Web of Science ID A1992KB97900011

  View details for PubMedID 1360870

• AN 11-YEAR EXPERIENCE WITH ADRENOCORTICAL CARCINOMA 13TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS Pommier, R. F., Brennan, M. F., Grant, C. S., Woltering, E., Newsome, H. H., Norton, J., Hickey, R., Rastad, J. MOSBY-YEAR BOOK INC. 1992: 963–71

  View details for Web of Science ID A1992KB29300001

• A PROSPECTIVE RANDOMIZED TRIAL COMPARING THE INFECTIOUS AND NONINFECTIOUS COMPLICATIONS OF AN EXTERNALIZED CATHETER VERSUS A SUBCUTANEOUSLY IMPLANTED DEVICE IN CANCER-PATIENTS JOURNAL OF CLINICAL ONCOLOGY Mueller, B. U., Skelton, J., CALLENDER, D. P., Marshall, D., Gress, J., Longo, D., Norton, J., Rubin, M., Venzon, D., Pizzo, P. A. 1992; 10 (12): 1943-1948

  Abstract

  To compare the frequency of infectious episodes or other problems occurring with an externalized catheter (Hickman) versus a subcutaneously implanted device (Port-a-Cath, Pharmacia, Piscataway, NJ) in cancer patients, we performed a prospective, randomized study in 100 cancer patients (age range, 5 to 74 years).Patients who were chemotherapy candidates and required an indwelling catheter were monitored prospectively and evaluated during the 180 days after the insertion of the catheter and again at time of study closure. The frequency of catheter use, reason for access, and any problems that might have been related to catheter use were noted. All data were collected prospectively and included the patient's age, sex, underlying malignancy, temperature, and leukocyte and absolute granulocyte counts at the time of catheter insertion and when complications occurred. The time to and reason for removal of the catheter, as well as any intercurrent infectious or mechanical problems, were also determined.Most of the infections that occurred were caused by gram-positive organisms, especially staphylococci or streptococci. A total of 22 complications (11 in each group) resulted in removal of the central line. Only one infection in the Hickman catheter group and four in the Port-a-Cath group led to removal of the central line. All other infectious episodes were successfully treated without removal of the catheters. The mean device life was 230 days for the Hickman catheter and 318 days for the Port-a-Cath (not significant).There were no differences between the two study groups regarding incidence of documented infections or mechanical or thrombotic complications.

  View details for Web of Science ID A1992KA72200017

  View details for PubMedID 1453208

• A randomized, prospective trial of postoperative somatostatin analogue in patients with neuroendocrine tumors of the pancreas. Surgery Lange, J. R., STEINBERG, S. M., Doherty, G. M., Langstein, H. N., White, D. E., Shawker, T. H., Eastman, R. C., Jensen, R. T., NORTON, J. A. 1992; 112 (6): 1033-1037

  Abstract

  Pancreatic surgery is not uncommonly complicated by prolonged pancreatic drainage and fistula. Octreotide decreases pancreatic exocrine function and has been reported to improve closure of pancreatic and intestinal fistulae. This randomized, prospective trial was designed to evaluate the efficacy of postoperative octreotide in reducing pancreatic drainage and complications after resection of neuroendocrine tumors of the pancreas.Patients with neuroendocrine tumors of the pancreas were entered into the study and randomized after operation to receive octreotide 150 micrograms subcutaneously every 8 hours or saline solution subcutaneously every 8 hours in a double-blinded fashion. Daily pancreatic drainage, total drainage, number of days to drain removal, and complications were recorded.Ten patients were given octreotide; eleven patients were given saline solution. The number of days to drain removal, daily drainage, and total drainage were not significantly different. Complications related to pancreatic drainage were not significantly different.Octreotide is not indicated for the routine postoperative management of patients with neuroendocrine tumors of the pancreas.

  View details for PubMedID 1455306

• OCCULT FUNCTIONING INSULINOMAS - WHICH LOCALIZING STUDIES ARE INDICATED 13TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS vanHeerden, J. A., Grant, C. S., Czako, P. F., Service, F. J., Charboneau, J. W., Thompson, N., Fabri, P. J., Wilson, S., Norton, J., Talpos, G., Carty, S. E. MOSBY-YEAR BOOK INC. 1992: 1010–15

  Abstract

  An occult insulinoma refers to a biochemically proven tumor with an anatomic site that remains indeterminate before operation. The amount of radiologic localization for such patients is debatable.Sixty-five patients with sporadic insulinomas were surgically treated at the Mayo Clinic between January 1980 and December 1990. True occult tumors were present in 31% of these patients (n = 20). Thirty-eight negative preoperative localization studies were performed, with 10 patients undergoing more than one study. A benign adenoma was found in 19 patients when they underwent exploratory operation, whereas one patient had malignant disease with hepatic metastases. Thirteen patients underwent intraoperative ultrasonography with a 7.5 MHz real-time high-resolution transducer.Solitary lesions were successfully removed either by enucleation or by distal pancreatectomy in all 19 patients with benign disease.This high success rate in the management of occult insulinomas suggests that extensive preoperative radiologic investigation is neither indicated nor cost-effective.

  View details for Web of Science ID A1992KB29300007

  View details for PubMedID 1455304

• SURGICAL STRATEGY IN THE MANAGEMENT OF NON-SMALL-CELL ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME 13TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS ZEIGER, M. A., PASS, H. I., DOPPMAN, J. D., NIEMAN, L. K., Chrousos, G. P., Cutler, G. B., Jensen, R. T., NORTON, J. A., Udelsman, R., Prinz, R., Aun, F., Kinder, B., Thompson, N., Clark, O. MOSBY-YEAR BOOK INC. 1992: 994–1001

  Abstract

  Non-small cell ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare cause of hypercortisolism that may require surgery for either curative resection or palliative adrenalectomy.We report our surgical experience with 41 patients with ectopic ACTH syndrome and no evidence of small cell lung cancer at initial evaluation.All 41 patients had documented hypercortisolism secondary to ectopic production of ACTH. Based on imaging study results, we determined that 21 patients had localized/resectable disease; eight patients had metastatic disease, and 12 patients had occult disease at examination. Of the 21 patients with localized disease, 16 (76%) were cured of ectopic ACTH by surgery (15 bronchial carcinoid, one pheochromocytoma). Patients with bronchial carcinoid had the greatest probability for cure of ectopic ACTH syndrome, and patients with thoracic primary tumor were more likely to be cured than patients with abdominal primaries. Of the eight patients who had metastatic disease, none were cured of the disease; five patients underwent bilateral adrenalectomy, and three patients were given medical therapy. Only one patient was alive after 5 years. Of the 12 patients who had occult disease, four patients were eventually cured of the disease (three bronchial carcinoid, one thymic carcinoid); one patient died of disease (small cell lung cancer), and seven patients still have occult disease. Nine of 12 patients with occult disease underwent bilateral adrenalectomy for surgical management of hypercortisolism.This study suggests that the most common primary focus of ectopic ACTH production is within the thorax with 25 of 34 (74%) identifiable tumors originating within either the thymus or bronchus. Adrenalectomy offers excellent palliation of hypercortisolism secondary to either occult or metastatic disease. Patients who initially have localized disease usually have bronchial carcinoids and have a high probability of cure with surgical resection (81%).

  View details for Web of Science ID A1992KB29300005

  View details for PubMedID 1333646

• PROSPECTIVE-STUDY OF THE USE OF INTRAARTERIAL SECRETIN INJECTION AND PORTAL VENOUS SAMPLING TO LOCALIZE DUODENAL GASTRINOMAS 13TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS THOM, A. K., NORTON, J. A., DOPPMAN, J. L., MILLER, D. L., Chang, R., Jensen, R. T., VANHEERDEN, J., Woltering, E., Saxe, A., Thompson, N., Prinz, R. A. MOSBY-YEAR BOOK INC. 1992: 1002–9

  Abstract

  Duodenal gastrinomas producing Zollinger-Ellison syndrome (ZES) are rarely imaged on preoperative studies. Measurement of serum gastrin levels by transhepatic portal venous sampling (PVS) or by sampling from hepatic veins after intraarterial secretin injection have been advocated as useful tests to identify these tumors before operation.As part of a prospective study, selective intraarterial secretin injection has been performed in 36 consecutive patients with ZES, PVS has been performed in 30 of these patients, and the results have been compared.Gastrinomas were found at laparotomy in 33 of 36 patients (92%). Duodenal tumors were found in 18 patients (50%). The remaining patients had liver, pancreatic, or nodal disease (n = 15). Thirty-two of 36 patients (89%) had positive results with intraarterial secretin injection study, whereas 18 of 30 (60%) had a positive PVS gradient (p = 0.02, Fisher's exact test). The most common positive gradient with intraarterial secretin injection was found with injections of the gastroduodenal artery, and the most common positive gradient with PVS was found in the inferior pancreaticoduodenal (IPDV) or superior pancreaticoduodenal vein (SPDV). Fourteen of 18 (78%) patients with duodenal gastrinomas had a positive GDA injection, whereas five of 18 (28%) without duodenal tumors had a positive GDA injection (p = 0.006). Five of 16 patients with duodenal gastrinomas had a positive gradient in the IPDV or SPDV, whereas four of 14 without duodenal tumors had a positive gradient in the IPDV or SPDV (not significant).Intraarterial secretin injection is more sensitive than PVS at localizing duodenal gastrinomas and should replace PVS in patients with ZES and occult tumors.

  View details for Web of Science ID A1992KB29300006

  View details for PubMedID 1455303

• A RANDOMIZED, PROSPECTIVE TRIAL OF POSTOPERATIVE SOMATOSTATIN ANALOG IN PATIENTS WITH NEUROENDOCRINE TUMORS OF THE PANCREAS 13TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS Lange, J. R., STEINBERG, S. M., Doherty, G. M., Langstein, H. N., White, D. E., Shawker, T. H., Eastman, R. C., Jensen, R. T., NORTON, J. A., Andersen, D. K., Proye, C., Rastad, J., PUARTE, B., Clark, O., Weber, C. MOSBY-YEAR BOOK INC. 1992: 1033–38

  View details for Web of Science ID A1992KB29300010

• PROSPECTIVE-STUDY OF AGGRESSIVE RESECTION OF METASTATIC PANCREATIC ENDOCRINE TUMORS 13TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS Carty, S. E., Jensen, R. T., NORTON, J. A., Ellison, C., Talpos, G., Kaplan, E. L., Modlin, I. MOSBY-YEAR BOOK INC. 1992: 1024–32

  Abstract

  Because metastatic pancreatic endocrine tumors (MPET) have a poor prognosis, 17 patients with potentially resectable MPET were prospectively studied to define the efficacy of aggressive resection.Patients underwent resection when the full extent of MPET was deemed operable after imaging studies were obtained. Two patients underwent three reoperations for recurrent tumor.MPET were completely excised in 16 of 20 cases by major resections of liver, viscera, and nodes, with no operative mortality. Survival was 87% at 2 years and 79% at 5 years with mean follow-up of 3.2 years. Median imaging disease-free interval was 1.8 years, and four of 17 patients remain biochemically cured. After aggressive resection patients with MPET limited in extent had higher survival than patients with extensive MPET (p < 0.019). In a nonrandomized cohort of 25 patients with inoperable tumor, survival was 60% at 2 years and 28% at 5 years.In select patients MPET can be resected safely with a favorable outcome; most patients will experience recurrence, but some may be cured. Resection of extensive MPET does not appear to improve survival. Resection of limited MPET should be considered as life-extending and potentially curative therapy.

  View details for Web of Science ID A1992KB29300009

  View details for PubMedID 1455305

• CYTOKINES AND THEIR ROLE IN THE PATHOPHYSIOLOGY OF CANCER CACHEXIA SYMP ON NUTRITION AND CANCER : CRITICAL ISSUES IN BASIC SCIENCE AND CLINICAL RESEARCH McNamara, M. J., Alexander, H. R., NORTON, J. A. AMER SOC PARENTERAL & ENTERAL NUTRITION. 1992: S50–S55

  View details for Web of Science ID A1992JY96400003

• CHOLERA-TOXIN PRETREATMENT PROTECTS AGAINST TUMOR-NECROSIS-FACTOR LETHALITY WITHOUT COMPROMISING TUMOR RESPONSE TO THERAPY 45TH ANNUAL CANCER SYMP OF THE SOC OF SURGICAL ONCOLOGY Block, M. I., Alexander, H. R., NORTON, J. A. AMER MEDICAL ASSOC. 1992: 1330–34

  Abstract

  Antitumor therapy with tumor necrosis factor is limited by systemic toxic effects. We studied whether cholera toxin, a bacterial exotoxin that adenosine diphosphate-ribosylates the alpha-subunit of Gs proteins, could separate the lethal from the antitumor effects of tumor necrosis factor. A single dose of intravenous cholera toxin protected non-tumor-bearing mice from a lethal dose of Escherichia coli endotoxin administered 6 or 24 hours later. On the basis of these results, tumor-bearing mice were randomized to receive either cholera toxin or saline, followed 6 hours later by either human tumor necrosis factor (400 micrograms/kg) or saline. Tumor-bearing mice pretreated with cholera toxin had (1) reduced treatment-related mortality (0/11 vs 5/11 for saline controls) and (2) tumor regression similar to that of controls. In a separate experiment in tumor-bearing mice, intravenous human tumor necrosis factor treatment induced an increase in serum levels of murine tumor necrosis factor to a peak of 500 pg/mL at 1 hour in saline-pretreated controls, while a similar increase could not be detected in those mice pretreated with cholera toxin. These results suggest that pretreatment with cholera toxin can reduce the endogenous tumor necrosis factor response to administered tumor necrosis factor and separate the lethal from the antitumor effects. Cholera toxin may prove to be a useful tool for investigating the mechanisms underlying the varied effects of tumor necrosis factor.

  View details for Web of Science ID A1992JW88400015

  View details for PubMedID 1444796

• PELVIC RADIOIODINE UPTAKE IN A RECTAL WALL TERATOMA AFTER THYROIDECTOMY FOR PAPILLARY CARCINOMA JOURNAL OF NUCLEAR MEDICINE Lakshmanan, M., Reynolds, J. C., Delvecchio, S., MERINO, M. J., NORTON, J. A., Robbins, J. 1992; 33 (10): 1848-1850

  Abstract

  A 30-yr-old woman with previously resected papillary thyroid carcinoma was found to have a pelvic lesion which concentrated radioiodine. By performing simultaneous 131I whole-body and 99mTc-methylene diphosphonate bone scans, we found the lesion to be in soft tissue between the sacrum and bladder. Radioiodine therapy was postponed so that the lesion, a benign teratoma of the rectal wall, could be surgically removed. Prior to laparotomy, the patient received a second tracer dose of 131I so that the lesion could be located at surgery with a hand-held gamma detector. A postoperative whole-body 131I scan confirmed that the lesion had been removed, thus reducing the absorbed radiation that would have been received by the ovaries during radioiodine therapy. Although the lesion contained both thyroid and gastric epithelium, accumulated 131I was limited to the area with thyroid follicles.

  View details for Web of Science ID A1992JU52000028

  View details for PubMedID 1403156

• EVIDENCE FOR IFN-GAMMA AS A MEDIATOR OF THE LETHALITY OF ENDOTOXIN AND TUMOR-NECROSIS-FACTOR-ALPHA JOURNAL OF IMMUNOLOGY Doherty, G. M., Lange, J. R., Langstein, H. N., Alexander, H. R., Buresh, C. M., NORTON, J. A. 1992; 149 (5): 1666-1670

  Abstract

  Current evidence indicates that endogenously produced peptide cytokines, most notably TNF-alpha and IL-1, mediate the lethality of experimental endotoxemia. Because circulating serum levels of IFN-gamma can be detected soon after TNF-alpha and IL-1 in response to endotoxin, we investigated the role of IFN-gamma in endotoxin and TNF-alpha lethality. Specific neutralizing antibodies to murine TNF-alpha (anti-TNF-alpha Ab) or murine IFN gamma (anti-IFN-gamma Ab) produced in our laboratory protected mice against the lethality of Escherichia coli endotoxin (LPS) administered 6 h later. Serum IFN-gamma levels 2 h after i.v. LPS were lower in mice treated with anti-TNF-alpha Ab compared to mice that received nonimmune IgG (median less than 2.5 vs 3.0 U/ml, P2 less than 0.05). In contrast, serum TNF-alpha levels 1 h after i.v. LPS peaked more than fourfold higher in mice treated with anti-IFN-gamma Ab compared to controls (median greater than 6400 vs 1405 pg/ml, p2 less than 0.05). Doses of TNF-alpha (300 micrograms/kg) and IFN-gamma (50,000 U) which were well tolerated when given individually were synergistically lethal in combination (0% lethality vs 100% lethality, P2 less than 0.001), and were associated with higher serum levels of IL-6 than with either cytokine alone. Anti-IFN-gamma Ab provided complete protection against exogenous human rTNF-alpha at the LD100 dose (1400 micrograms/kg, p2 less than 0.001), and in fact prevented lethality at doses four- to fivefold greater than the LD100 human rTNF-alpha (up to 6000 micrograms/kg). We conclude that IFN-gamma is synergistic with TNF-alpha, is essential for the lethality of LPS and TNF-alpha, and may have modulating effects on the negative control of serum levels of TNF-alpha after LPS in mice.

  View details for Web of Science ID A1992JJ89000027

  View details for PubMedID 1506688

• DISTINCTION BETWEEN HYPERALDOSTERONISM - DUE TO BILATERAL HYPERPLASIA AND UNILATERAL ALDOSTERONOMA - RELIABILITY OF CT RADIOLOGY DOPPMAN, J. L., Gill, J. R., MILLER, D. L., Chang, R., Gupta, R., Friedman, T. C., Choyke, P. L., Feuerstein, I. M., Dwyer, A. J., JICHA, D. L., Walther, M. M., NORTON, J. A., Linehan, W. M. 1992; 184 (3): 677-682

  Abstract

  Hyperaldosteronism due to a unilateral adenoma must be distinguished from hyperaldosteronism due to bilateral hyperplasia to enable the proper choice between surgical treatment (for adenoma) or medical treatment (for hyperplasia). To compare the efficacy of computed tomography (CT) and adrenal venous sampling, both examinations were performed in 24 patients with primary aldosteronism. All patients with a diagnosis of adenoma based on findings at venous sampling underwent adrenalectomy. The CT-based diagnosis was unilateral aldosteronoma in 17 patients and hyperplasia in seven patients. On the basis of venous sampling, unilateral adenoma was diagnosed in 22 patients; this diagnosis was confirmed by means of unilateral adrenalectomy in 21 patients. The most common error was diagnosis of hyperplasia based on the presence of bilateral nodules on CT scans: In six of seven patients with such a diagnosis, venous sampling and subsequent surgery revealed a unilateral adenoma. In hyperaldosteronism with multiple bilateral nodules, CT cannot reliably permit distinction between hyperplasia and adenoma.

  View details for Web of Science ID A1992JJ86600019

  View details for PubMedID 1509049

• RECOMBINANT INTERLEUKIN-1 RECEPTOR ANTAGONIST (IL-1RA) - EFFECTIVE THERAPY AGAINST GRAM-NEGATIVE SEPSIS IN RATS 53RD ANNUAL MEETING OF THE SOC OF UNIV SURGEONS Alexander, H. R., Doherty, G. M., VENZON, D. J., MERINO, M. J., FRAKER, D. L., NORTON, J. A. MOSBY-ELSEVIER. 1992: 188–94

  Abstract

  Morbidity and mortality from bacterial sepsis remain high despite aggressive diagnostic and therapeutic intervention. Interleukin-1 has been implicated as mediator of the lethal effects of endotoxemia or bacterial sepsis. The current experiments were designed to evaluate the therapeutic efficacy of a human recombinant interleukin-1 receptor antagonist (IL-1ra) against polymicrobial gram-negative septicemia in rats.Male rats underwent placement of indwelling carotid arterial and superior vena caval catheters followed by cecal ligation and puncture (CLP). After 3 hours rats received either IL-1ra (10 mg/kg intravenous bolus followed by 5 mg/kg/hr) or an equal volume of vehicle intravenously for 24 hours. Heart rate, respirations, mean arterial blood pressure, and temperature were recorded at frequent intervals, and survival was assessed for 30 hours after CLP.There were no differences in vital signs between groups at baseline or before treatment, and all animals appeared ill with huddled posture, piloerection, and hyperventilation. Twenty-four hours after CLP, IL-1ra significantly ameliorated bradycardia (p = 0.01), hypothermia (p = 0.001), and hypotension (p = 0.05), and 30-hour survival was significantly improved (71% vs 20%, p less than 0.05).IL-1ra lessens the acute hemodynamic, hypothermic, and mortal effects of gram-negative sepsis induced by CLP in rats. These data suggest that IL-1 receptor blockade may be an important new treatment strategy against overwhelming bacterial sepsis.

  View details for Web of Science ID A1992JG45100009

  View details for PubMedID 1386478

• STUDIES IN A KINDRED WITH PARATHYROID CARCINOMA JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Streeten, E. A., Weinstein, L. S., NORTON, J. A., Mulvihill, J. J., White, B. J., FRIEDMAN, E., Jaffe, G., Brandi, M. L., Stewart, K., Zimering, M. B., Spiegel, A. M., AURBACH, G. D., Marx, S. J. 1992; 75 (2): 362-366

  Abstract

  We report a family with primary hyperparathyroidism in four patients in two generations with apparent autosomal dominant transmission. A fifth member was probably affected. Two cases had definite parathyroid carcinoma (PC), and two had parathyroid adenoma with atypical features that could represent an early stage of cancer. In each of our patients, one parathyroid gland was abnormal. Five other parathyroid glands (in two patients) were normal in histology and size. There was no evidence of neoplasia in other tissues. Constitutional karyotypes were normal in all four patients. We identified three chromosomal abnormalities (a reciprocal translocation between chromosomes 3 and 4, trisomy 7, and a pericentric inversion in chromosome 9) in cultured PC tissue from one patient. These chromosomal changes are of unclear significance. Analyses on tumor DNA from one case of PC and one of atypical adenoma showed no evidence of ras gene mutations, PTH gene rearrangement, or allelic loss from chromosome 11q13 (locus of the gene for multiple endocrine neoplasia type 1). This family shows susceptibility to cancer without antecedent hyperplasia in all parathyroids. It could help identify a novel tumor susceptibility gene.

  View details for Web of Science ID A1992JG86700006

  View details for PubMedID 1639936

• PULSATILE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS DURING MAJOR SURGERY METABOLISM-CLINICAL AND EXPERIMENTAL Calogero, A. E., NORTON, J. A., Sheppard, B. C., Listwak, S. J., CROMACK, D. T., Wall, R., Jensen, R. T., Chrousos, G. P. 1992; 41 (8): 839-845

  Abstract

  To examine the response of the hypothalamic-pituitary-adrenal (HPA) axis to severe surgical stress, we measured the immunoreactive plasma levels of corticotropin-releasing hormone (CRH), corticotropin, cortisol, arginine-vasopressin (AVP), atrial natriuretic factor (ANF), neuropeptide Y (NPY), interleukin-1 (IL-1), IL-6, interferon gamma (INF), and tumor necrosis factor-alpha (TNF-alpha) in eight patients with Zollinger-Ellison syndrome (ZES) or mediastinal parathyroid carcinoma, all undergoing major surgery with a standardized anesthetic technique. Blood samples were drawn the morning before surgery, every 10 to 30 minutes throughout surgery (average, 308.7 +/- 15 minutes), and every morning for the next 4 postoperative days (POD). During surgery, plasma CRH concentrations were slightly but not significantly elevated compared with those before surgery and with those of the next 4 POD. However, the values were within the normal range (less than 2.2 pmol/L) and showed 8.9 +/- 0.6 pulses (one pulse every 34.7 +/- 1.6 minutes). Plasma corticotropin, on the other hand, was quite elevated, but was also released in a pulsatile fashion during the surgical procedure (one pulse every 36.7 +/- 1.6 minutes). Most of these secretory episodes of corticotropin were temporally related to those of CRH. Corticotropin returned to basal levels on the first POD and remained so for all 4 POD. Plasma cortisol concentrations increased steadily during surgery and remained elevated the first POD. Cortisol showed 6.2 +/- 1.1 pulses during the operative sampling period (one pulse every 71.8 +/- 13 minutes). Plasma AVP concentrations were also markedly elevated during surgery, but individual secretory pulses were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992JF81700006

  View details for PubMedID 1640860

• Effective regional therapy of experimental cancer with paralesional administration of tumour necrosis factor-alpha + interferon-gamma. Surgical oncology THOM, A. K., FRAKER, D. L., Taubenberger, J. K., NORTON, J. A. 1992; 1 (4): 291-298

  Abstract

  Systemically administered tumour necrosis factor (TNF) has anti-tumour effects in animal tumour models but its clinical application is limited by severe toxicity. Interferon-gamma(IFN-gamma) has been shown to augment the anti-tumour effect of TNF. We evaluated the effect of paralesional (p.I.) injections of TNF plus IFN-gamma in a murine tumour model and compared the toxicity and anti-tumour effect with that seen with systemic administration. C57BL6 mice with 10-day subcutaneous MCA sarcomas were treated with daily p.I. injections of recombinant huTNF +/- IFN-gamma for 5 days. Optimal mean survival and 30-day cure rate was seen with doses of 5 micrograms TNF-alpha + 5000 U IFN-gamma (P < 0.05 vs. control or IFN-gamma alone). Tumour response after a single i.v. injection of 0-15 micrograms TNF + 5000 U IFN-gamma was then compared with five daily p.I. injections of the same dose of TNF-alpha and IFN-gamma. All animals with p.I. injections of > 5 micrograms TNF had initial complete necrosis of tumour with a variable degree of surrounding tissue necrosis, with rapid regrowth of tumour seen in some animals. Although treatment-related mortality was similar between i.v. and p.I. therapy, there was a higher percentage of animals cured with p.I. injections with overall cure rates in treated animals at 30 days of 17% vs. 72% (i.v. vs. p.I., P < 0.01) and 13% vs. 67% (P < 0.04) in a repeat study. 2+ clinical applications.

  View details for PubMedID 1341263

• CORTICOTROPIN-SECRETING CARCINOID-TUMORS OF THE THYMUS - DIAGNOSTIC UNRELIABILITY OF THYMIC VENOUS SAMPLING RADIOLOGY DOPPMAN, J. L., PASS, H. I., NIEMAN, L. K., MILLER, D. L., Chang, R., Cutler, G. B., Chrousos, G. P., JAFFE, G. S., NORTON, J. A. 1992; 184 (1): 71-74

  Abstract

  Three patients with Cushing syndrome due to ectopic production of corticotropin underwent total thymectomy on the basis of elevated concentrations of corticotropin in selective samples from thymic veins but in the absence of a radiographically detectible thymic mass. In one patient, radiologic examination demonstrated hyperplasia of neuroendocrine cells staining positively for corticotropin throughout the thymus but no discrete mass. This patient had complete remission after total thymectomy. The other two patients had no evidence of an intrathymic source of corticotropin, and both had persistent Cushing syndrome. Elevated levels of corticotropin in thymic vein samples may reflect corticotropin production by pulmonary bronchial carcinoid tumors, mediastinal metastases, thymic carcinoids, or diffuse hyperplasia of intrathymic neuroendocrine elements. In the absence of a demonstrable intrathymic mass, corticotropin gradients in thymic veins do not reliably indicate a thymic source of corticotropin and should not necessarily be used as a basis for exploratory thoracotomy or blind thymectomy.

  View details for Web of Science ID A1992HZ68200016

  View details for PubMedID 1319078

• TC-99M UPTAKE IN A PARATHYROID ADENOMA - POTENTIAL PITFALL IN TC-99M/TL-201 SUBTRACTION IMAGING CLINICAL NUCLEAR MEDICINE Chen, C. C., Irony, I., JAFFE, G. S., NORTON, J. A. 1992; 17 (7): 539-541

  Abstract

  The authors describe a patient with primary hyperparathyroidism who had a large mediastinal parathyroid adenoma that avidly concentrated both Tc-99m pertechnetate and Tl-201. This unusual finding is presented as another potential reason for false-negative findings in Tc-99m/Tl-201 subtraction scintigraphy in hyperparathyroidism.

  View details for Web of Science ID A1992JC50500001

  View details for PubMedID 1322258

• INTERLEUKIN-1-ALPHA PREVENTION OF THE LETHALITY OF ESCHERICHIA-COLI PERITONITIS 1991 ANNUAL MEETING OF THE ASSOC FOR ACADEMIC SURGERY Lange, J. R., Alexander, H. R., MERINO, M. J., Doherty, G. M., NORTON, J. A. ACADEMIC PRESS INC ELSEVIER SCIENCE. 1992: 555–59

  Abstract

  Interleukin-1 (IL-1) is an inflammatory mediator with a variety of described physiologic functions. IL-1 alpha has been shown to confer a survival advantage to experimental animals when administered before a lethal bacterial challenge. The experiments reported here were performed to define the effective pretreatment interval of a single intravenous dose of IL-1 alpha in a murine model of bacterial peritonitis, to examine the differential induction of cytokines in animals with and without IL-1 alpha pretreatment, and to assess differences in histologic evidence of end organ damage. IL-1 alpha (27 micrograms/kg iv) conferred a survival advantage to mice given a lethal challenge of live Escherichia coli (2 x 10(8) CFU/mouse ip) when the pretreatment was given 2 to 24 hr before the bacterial inoculum. Longer pretreatment intervals were not significantly protective. Treatment with IL-1 alpha at 1 hr after bacterial inoculum also did not improve survival. Mice pretreated with IL-1 alpha developed significantly lower peak serum levels of TNF-alpha after E. coli injection than did control mice. Pretreated and control mice had similar peak serum levels of IL-6 after bacterial challenge; however, IL-1 alpha-pretreated mice had a less prolonged elevation of serum levels of IL-6. IL-1 alpha-pretreated animals were protected from the histologic evidence of end organ damage seen in control animals. Thus, in this model of E. coli peritonitis pretreatment with a single intravenous dose of IL-1 alpha confers a significant protective effect when given within a limited time range. Treatment outside this interval has no apparent beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992JN40500004

  View details for PubMedID 1528030

• ROLE OF TUMOR-NECROSIS-FACTOR IN OXYGEN-TOXICITY JOURNAL OF APPLIED PHYSIOLOGY Jensen, J. C., POGREBNIAK, H. W., PASS, H. I., Buresh, C., MERINO, M. J., Kauffman, D., Venzon, D., Langstein, H. N., NORTON, J. A. 1992; 72 (5): 1902-1907

  Abstract

  mRNA from lungs of mice exposed to high-dose oxygen (greater than 95%) for 3 days demonstrated increased expression of the genes for tumor necrosis factor (TNF), interleukin-1, and interleukin-6 compared with mRNA from lungs of mice exposed to room air. Daily treatment of mice exposed to high-dose oxygen with an antibody to TNF improved survival compared with mice receiving a similar dose of control immunoglobulin G. Pretreatment of mice with repetitive sublethal intraperitoneal doses of recombinant human TNF for 3 days or a single intravenous dose followed by exposure to high-dose oxygen afforded a significant survival advantage compared with high-dose oxygen-exposed mice pretreated with vehicle or interleukin-1. The repetitive intraperitoneal TNF pretreatment reduced the development of interstitial pneumonitis, pulmonary edema, and lung weight gain associated with oxygen toxicity and enhanced expression of the gene for the free radical protective enzyme manganous superoxide dismutase in lung tissue, a gene that is augmented as mice are exposed to high-dose oxygen. Furthermore a single intravenous dose of TNF 24 h after oxygen exposure was still protective. The results suggest that the toxicity of oxygen therapy can be partially ameliorated by either treatment with anti-TNF antibody or pretreatment and early treatment with TNF. These findings are consistent with the hypothesis that oxygen exposure induces TNF, which causes part of the toxicity of high-dose oxygen, and that pretreatment or early treatment with TNF induces the gene for an enzyme that recently has been shown to be very effective in protecting mice from the toxicity of oxygen.

  View details for Web of Science ID A1992HU33100036

  View details for PubMedID 1601798

• EFFECTS OF CURATIVE GASTRINOMA RESECTION ON GASTRIC SECRETORY FUNCTION AND ANTISECRETORY DRUG REQUIREMENT IN THE ZOLLINGER-ELLISON SYNDROME GASTROENTEROLOGY Pisegna, J. R., NORTON, J. A., SLIMAK, G. G., Metz, D. C., Maton, P. N., Gardner, J. D., Jensen, R. T. 1992; 102 (3): 767-778

  Abstract

  The chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome has trophic effects on the gastric mucosa, causing increased parietal cell mass reflected by increased maximal acid output (MAO) and basal acid output (BAO). The time course for the development of these gastric changes in humans is unknown, and controversy exists regarding whether reversal of the hypergastrinemia results in rapid normalization of gastric secretory function. To address these uncertainties, gastric secretory function was prospectively evaluated in 20 patients with the Zollinger-Ellison syndrome undergoing successful curative resection of gastrinoma. Each patient had gastric acid measurements, imaging studies, fasting serum gastrin and secretin provocative testing preoperatively, postoperatively at 3-6 months, and yearly thereafter. Preoperative mean BAO was 39 mEq/h, MAO 56 mEq/h, BAO-MAO ratio 0.73, and fasting gastrin output 1020 pg/mL. All patients were evaluated at 6 months, 17 at 1 year, 15 at 2 years, 13 at 3 years, and 9 at 4 years. By 3-6 months, MAO decreased by 50% in men (mean, 30 mEq/h) and by 35% in women (mean, 29 mEq/h) and then remained relatively unchanged for up to 4 years. Before surgery, 14 of 20 patients (70%) had an elevated MAO, whereas 4 years after resection, none of 9 patients had elevated levels. By 3-6 months, BAO decreased by 75% and remained unchanged for up to 4 years. At 3-6 months, 56% of patients were mild hypersecretors and 67% remained hypersecretors up to 4 years. Preoperatively, the BAO-MAO ratio was elevated in 16 of 20 patients (80%); postoperatively, only 5 of 18 patients (28%) at 3-6 months, 2 of 15 (13%) at 1 year, and 2 of 10 (20%) at 4 years continued to have elevated ratios. Preoperatively, the mean ranitidine dose was 1597 mg/day, whereas after surgery the mean dose was 535 mg/day at 3-6 months and approximately 300 mg/day at 1-4 years with 8 patients requiring no antisecretory drug. These results show that the trophic effects of chronic hypergastrinemia are, in general, rapidly reversible with a 50% decrease in MAO within 3-6 months of cure. Similarly, BAO decreased by 75% within 3-6 months. Despite these decreases, careful monitoring of acid secretion is required after reversal of the chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome, because 55% of patients at 3-6 months and up to 67% at 4 years continue to remain mild hypersecretors and require low doses of antisecretory drugs.

  View details for Web of Science ID A1992HF72100003

  View details for PubMedID 1537514

• RESULTS OF A MULTIDISCIPLINARY STRATEGY FOR MANAGEMENT OF MEDIASTINAL PARATHYROID ADENOMA AS A CAUSE OF PERSISTENT PRIMARY HYPERPARATHYROIDISM ANNALS OF SURGERY Doherty, G. M., DOPPMAN, J. L., MILLER, D. L., Gee, M. S., Marx, S. J., Spiegel, A. M., AURBACH, G. D., PASS, H. I., Brennan, M. F., NORTON, J. A. 1992; 215 (2): 101-106

  Abstract

  Persistent primary hyperparathyroidism due to mediastinal parathyroid adenoma was effectively treated by either angiographic ablation or median sternotomy in this study of 49 patients managed at the National Institutes of Health since 1977. Each patient presented here with symptomatic persistent primary hyperparathyroidism after failed initial surgical procedures done at other institutions. Each patient underwent extensive parathyroid localization procedures, including selective angiography, and most had a parathyroid adenoma localized to the mediastinum. Angiographic ablation, the deliberate injection of large doses of contrast material into the artery that selectively perfuses the adenoma, was initially successful in 22 of 30 procedures (73%) in 27 patients. Long-term control of persistent primary hyperparathyroidism was achieved in 17 of 27 patients (63%) by angiographic ablation. Each unsuccessful ablation could be easily salvaged by surgical resection. Surgical resection of the parathyroid adenoma by median sternotomy achieved immediate success in 24 of 24 procedures (p2 less than 0.02 versus ablation), and long-term cure in 23 of 23 evaluable patients (p2 less than 0.001 versus ablation). However, ablation did have benefits for the patients in whom it was successfully performed. It was associated with a significantly shorter hospital stay (median, 6 days versus 9 days for sternotomy, p2 less than 0.003), much less pain, and easier recuperation. Complications of each procedure were transient and similar in both groups. Operative resection is the most effective single means to eradicate mediastinal parathyroid adenoma; however, angiographic ablation can provide similar long-term control of hyperparathyroidism in 63% of patients with less pain and shorter convalescence than that seen in patients after median sternotomy. Our results suggest that angiographic ablation should be attempted as the initial procedure for patients with persistent primary hyperparathyroidism caused by an angiographically identified mediastinal parathyroid adenoma. Operation can be reserved for those who fail ablation.

  View details for Web of Science ID A1992HD46200002

  View details for PubMedID 1546895

• Tumour necrosis factor mediates the survival benefit of interleukin 2 in a murine pulmonary metastases model. Surgical oncology FRAKER, D. L., THOM, A. K., Doherty, G. M., Langstein, H. N., Buresh, C. M., NORTON, J. A. 1992; 1 (1): 1-9

  Abstract

  Antibody to tumour necrosis factor (TNF Ab) markedly decreases the toxicity of systemic interleukin-2 (IL-2) in mice but does not completely abrogate the anti-tumour response in terms of number of pulmonary metastases. Experiments were performed with a murine model of pulmonary metastases treated with high-dose IL-2 and concomitant TNF Ab or control antibody (CON Ab) to determine the effects of TNF Ab on survival. Mice were given either equal doses of IL-2 and TNF Ab or CON Ab or equitoxic doses of IL-2. In four consecutive experiments mice given TNF Ab tolerated 5 to 6 additional IL-2 doses (a 40-60% increase in total doses) in the equitoxic IL-2 dose group compared to the maximally tolerated dose with CON Ab. In all four experiments TNF Ab-treated mice had decreased survival compared to the CON Ab group given equal doses of IL-2 and in two of four experiments this difference was statistically significant (P2 < 0.01). Mice given 40-60% additional doses of IL-2 with TNF Ab had no improvement in survival compared with equitoxic doses of IL-2 with CON Ab in three of four experiments (P2 = 0.32, P2 = 0.67, P2 = 0.69). The TNF Ab preparation had no direct inhibition of IL-2 activity in an in vitro IL-2 proliferation bioassay. TNF Ab consistently blocks IL-2 toxicity and it also abrogates IL-2 therapeutic efficacy such that survival parallels treatment toxicity in this experimental model.

  View details for PubMedID 1341229

• CURATIVE RESECTION IN ZOLLINGER-ELLISON SYNDROME - RESULTS OF A 10-YEAR PROSPECTIVE-STUDY ANNALS OF SURGERY NORTON, J. A., DOPPMAN, J. L., Jensen, R. T. 1992; 215 (1): 8-18

  Abstract

  Since 1980, 73 patients with Zollinger-Ellison syndrome (ZES) without radiographic evidence of liver metastases were studied on a prospective protocol including medical management of gastric acid hypersecretion, extensive radiographic tumor localization, and exploratory surgery to find and resect gastrinoma for potential cure. Each patient had gastric acid hypersecretion effectively controlled with either H2-blockers or omeprazole. Patients were divided prospectively into two groups, with all patients undergoing the same preoperative localization studies and extensive laparotomy. In contrast to group 1 (1980-1986) (36 patients), group 2 (1987-Oct. 1990) (37 patients) also underwent additional procedures (transillumination and duodenotomy) at surgery to find duodenal gastrinomas. Preoperative imaging studies localized tumor in 38 (52%) patients, and portal venous sampling for gastrin determinations was positive in 49 (67%) patients. Gastrinomas were found and resected in 57 (78%) patients. Significantly more gastrinomas (92% of patients) were found in group 2 than in group 1 patients (64%) (p less than 0.01). This increase was due to increased numbers of duodenal gastrinomas in group 2 than in group 1 patients (43% versus 11%; p less than 0.01). The increased ability to find duodenal gastrinomas did not significantly improve the immediate disease-free rate, which was 58% for all patients. Duodenal primary gastrinomas were found to have a significantly greater incidence of metastases (55%) and a significantly shorter disease-free interval (12 months) than pancreatic gastrinomas (22% and 84 months, respectively) suggesting that duodenal gastrinomas may be more malignant and not more frequently curable than pancreatic gastrinomas. Operations were performed with no deaths and 11% morbidity rate. Long-term follow-up showed that 50% of patients initially rendered disease free would develop recurrent disease by 5 years. Survival was excellent for all patients, and none died of malignant spread of the tumor or uncontrolled peptic ulcer disease, with a mean follow-up of 5 years. This finding is in contrast to patients who presented with metastatic disease on imaging studies and had a 20% 5-year survival rate. This study suggests that all patients with localized sporadic ZES can have the gastric acid hypersecretion managed medically, that overall survival of these patients is excellent, most (78%) can have all gastrinoma found and resected, and some (30%) will be cured (long-term disease-free survival).

  View details for Web of Science ID A1992GY75700003

  View details for PubMedID 1531004

• HORMONAL-REGULATION OF INFLAMMATORY CELL CYTOKINE TRANSCRIPT AND BIOACTIVITY PRODUCTION IN RESPONSE TO ENDOTOXIN CYTOKINE Doherty, G. M., Jensen, J. C., Buresh, C. M., NORTON, J. A. 1992; 4 (1): 55-62

  Abstract

  Tumor necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6) are central mediators of the inflammatory response. We investigated the modulation of these cytokines by hormones in vitro. Murine adherent peritoneal exudate cells (PEC) were exposed to various concentrations of hormones followed by lipopolysaccharide (LPS, 10 micrograms/ml). TNF, IL-1 and IL-6 production were assessed by bioassays, enzyme-linked immunosorbent assays (ELISA) or Western blot, and specific RNA transcripts by Northern blot. Hydrocortisone in concentrations as low as 10 ng/ml had dramatic inhibitory effects on supernatant levels of TNF and IL-1 and on TNF, IL-1 and IL-6 transcript number. Supernatant levels of IL-6 were only slightly diminished by hydrocortisone. Adrenocorticotrophic hormone (ACTH) and insulin increased supernatant levels of TNF bioactivity in response to LPS, while each decreased available TNF-alpha gene transcripts. Thus TNF protein production was affected at a post-transcriptional level. ACTH and insulin increased supernatant levels of IL-6 produced in response to LPS without altering available transcripts. Corticotrophin-releasing factor (CRF), epinephrine and glucagon had no effect on supernatant levels of cytokine. Thus, physiological and pharmacological concentrations of hydrocortisone had dramatic inhibitory effects on the supernatant levels of TNF and IL-1, and on the number of available TNF, IL-1 and IL-6 transcripts in PEC exposed to LPS, but had minimal effects on supernatant levels of IL-6 bioactivity. This hydrocortisone action may be a specific negative feedback system for IL-1 and TNF, with relative sparing of IL-6.

  View details for Web of Science ID A1992HG57900010

  View details for PubMedID 1319763

• The use of intraoperative ultrasound during cancer surgery. Important advances in oncology Shawker, T. H., NORTON, J. A., Oldfield, E. H. 1992: 167-187

  View details for PubMedID 1582672

• RESULTS OF A PROSPECTIVE STRATEGY TO DIAGNOSE, LOCALIZE, AND RESECT INSULINOMAS 12TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS Doherty, G. M., DOPPMAN, J. L., Shawker, T. H., MILLER, D. L., Eastman, R. C., GORDEN, P., NORTON, J. A. MOSBY-YEAR BOOK INC. 1991: 989–97

  Abstract

  Since 1982, 25 consecutive patients with benign sporadic (non-multiple endocrine neoplasia type I) insulinomas have been studied. Most were referred because either the tumor was not identified at the referring institution or the diagnosis was unclear. Each patient suffered severe neuroglycopenic symptoms for a median of 24 months before diagnosis of insulinoma, and 32% had hypoglycemic seizures. Eighteen patients (72%) had a confirmed weight gain. Each patient underwent a supervised fast until 72 hours or the onset of significant neuroglycopenic symptoms (median duration 16 hours), with serum levels of glucose (median 35 mg/dl; range 24 to 46 mg/dl), insulin (median 21 microU/ml; range 11 to 230 microU/ml), C-peptide (median 2.5 ng/ml; range 1.0 to 7.2 ng/ml), and proinsulin fraction (median 55%; range 14% to 86%) measured at the termination of the fast. Preoperative imaging with ultrasonography, computed tomography, magnetic resonance, and angiography visualized tumor in a minority of patients (26%, 17%, 25%, and 35%, respectively); in 48% of patients one or more imaging study results was positive. Selective portal venous sampling for insulin was the most informative localizing test (77% positive; no false-positive results). Tumor was resected for cure in 24 of 25 patients. Intraoperative ultrasonography identified nonpalpable tumor in seven patients and was crucial to the achievement of this high rate of surgical cure. We conclude that the diagnosis of insulinoma can be made by the results of a supervised fast, portal venous sampling is the most sensitive preoperative test for localizing insulinomas, and intraoperative ultrasonography is essential for intraoperative detection of insulinomas.

  View details for Web of Science ID A1991GU13000010

  View details for PubMedID 1745987

• LOCATION, INCIDENCE, AND MALIGNANT POTENTIAL OF DUODENAL GASTRINOMAS 12TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS THOM, A. K., NORTON, J. A., Axiotis, C. A., Jensen, R. T. MOSBY-YEAR BOOK INC. 1991: 1086–93

  Abstract

  Duodenal gastrinomas are increasingly found at surgery, yet information about their location and characteristics is based on the results of either pooled series or retrospective reviews of small numbers of selected cases. To address these issues we have analyzed the location, incidence, and malignant potential of duodenal gastrinomas in 65 consecutive patients who underwent removal of all tumor as part of a 10-year prospective study to resect gastrinomas in patients with sporadic Zollinger-Ellison syndrome. The primary gastrinoma was located in the duodenum in 24 patients (37%). There were 19 men and five women aged 32 to 69 years (mean 49.4 years), with symptoms for 0.6 to 35 years (mean 7.9 years). Preoperative studies included serum gastrin levels of 114 to 35,798 pg/ml (mean 2060 pg/ml), basal acid output of 7 to 95 mEq/hr (mean 37.6 mEq/hr), and a positive secretin test result in 22 patients. Preoperative imaging studies identified tumor in the duodenal area in 11 patients (46%), but most positive imaging findings were metastatic gastrinoma in lymph nodes, and the primary duodenal tumor itself was identified in only two patients. Portal venous sampling had a localizing gastrin gradient in the inferior or superior pancreaticoduodenal vein in 17 of 23 patients (74%). Each of the 24 patients had a single, small duodenal wall tumor of 2.8 to 10.1 mm diameter (mean 6 mm). Each tumor stained positive for gastrin by immunohistochemistry. Seventeen tumors (71%) were located in the first portion of the duodenum, five (21%) in the second, and two (8%) in the third. Each tumor originated in the submucosa, and 13 (54%) were limited to the submucosa, whereas 11 (46%) were locally invasive, four (16%) extending into the muscularis mucosa and seven (29%) into the muscularis propria. Thirteen patients (54%) had spread to regional lymph nodes, whereas two (8%) had liver metastases. Lymph node metastases were seen with larger duodenal tumors (mean 7.1 vs 5.4 mm; p less than 0.01). The data suggest that a single duodenal wall gastrinoma is a common cause of Zollinger-Ellison syndrome (37%). These small (less than 1 cm) tumors are located in the submucosal layer of the proximal duodenum (92%) and are malignant more often than previously thought (54%).

  View details for Web of Science ID A1991GU13000023

  View details for PubMedID 1745977

• PRIMARY BILATERAL ADRENOCORTICAL CAUSES OF CUSHINGS-SYNDROME 12TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS ZEIGER, M. A., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., DOPPMAN, J. L., TRAVIS, W. D., NORTON, J. A. MOSBY-YEAR BOOK INC. 1991: 1106–15

  Abstract

  Nontumorous primary adrenal causes of Cushing's syndrome are exceedingly rare. Herein we review our results with seven patients in whom there is biochemical evidence of a primary (adrenocorticotropin independent) bilateral adrenal cause of endogenous hypercortisolism. Each patient had low plasma adrenocorticotropin levels. All patients had elevated 24-hour urinary free cortisol levels and 17-hydroxycorticosteroids that were not suppressed by high-dose dexamethasone. Plasma levels of adrenocorticotropin and cortisol were not elevated by ovine corticotropin-releasing factor. No patient had a gradient between petrosal and peripheral adrenocorticotropin levels. No pituitary tumors were detected by magnetic resonance imaging or computed tomography. Five of six patients who underwent iodocholesterol scanning showed bilateral adrenal activity. Computed tomographic and magnetic resonance imaging of the abdomen demonstrated bilateral small adrenal glands in three patients, an adrenal mass in one patient with Carney's complex, and massively enlarged glands in three patients. Each patient underwent bilateral adrenalectomy and was given glucocorticoid and mineralocorticoid replacement. Pathologic examination of four of these bilateral adrenal specimens revealed primary pigmented micronodular adrenocortical disease, with adrenal gland weights between 2.5 and 13.4 gm (mean 5.2 gm). However, the remaining three patients had primary adrenocorticotropin-independent bilateral macronodular adrenocortical disease with adrenal gland weights between 32 and 81 gm (mean 52 gm). Although each of the patients with primary pigmented micronodular adrenocortical disease was cured by bilateral adrenalectomy through a posterior approach, two of the three patients required an anterior approach. We conclude that Cushing's syndrome can arise through two distinct forms of primary bilateral adrenal cortical disease. Computed tomography is important in evaluation of these patients because the size of the adrenal glands influences the surgical approach.

  View details for Web of Science ID A1991GU13000026

  View details for PubMedID 1745978

• MANAGEMENT OF PATIENTS WITH PERSISTENT OR RECURRENT PRIMARY HYPERPARATHYROIDISM WORLD JOURNAL OF SURGERY Carty, S. E., NORTON, J. A. 1991; 15 (6): 716-723

  Abstract

  The surgical management of patients with persistent or recurrent primary hyperparathyroidism is reviewed. The several factors allowing the surgeon to formulate a correct working diagnosis and to successfully remove all abnormal parathyroid tissue are individually discussed and recent results of re-operative parathyroid surgery are presented. In particular, direct surgical exploration based on aggressive pre-operative localization studies, the use of intra-operative ultrasound to facilitate intra-operative dissection, cryopreservation of excised parathyroid tissue with potential for delayed autograft to avoid permanent hypoparathyroidism, and the use of intra-operative monitoring of urinary cyclic adenosine monophosphate levels in patients with parathyroid hyperplasia in whom the surgeon is uncertain whether all abnormal parathyroid tissue has been removed, each contribute to a high rate of successful management (greater than 95%) for patients with the difficult problem of persistent or recurrent primary hyperparathyroidism.

  View details for Web of Science ID A1991GQ01800008

  View details for PubMedID 1767537

• SINGLE-DOSE TUMOR-NECROSIS-FACTOR PROTECTION AGAINST ENDOTOXIN-INDUCED SHOCK AND TISSUE-INJURY IN RATS INFECTION AND IMMUNITY Alexander, H. R., Doherty, G. M., Block, M. I., KRAGEL, P. J., Jensen, J. C., Langstein, H. N., Walker, E., NORTON, J. A. 1991; 59 (11): 3889-3894

  Abstract

  Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.

  View details for Web of Science ID A1991GM53000007

  View details for PubMedID 1937748

• TRANSFORMING GROWTH-FACTOR-BETA IMPROVES HEALING OF RADIATION-IMPAIRED WOUNDS JOURNAL OF INVESTIGATIVE DERMATOLOGY Bernstein, E. F., HARISIADIS, L., Salomon, G., Norton, J., Sollberg, S., UITTO, J., Glatstein, E., Glass, J., Talbot, T., Russo, A., Mitchell, J. B. 1991; 97 (3): 430-434

  Abstract

  Exogenously applied TGF-beta 1 has been shown to increase wound strength in incisional wounds early in the healing process. An impaired wound healing model was first established in guinea pigs by isolating flaps of skin and irradiating the flaps to 15 Gray in one fraction using a 4-MeV linear accelerator. Incisions made 2 d after irradiation were excised 7 d later, and showed decreased linear wound bursting strength (WBS) as compared to non-irradiated control wounds on the contralateral side of each animal (p = 0.001). The effect of TGF-beta on healing of radiation-impaired wounds was studied using this model. Skin on both left and right sides of guinea pigs was irradiated as above. A linear incision was made in each side. Collagen with either 1, 5, or 20 micrograms of TGF-beta was applied to one side prior to closure with staples, whereas the contralateral side received saline in collagen. Wounds given either 1 or 5 micrograms of TGF-beta were found to be stronger than controls at 7 d (p less than 0.05), whereas those receiving the higher 20-micrograms dose were weaker than controls (p less than 0.05). Thus, TGF-beta in lower doses improved healing at 7 d but very large amounts of the growth factor actually impaired healing. In situ hybridization done on wound samples showed increased type I collagen gene expression by fibroblasts in wounds treated with 1 micrograms TGF-beta over control wounds. These results indicate that TGF-beta improved wound healing as demonstrated by increased WBS. This improvement is accompanied by an up-regulation of collagen gene expression by resident fibroblasts.

  View details for Web of Science ID A1991GD66800009

  View details for PubMedID 1875042

• CT AND MR IMAGING OF MASSIVE MACRONODULAR ADRENOCORTICAL DISEASE - A RARE CAUSE OF AUTONOMOUS PRIMARY ADRENAL HYPERCORTISOLISM JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY DOPPMAN, J. L., NIEMAN, L. K., TRAVIS, W. D., MILLER, D. L., Cutler, G. B., Chrousos, G. P., NORTON, J. A. 1991; 15 (5): 773-779

  Abstract

  We studied four patients with adrenocorticotropic hormone (ACTH)-independent hypercortisolism due to bilateral massive enlargement of the adrenal glands. The combined weight of the adrenal glands ranged from 69 to 149 g and the adrenal cortex was replaced in three of four patients by multiple nodules ranging from microscopic to 4 cm in diameter. One patient had massive diffuse enlargement. All patients had low or undetectable levels of serum ACTH, absence of petrosal sinus to peripheral gradients of ACTH in bilateral samples from the inferior petrosal sinuses before and after stimulation by corticotropin releasing hormone, and absence of an adenoma on MR imaging of the pituitary gland. The marked degree of adrenocortical enlargement and absence of ACTH dependency separates this massive macronodular disease from the more common ACTH-dependent macronodular hyperplasia encountered in older patients with pituitary-dependent Cushing disease. All patients required bilateral adrenalectomy to control hypercortisolism. We present the spectrum of nodular adrenal disease associated with hypercortisolism and a differential diagnosis based on morphologic criteria.

  View details for Web of Science ID A1991GF35400009

  View details for PubMedID 1653280

• THE LOCAL-EFFECTS OF CACHECTIN TUMOR-NECROSIS-FACTOR ON WOUND-HEALING ANNALS OF SURGERY SALOMON, G. D., KASID, A., CROMACK, D. T., DIRECTOR, E., Talbot, T. L., SANK, A., NORTON, J. A. 1991; 214 (2): 175-180

  Abstract

  Previous experimental studies have suggested that tumor necrosis factor (TNF) may have either a beneficial or a detrimental role in wound healing. Control and doxorubicin-treated (6 mg/kg, intravenously) rats underwent paired dorsal 5-cm linear wounds and had either vehicle or recombinant (r)TNF (0.5, 5, or 50 micrograms) applied locally to the wound. Paired wounds were harvested at 7 and 14 days after wounding and analyzed for wound-bursting strength (WBS) and activity of the gene for type 1 collagen and TNF. Doxorubicin treatment decreased WBS at 14 days but not at 7 days after wounding. Local application of 50 micrograms of rTNF decreased WBS in saline-treated rats and concentrations of 5 and 50 micrograms decreased WBS in doxorubicin-treated rats when measured 7 days after wounding. These effects dissipated when WBS was measured 14 days after wounding. Doxorubicin decreased wound collagen gene expression and local TNF treatment decreased wound collagen gene expression in saline-treated rats and further decreased it in doxorubicin-treated rats. The decrement in collagen gene expression induced by rTNF increased as the local dose of rTNF increased. The gene for TNF was not detectable in wounds from normal or doxorubicin-treated rats at 3, 7, 10, or 14 days after wounding. These data suggest that the gene for TNF is not expressed in wounds and that the local application of TNF is detrimental to wound healing as it decreases WBS and activity of the gene for collagen.

  View details for Web of Science ID A1991GB58000012

  View details for PubMedID 1714269

• PENTOXIFYLLINE SUPPRESSION OF TUMOR-NECROSIS-FACTOR GENE-TRANSCRIPTION 52ND ANNUAL MEETING OF THE SOC OF UNIVERSITY SURGEONS Doherty, G. M., Jensen, J. C., Alexander, H. R., Buresh, C. M., NORTON, J. A. MOSBY-YEAR BOOK INC. 1991: 192–98

  Abstract

  Pentoxifylline decreases lung injury after intravenous endotoxin; the mechanism is unknown. Tumor necrosis factor-alpha (TNF) is secreted by macrophages in response to endotoxin and mediates some of the toxicity of endotoxin. This study investigates the effects of pentoxifylline on endotoxin-stimulated TNF production in vitro and in vivo. Pentoxifylline concentrations of 100 and 1000 micrograms/ml inhibited TNF production by murine adherent peritoneal exudate cells incubated with endotoxin 1 microgram/ml. Similarly, pentoxifylline at 100 and 1000 micrograms/ml decreased the number of available TNF messenger RNA transcripts in peritoneal exudate cells assessed by Northern blot. Pentoxifylline had no effect on TNF mRNA stability, but appeared to act by inhibiting the rate of TNF mRNA production (transcription). In murine in vivo experiments at each dose of endotoxin administered from 0.01 to 30 mg/kg, pentoxifylline treatment significantly reduced serum TNF levels, suggesting a favorable shift of the endotoxin dose-response curve. Expression of murine TNF gene in the livers of these animals showed fewer TNF transcripts in the pentoxifylline-treated animals compared to controls. Pentoxifylline inhibited endotoxin-induced TNF production both in vivo and in vitro and exerted this control by inhibiting endotoxin-induced transcription of the TNF gene. This study suggests that pentoxifylline may ameliorate endotoxic shock by decreasing macrophage TNF production.

  View details for Web of Science ID A1991FZ62800010

  View details for PubMedID 1858029

• THYROID-CANCER - A LETHAL ENDOCRINE NEOPLASM ANNALS OF INTERNAL MEDICINE Robbins, J., MERINO, M. J., Boice, J. D., Ron, E., Ain, K. B., Alexander, H. R., NORTON, J. A., Reynolds, J. 1991; 115 (2): 133-147

  Abstract

  This conference focuses on the controversies about managing thyroid cancer, emphasizing the possibility that the treatment of patients with potentially fatal thyroid cancer may be improved. Although the mortality rate from thyroid cancer is low, it is the highest among cancers affecting the endocrine glands (excluding the ovary). Exposure to radiation during childhood in the 1930s and 1940s increased the incidence of but not the mortality from thyroid cancer, because these tumors are mainly papillary cancers developing in young adults. These rates may change as the exposed cohort ages. Risk factors that increase mortality include older patient age and the growth characteristics of the tumor at diagnosis, the presence of distant metastases, and cell type (for example, the tall-cell variants of papillary cancer, follicular cancer [to be distinguished from the more benign follicular variant of papillary cancer], medullary cancer, and anaplastic cancer). Local metastases in lymph nodes do not seem to increase the risk for death from papillary cancer, but they do increase the risk for death from follicular and medullary cancer. In the latter, mortality is decreased by the early detection and treatment of patients with the familial multiple endocrine neoplasia syndrome 2a. There are excellent tumor markers for differentiated cancer of the parafollicular and of the follicular cells (serum calcitonin and serum thyroglobulin levels, respectively). Measuring the calcitonin level allows early diagnosis of familial medullary cancer, whereas measuring the thyroglobulin level, although useful only after total thyroidectomy, allows early recognition of recurrence or metastases of papillary or follicular cancer. Initial surgery, protocols for follow-up, and the use of radioiodine for the ablation of any residual thyroid and the treatment of metastatic cancer are discussed. Because these tumors resist currently available chemotherapy regimens, possible ways to increase the effectiveness of radioiodine therapy are considered as are new approaches to treatment.

  View details for Web of Science ID A1991FW09100010

  View details for PubMedID 2058861

• DECREASED IL-6 SECRETION BY FIBROBLASTS FOLLOWING REPEATED DOSES OF TNF-ALPHA OR IL-1-ALPHA - POSTTRANSCRIPTIONAL GENE-REGULATION 1990 ANNUAL MEETING OF THE ASSOC FOR ACADEMIC SURGERY Carty, S. E., Buresh, C. M., NORTON, J. A. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1991: 24–32

  Abstract

  Tumor necrosis factor-alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) are pluripotent cytokines mediating the host response to sepsis, injury, and cancer. Animals can be protected from the lethal effects of TNF alpha by repeated administration of sublethal doses, but the mechanism of this effect is not known. Human foreskin fibroblasts (FS4 cells), which rapidly elaborate interleukin-6 (IL-6) when stimulated with TNF alpha or IL-1 alpha, were grown in culture as confluent monolayers and their secretion of IL-6 was quantitated using the murine B9-hybridoma bioassay against an external reference of human recombinant IL-6 (Genetics Institute). When FS4 cells were incubated with human recombinant TNF alpha (50 ng/ml; Cetus) or recombinant IL-1 alpha (30 pg/ml; Genzyme) a rapid increase in IL-6 production was measured over control, rising to IL-6 levels of 71.7 +/- 5.9 units/ml with TNF alpha and 54.0 +/- 1.2 units/ml with IL-1 alpha after 7.5 hr incubation. FS4 cells which were exposed to cytokine, rinsed, and then reexposed to cytokine 24 hr later produced significantly less IL-6 [38.1 +/- 2.8 units/ml with second exposure to TNF alpha (P less than 0.05), and 18.3 +/- 1.9 units/ml with second exposure to IL-1 alpha (P less than 0.01)]. Successive daily exposure to TNF alpha or IL-1 alpha caused a further stepwise diminution of IL-6 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1991FW32400005

  View details for PubMedID 2067355

• TREATMENT WITH RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR-ALPHA PROTECTS RATS AGAINST THE LETHALITY, HYPOTENSION, AND HYPOTHERMIA OF GRAM-NEGATIVE SEPSIS JOURNAL OF CLINICAL INVESTIGATION Alexander, H. R., Sheppard, B. C., Jensen, J. C., Langstein, H. N., Buresh, C. M., Venzon, D., Walker, E. C., FRAKER, D. L., STOVROFF, M. C., NORTON, J. A. 1991; 88 (1): 34-39

  Abstract

  Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

  View details for Web of Science ID A1991FU44300006

  View details for PubMedID 2056127

• TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 PROTECTION AGAINST THE LETHAL EFFECTS OF TUMOR-NECROSIS-FACTOR SURGERY Sheppard, B. C., NORTON, J. A. 1991; 109 (6): 698-705

  Abstract

  Based on the hypothesis that tumor necrosis factor (TNF) causes the lethality of gram-negative sepsis and previous work of tolerance to the lethal effects of TNF induced by repetitive exposure to sublethal intraperitoneal doses of human recombinant (r) TNF, we studied the protective role of a single sublethal intravenous dose of either rTNF (100 micrograms/kg) or recombinant interleukin-1 (rIL-1; 10(5) units/kg) or both before a subsequent lethal intravenous dose of rTNF (800 to 1000 micrograms/kg) in C3H/HEN mice. Mice were treated with a single intravenous dose of saline, rTNF, rIL-1 or both cytokines and challenged within 2 hours to 10 days with a lethal dose of rTNF. Mice treated with rTNF showed significant protection against the lethal effects of TNF when the treatment dose was given only 2 hours before the lethal dose, but maximal protection required a 24-hour interval and lasted as long as 8 days. The treatment dose of rTNF was toxic, and it resulted in occasional treatment deaths. Mice treated with rIL-1 showed maximal protection when treatment was given only 2 hours before challenge and protection lasted for 8 days. No toxicity was apparent secondary to IL-1 treatment. The combination of rIL-1 and rTNF was not as effective as either cytokine alone. The results suggest that rTNF or rIL-1 may be clinically useful in the prevention and treatment of sepsis lethality by the induction of tolerance to the lethal effects of TNF. The more promising cytokine appears to be rIL-1 because it has less toxicity and more rapid induction of full therapeutic effectiveness.

  View details for Web of Science ID A1991FQ37200003

  View details for PubMedID 2042087

• HUMAN RECOMBINANT INTERLEUKIN-1-ALPHA PROTECTION AGAINST THE LETHALITY OF ENDOTOXIN AND EXPERIMENTAL SEPSIS IN MICE 1990 ANNUAL MEETING OF THE ASSOC FOR ACADEMIC SURGERY Alexander, H. R., Doherty, G. M., FRAKER, D. L., Block, M. I., SWEDENBORG, J. E., NORTON, J. A. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1991: 421–24

  Abstract

  Human recombinant interleukin-1 alpha (IL-1) has a diverse range of physiological activities which may be beneficial or deleterious to the host. Pretreatment with doses of IL-1 has been shown to protect mice against a subsequent lethal bacterial injection; however, the protective effects of a single intravenous (iv) dose of IL-1 have not been well characterized. The current experiments were performed to determine the best dose, timing, and duration of action of a single iv dose of IL-1 against a subsequent lethal challenge with intraperitoneal endotoxin (LPS) or experimental sepsis induced by cecal ligation and puncture (CLP). Female C57B1/6 mice treated with iv IL-1 24 hr prior to 30 mg/kg LPS ip had improved survival compared to saline-treated controls (P less than 0.01). IL-1 was also protective when given 6 to 72 hr, but not 2 or 96 hr, prior to LPS. IL-1 protection against LPS lethality was similar to protection seen with an iv dose of tumor necrosis factor (TNF). After CLP, survival was improved with IL-1 versus saline pretreatment (P = 0.02). Unlike previous work with TNF, no toxicity or lethality was observed at any dose of IL-1 administered. A single iv dose of IL-1 protects against the lethality of LPS and CLP in mice. IL-1 may be a useful treatment strategy in patients at risk for the development of life-threatening sepsis.

  View details for Web of Science ID A1991FM48300002

  View details for PubMedID 2038179

• THE ROLES OF GAMMA-INTERFERON AND TUMOR-NECROSIS-FACTOR-ALPHA IN AN EXPERIMENTAL RAT MODEL OF CANCER CACHEXIA CANCER RESEARCH Langstein, H. N., Doherty, G. M., FRAKER, D. L., Buresh, C. M., NORTON, J. A. 1991; 51 (9): 2302-2306

  Abstract

  Administration of repetitive sublethal doses of either recombinant human tumor necrosis factor (TNF) or recombinant murine gamma-interferon (IFN) to non-tumor-bearing (NTB) rats caused a significant decline in food intake and body weight. After 3 days rats became resistant to the anorectic and weight loss effects of TNF but maintained persistent diminished food intake and diminished body weight gain while receiving recombinant murine IFN. Passive immunization against recombinant rat gamma-interferon allowed cachectic tumor-bearing (TB) rats to eat more food, have a lesser decline in body weight, live longer, and tolerate larger tumors than similar TB rats given nonspecific control antibody. TB rats treated with an antisera to recombinant murine TNF, which was 100% protective when given to NTB rats 6 h before a lethal endotoxin challenge, did not differ significantly from TB rats treated with control antibody with respect to food intake, body weight, survival, or tumor size. Serum levels of TNF or IFN were not detectable in cachectic tumor-bearing rats. The data indicate that the administration of exogenous IFN can simulate cachexia in NTB rats and that passive immunization against it can partially reverse the cachectic changes associated with cancer and prolong survival. These findings suggest that gamma-interferon may be an important mediator of cachexia in this rat tumor model.

  View details for Web of Science ID A1991FJ82100010

  View details for PubMedID 1901758

• RECURRENT OR METASTATIC DISEASE IN SELECT PATIENTS WITH ADRENOCORTICAL CARCINOMA - AGGRESSIVE RESECTION VS CHEMOTHERAPY ARCHIVES OF SURGERY Jensen, J. C., PASS, H. I., SINDELAR, W. F., NORTON, J. A. 1991; 126 (4): 457-461

  Abstract

  In a retrospective, nonrandomized comparison of patients with first recurrence of adrenocortical cancer, 18 patients were treated with chemotherapy (primarily mitotane) and 15 patients were treated with surgical resection plus similar chemotherapy. Surgical resection of recurrent adrenocortical cancer was often extensive, with morbidity in 20% of patients and no mortality. Mitotane therapy was ineffective at controlling tumor growth. Median survival from the time of diagnosis for all patients was only 23 months and no patient was cured. Disease-free interval greater than 12 months was associated with prolonged survival, but it only occurred in six patients (18%), with a similar frequency in both treatment groups. Surgical resection of recurrent disease was associated with prolonged survival from the time of first recurrence. The potential benefit of this resection was evident in the 5 patients (33%) who were able to live greater than 5 years from the time of first recurrence with improvement in symptoms and signs of hypercortisolism. Although no patient with recurrent adrenal cancer could be cured, resection of recurrent disease was associated with a slight prolongation of survival and good palliation of Cushing's syndrome.

  View details for Web of Science ID A1991FE87600010

  View details for PubMedID 1706914

• PAPILLARY ENDOTHELIAL HYPERPLASIA IN THE THYROID FOLLOWING FINE-NEEDLE ASPIRATION ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Axiotis, C. A., MERINO, M. J., Ain, K., NORTON, J. A. 1991; 115 (3): 240-242

  Abstract

  A 74-year-old woman was found to have exuberant papillary endothelial hyperplasia within her thyroid gland subsequent to multiple fine-needle aspiration biopsies of a Hürthle cell neoplasm. To our knowledge, this histologic alteration in the thyroid has not been previously reported. We describe this unusual complication following fine-needle aspiration, and we delineate the clinicopathologic and differential diagnostic features.

  View details for Web of Science ID A1991FA66600014

  View details for PubMedID 2001162

• MECHANISMS OF CANCER CACHEXIA HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Langstein, H. N., NORTON, J. A. 1991; 5 (1): 103-123

  Abstract

  It is currently hypothesized that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death (see Fig. 1). The metabolic changes seen in the tumor-bearing host are similar, but not identical, to those seen in sepsis and inflammation and appear to result from a generalized response of the host to the stimulus of invasion--the tumor. Although there are likely to be several humoral factors, of either host or tumor origin (see Fig. 1), involved in cancer cachexia, recombinant DNA methodology has provided sufficient amounts of only a few cytokines to enable careful investigation of their cachectic potential. TNF/cachectin has been most extensively studied and appears to play a clear role, because administration of low-dose continuous or escalating doses simulates changes associated with cancer cachexia. In addition, these cachectic changes have been blocked by a specific antisera. IL-1, IL-6, and interferon-gamma all have potential as mediators of cancer cachexia and more work is clearly indicated. It is possible that, given our current understanding of the mechanisms of cancer cachexia, it can be theorized that TNF, which causes many of the manifestations of cancer cachexia, and IL-1 are released by macrophages in response to tumor (see Fig. 1). Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Other factors are certain to be involved. Further study into the mechanisms and possible treatment of cancer cachexia is needed, because a large proportion of cancer patients who are incurable by current therapies continue to suffer from this lethal wasting diathesis. Furthermore, specific strategies to reverse the cachectic changes associated with cancer will likely improve antitumor treatment.

  View details for Web of Science ID A1991EZ50600009

  View details for PubMedID 2026566

• INSULINOMAS - LOCALIZATION WITH SELECTIVE INTRAARTERIAL INJECTION OF CALCIUM RADIOLOGY DOPPMAN, J. L., MILLER, D. L., Chang, R., Shawker, T. H., GORDEN, P., NORTON, J. A. 1991; 178 (1): 237-241

  Abstract

  To facilitate the noninvasive preoperative localization of islet cell tumors less than 15 mm in diameter, the authors examined the use of calcium as an insulin secretagogue in an arterial stimulation venous sampling (ASVS) technique. In four patients with episodic hypoglycemia, calcium gluconate (0.01-0.025 mEq Ca2+/kg) was injected directly into branches of the celiac plexus (gastroduodenal, splenic, and hepatic arteries) and the superior mesenteric artery. In all patients, serum levels of insulin rose abruptly in blood samples taken from the right hepatic vein 30 and 60 seconds after the infusion of calcium into the artery supplying the tumor; injection into an artery not supplying the tumor did not result in a similar rise. Accurate localization of the insulinomas was verified at surgery in three patients. In the fourth patient, who did not undergo surgery, arteriographic results were positive for insulinoma at the predicted site. On the basis of these results, the authors believe noninvasive ASVS may replace invasive portal venous sampling as the most effective method for the localization of occult insulinomas.

  View details for Web of Science ID A1991EP11700044

  View details for PubMedID 1984311

• UNRESOLVED SURGICAL ISSUES IN THE MANAGEMENT OF PATIENTS WITH ZOLLINGER-ELLISON SYNDROME WORLD JOURNAL OF SURGERY NORTON, J. A., Jensen, R. T. 1991; 15 (1): 151-159

  Abstract

  In the last 10 years, there have been a number of major advances that have markedly changed the management of patients with Zollinger-Ellison syndrome. These advances have been described recently in a number of excellent reviews. After reading each of these reviews, including our own, one is left generally with the impression that most of the important problems and particularly those involving surgery in the treatment of this disease have been resolved; however, in considering the possible problems to address in protocols in the coming years in our patients with Zollinger-Ellison syndrome followed at the National Institutes of Health, it became apparent to us that not only will surgery play an increasingly important role in the management of this disease, but that there are a number of major questions in which various aspects involving surgery are not resolved. Furthermore, resolution of a number of these areas will have applicability to the surgical treatment of other islet cell tumors. The purpose of this article is to call attention to these questions with the hope that other investigators may also consider these and specifically attempt to address some of these issues in the surgical treatment of Zollinger-Ellison syndrome in prospective studies.

  View details for Web of Science ID A1991FB90200027

  View details for PubMedID 1671617

• ULTRASTRUCTURAL PATHOLOGY EXPLAINS RESULTS OF TL-201/TC-99M PARATHYROID SUBTRACTION SCINTIGRAPHY 19TH INTERNATIONAL SYMP ON RADIOACTIVE ISOTOPES IN CLINICAL MEDICINE AND RESEARCH Sandrock, D., MERINO, M. J., NORTON, J. A., MILLER, D. L., Neumann, R. D. F K SCHATTAUER VERLAG. 1991: 328–332

  View details for Web of Science ID A1991BX93L00056

• THE UTILITY OF CIRCULATING LEVELS OF HUMAN PANCREATIC-POLYPEPTIDE AS A MARKER FOR ISLET CELL TUMORS 11TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS Langstein, H. N., NORTON, J. A., CHIANG, H. C., Odorisio, T. M., Maton, P. N., Marx, S. J., Jensen, R. T. MOSBY-YEAR BOOK INC. 1990: 1109–16

  Abstract

  The measurement of plasma levels of human pancreatic polypeptide (hPP) has been reported to be clinically useful in predicting the existence of pancreatic islet cell neoplasms in patients with familial multiple endocrine neoplasia type 1 (FMEN-I) and the possible presence of metastatic disease in patients with islet cell tumors. However, these studies have not been prospective and involve small numbers of patients. In this study, fasting plasma samples from 36 patients with biopsy-proved islet cell tumors were analyzed for hPP by radioimmunoassay and compared with age-matched control subjects. Of 13 patients with FMEN-I who had islet cell tumors, 7 (54%) had elevated plasma hPP levels before surgery. After resection of all islet cell tumors, 4 of 12 patients evaluated after surgery still had elevated levels. Fifteen patients had islet cell tumors that were localized (seven insulinomas and eight gastrinomas), but none of these patients had elevated hPP levels, either before or after surgery. Nine patients, including one with FMEN-I, with metastatic islet cell tumors to the liver were studied; three with more advanced disease had elevated hPP levels before surgery. Each of the nine patients underwent resection of all gross disease and the three patients with elevated preoperative levels had normal postoperative hPP levels. Our results indicate that basal plasma levels of hPP were not clinically useful. The hPP levels did not reliably predict the presence of islet cell tumors in patients with FMEN-I, because 46% of patients with tumors did not have elevated plasma levels, and in those with elevated values hPP levels did not reliably predict the resection of all tumor. Plasma levels of hPP have no utility in patients with localized sporadically occurring islet cell tumors and limited utility (33%) in predicting the presence of metastatic islet cell tumors to the liver.

  View details for Web of Science ID A1990EL87300026

  View details for PubMedID 2174193

• PREOPERATIVE AND INTRAOPERATIVE LOCALIZATION OF GASTRINOMAS PROBLEMS IN GENERAL SURGERY Doherty, G. M., NORTON, J. A. 1990; 7 (4): 521-532

  View details for Web of Science ID A1990EN18700004

• TIME TO RECOVERY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AFTER CURATIVE RESECTION OF ADRENAL-TUMORS IN PATIENTS WITH CUSHINGS-SYNDROME 11TH ANNUAL MEETING OF THE AMERICAN ASSOC OF ENDOCRINE SURGEONS Doherty, G. M., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., NORTON, J. A. MOSBY-YEAR BOOK INC. 1990: 1085–90

  Abstract

  The recovery time of the hypothalamic-pituitary-adrenal (HPA) axis after curative resection of adrenal tumors in patients with Cushing's syndrome is poorly documented. Eight consecutive patients were treated with a standardized hydrocortisone replacement strategy after curative resection of a cortisol-secreting tumor and the time to recovery of the HPA axis was determined. Hypercortisolism was documented by elevated 24-hour urinary free cortisol levels. Cure was documented by undetectable postoperative morning serum cortisol levels. Each patient received replacement hydrocortisone after surgery and was reevaluated every 3 to 6 months with an adrenocorticotrophic hormone (ACTH) stimulation test. Each patient was also monitored carefully for symptoms and signs of adrenal insufficiency, which was defined as symptoms consistent with this diagnosis that responded to increases in hydrocortisone levels. After surgical resection, each patient was cured of hypercortisolism. Subsequently, despite replacement hydrocortisone, each patient had symptoms of hypocortisolism, and in four of eight patients the dose of hydrocortisone was increased to relieve the symptoms. Patients required a median time of 15 months (range, 9 to 22 months) to recover a normal ACTH stimulation test and 19 months (range, 12 to 24 months) to allow discontinuation of replacement doses of hydrocortisone. The results suggest that surgical resection of a cortisol-secreting adrenal tumor will result in rapid cure of hypercortisolism, but complete recovery of the HPA axis and discontinuation of replacement steroids will require between 1 and 2 years. Normal adrenal function, as assessed by the cortisol response to ACTH, returns despite replacement doses of hydrocortisone, and replacement doses of hydrocortisone can be tapered rapidly or discontinued after a normal ACTH stimulation test.

  View details for Web of Science ID A1990EL87300022

  View details for PubMedID 2247834

• LOCALIZATION AND SURGICAL-TREATMENT OF OCCULT INSULINOMAS ANNALS OF SURGERY NORTON, J. A., Shawker, T. H., DOPPMAN, J. L., MILLER, D. L., FRAKER, D. L., CROMACK, D. T., GORDEN, P., Jensen, R. T. 1990; 212 (5): 615-620

  Abstract

  Management of patients with biochemical evidence of insulinoma and negative preoperative imaging studies (occult) tumors is controversial, varying from primarily medical management to aggressive, blind nearly total pancreatectomy to extirpate the tumor. Since 1982, 12 consecutive patients with occult insulinoma underwent preoperative portal venous sampling (PVS) for insulin followed by surgical exploration with intraoperative ultrasound (IOUS). Eleven of twelve patients (92%) had insulinoma removed and were cured. Portal venous sampling correctly predicted the location of the insulinoma in 9 patients (75%) and that no tumor would be found in another patient. A fourfold insulin gradient in the pancreatic tail of one patient correctly predicted that a distal pancreatectomy would remove the insulinoma despite the fact that neither palpation nor IOUS identified any tumor. Intraoperative ultrasound was the single best method to identify occult tumors because it correctly identified 10 of 11 insulinomas that were found, including five pancreatic head tumors that were not palpable. Palpation identified five insulinomas. Of the 10 tumors that were identified during operation by palpation or ultrasound, IOUS identified significantly more (100% versus 50%, p = 0.03) and guided the successful enucleation of each. The results support the strategy of preoperative PVS and operation with IOUS to localize and remove insulinoma in patients with occult tumors. Most tumors (75%) will be correctly localized to a specific pancreatic region by preoperative PVS and identified by IOUS (83%), allowing simple enucleation and biochemical correction of hypoglycemia. Morbid blind pancreatic resections are no longer indicated and long-term medical management of hypoglycemia should be reserved for the occasional patient (8%) who fails preoperative PVS and operation guided by IOUS.

  View details for Web of Science ID A1990EG93000009

  View details for PubMedID 2241318

• SURGICAL-MANAGEMENT OF PHEOCHROMOCYTOMA WITH THE USE OF METYROSINE ANNALS OF SURGERY Perry, R. R., Keiser, H. R., NORTON, J. A., Wall, R. T., Robertson, C. N., Travis, W., PASS, H. I., Walther, M. M., Linehan, W. M. 1990; 212 (5): 621-628

  Abstract

  Despite recommended preoperative preparation with alpha-adrenergic blockers, severe hemodynamic instability may occur during operations to resect pheochromocytoma. We combined the alpha-blocker phenoxybenzamine with the tyrosine hydroxylase inhibitor metyrosine in an attempt to better manage the hypertension of patients with pheochromocytoma undergoing surgical resection. This report reviews the cases of 25 consecutive patients undergoing surgery for known intra-abdominal pheochromocytoma. Each patient had elevated serum or urine levels of catecholamines or their metabolites. Nineteen patients were prepared before operation with phenoxybenzamine and metyrosine and six patients were given phenoxybenzamine alone. There were no significant differences in maximum, minimum, or mean blood pressure before or after tumor resection between patients who received metyrosine and those who did not. However careful review suggested that those who received metyrosine had more severe disease as judged by biochemical criteria. Study of selected patients matched for age and severity of disease suggested that the intraoperative blood pressure management of patients prepared with phenoxybenzamine and metyrosine was facilitated. In addition metyrosine-prepared patients lost less blood and required less volume replacement during surgery than did non-metyrosine-prepared patients. There were no apparent differences in postoperative fluid requirements. Although the study is not a prospective randomized trial, a retrospective review of patients managed with the combination of phenoxybenzamine and metyrosine suggests that surgery to resect pheochromocytoma can be better performed with both drugs than with phenoxybenzamine alone. The combination regimen appears to result in better blood pressure control, less blood loss, and the need for less intraoperative fluid replacement than does the traditional method of single-agent alpha-adrenergic blockade.

  View details for Web of Science ID A1990EG93000010

  View details for PubMedID 1978640

• LACTIC-ACIDOSIS INCREASES TUMOR-NECROSIS-FACTOR SECRETION AND TRANSCRIPTION INVITRO 1989 ANNUAL MEETING OF THE ASSOC FOR ACADEMIC SURGERY Jensen, J. C., Buresh, C., NORTON, J. A. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1990: 350–53

  Abstract

  Lactic acid has been shown to affect numerous biologic processes. We investigated the role of lactic acidosis as a signal for the production of TNF by macrophages in vitro. Male F344 rats were administered thioglycolate media intraperitoneally. Macrophages were recovered 7 days later, cultured for 24 hr in complete media (CM), or CM with L-lactic acid (5, 10, or 15 mM), or with endotoxin (LPS) (10 micrograms/ml). TNF levels were measured in the supernatants. Female C57BL/6 mice were similarly treated, and macrophages were harvested and cultured in CM or CM containing lactic acid (15 mM), or LPS (10 micrograms/ml). RNA was extracted after 24 hr, separated by electrophoresis, and transferred to nitrocellulose. Human 32P-cDNA TNF and actin probes were used to determine relative TNF gene expression. Gel densitometry was used to calculate the TNF expression index (EI) in lactic acid and LPS treated cells as described. pH levels of the supernatant indicated that increasing concentrations of lactic acid caused increasing acidosis. Trypan blue exclusion demonstrated that lactic acidosis did not reduce cell viability. LPS significantly increased secretion of TNF relative to control (P less than 0.001). Each concentration of lactic acid significantly increased TNF secretion (P less than 0.05), but not in a dose-dependent manner. TNF gene transcription was elevated in macrophages cultured with lactic acid and LPS relative to control (EI = 1.13 and 1.18, respectively). This suggests that lactic acid concentration can regulate TNF secretion at the level of transcription, and is consistent with the hypothesis that local levels of lactic acid (lactic acidosis) may be a regulator of cytokine secretion.

  View details for Web of Science ID A1990EC40800015

  View details for PubMedID 2214745

• GENE-EXPRESSION IN NORMAL AND DOXORUBICIN-IMPAIRED WOUNDS - IMPORTANCE OF TRANSFORMING GROWTH-FACTOR-BETA 51ST ANNUAL MEETING OF THE SOC OF UNIV SURGEONS SALOMON, G. D., KASID, A., Bernstein, E., Buresh, C., DIRECTOR, E., NORTON, J. A. MOSBY-YEAR BOOK INC. 1990: 318–23

  Abstract

  The function of transforming growth factor-beta (TGF-beta) in vivo remains unknown despite the fact that it has been identified in numerous biologic processes involving the regulation of cell growth including tissue repair. Doxorubicin is a potent antitumor drug that has been shown to have detrimental effects on wound healing. With specific complementary DNA probes for TFG-beta and type 1 collagen, RNA from wounds of rats treated with saline solution and doxorubicin was analyzed for the expression of each gene at different times after wounding. In a second study, either 2 micrograms exogenous TGF-beta or vehicle was added to wounds of rats treated with doxorubicin, and wound RNA was analyzed in a similar manner. In wounds from rats treated with saline solution, messenger RNA (mRNA) for TGF-beta peaks on day 7 after wounding and is also elevated on days 3 and 10; mRNA for collagen is elevated on days 7 and 10. Doxorubicin decreases mRNA for TGF-beta and collagen on each day. Topical application of TGF-beta to wounds of rats treated with doxorubicin increases collagen mRNA levels to normal or supranormal levels. This study suggests that the impaired healing induced by doxorubicin may be a result of decreased gene expression for TGF-beta and that topical replacement of this growth factor may correct the defect.

  View details for Web of Science ID A1990DT13100027

  View details for PubMedID 2382227

• INTRAVENOUS OMEPRAZOLE IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME UNDERGOING SURGERY GASTROENTEROLOGY Vinayek, R., Frucht, H., London, J. F., Miller, L. S., Stark, H. A., NORTON, J. A., Cederberg, C., Jensen, R. T., Gardner, J. D., Maton, P. N. 1990; 99 (1): 10-16

  Abstract

  Twenty patients with Zollinger-Ellison syndrome who were undergoing surgery were studied prospectively to assess the efficacy and safety of IV omeprazole. During the preoperative period, in 19 of 20 patients, omeprazole 60 mg administered as an IV bolus every 12 hours inhibited acid output to less than 5 mEq/h measured in the last hour before the next dose of drug. In one patient, acid output was 25 mEq/h 12 hours after omeprazole, 60 mg, and increasing the dose to 100 mg every 12 hours reduced acid output to less than 5 mEq/h. During the operative and postoperative periods, IV omeprazole controlled gastric acid hypersecretion in all patients for up to 15 days. During this time, all patients received the dose determined preoperatively. No patient developed any clinical, hematological, or biochemical toxicity that could be attributed to omeprazole therapy during the preoperative or postoperative period. The present study demonstrates that omeprazole administered by IV bolus is safe and effective for controlling gastric acid hypersecretion. In contrast to IV histamine H2-receptor antagonists, IV omeprazole has the advantages of not requiring continuous infusion or postoperative dose adjustments. Intravenous omeprazole will become the drug of choice in patients with Zollinger-Ellison syndrome undergoing surgery.

  View details for Web of Science ID A1990DH80400002

  View details for PubMedID 1971604

• CACHECTIC EFFECTS OF RECOMBINANT HUMAN TUMOR-NECROSIS-FACTOR IN RATS CANCER RESEARCH Darling, G., FRAKER, D. L., Jensen, J. C., GORSCHBOTH, C. M., NORTON, J. A. 1990; 50 (13): 4008-4013

  Abstract

  Treatment of rats with either intermittent bolus i.v. injections or continuous i.v. infusions of the same sublethal daily dose of tumor necrosis factor (TNF) results in decreased food intake and decreased nitrogen balance compared to saline-treated control rats. After 4 days of treatment, rats treated with intermittent bolus doses of TNF develop tolerance to the nutritional effects and consume normal amounts of food and have nitrogen balance similar to those of saline treated rats. Rats receiving the continuous infusion of TNF do not. Rats treated with both routes of TNF lose more weight than pair fed rats who eat the same mean amount as the continuous TNF treated group. In addition, 56% of rats receiving continuous infusion TNF die during the 8-day experimental period while rats receiving either intermittent bolus TNF or similar food intake (pair fed) do not. Body composition studies of rats that completed the 8 days of treatment indicate that rats receiving either continuous infusion or intermittent bolus TNF have increased percentages of body water and reduced percentages of body solid compared to saline treated control rats. Rats pair fed to the food intake of continuous TNF treated rats also had increased percentages of body water and reduced percentages of body solid, but changes were significantly less than those observed in continuous TNF infused rats. Continuous TNF infusion reduced total body nitrogen and potassium while pair feeding did not reduce potassium and reduced nitrogen to a lesser degree. Pair feeding and continuous TNF infusion reduced total body fat to a similar extent. Twice a day administration of TNF resulted in lesser changes in carcass water, solid, nitrogen, lipid, and potassium than continuous infusion of the same dose of TNF. The results indicate that continuous infusion of TNF can produce anorexia, weight loss, edema, loss of body protein, lipid and cell mass, and lethality which is markedly ameliorated with bolus doses of TNF. The findings are consistent with the hypothesis that slow continuous secretion of sublethal amounts of TNF may mediate cancer cachexia.

  View details for Web of Science ID A1990DK78300035

  View details for PubMedID 2354450

• MANAGEMENT OF THE ECTOPIC ACTH SYNDROME DUE TO THORACIC CARCINOIDS ANNALS OF THORACIC SURGERY PASS, H. I., DOPPMAN, J. L., Nieman, L., Stovroff, M., Vetto, J., NORTON, J. A., Travis, W., Chrousos, G. P., Oldfield, E. H., Cutler, G. B. 1990; 50 (1): 52-57

  Abstract

  The association of a bronchial or thymic carcinoid as a source for the ectopic production of adrenocorticotropic hormone (ACTH) has been reported since 1957, with approximately 72 cases in the literature. These patients are characterized by young age, long duration of Cushing's syndrome because of the inability to find the ectopic source, and a high incidence of hypophysectomy or adrenalectomy without curing the disease. A substantial number of patients, upon discovery of the thoracic ectopic source, are also found to have malignant carcinoid tumors with lymph node metastases. Fifteen patients have been explored for a presumed intrathoracic source of ACTH at our institution since 1983 and 14 carcinoids (13 bronchial, one thymic) have been resected. Seventy-one percent (10/14) of the patients appear cured with normal plasma ACTH levels 5 to 57 months after resection, despite a 50% incidence of positive lymph node disease. Management of these patients demands an aggressive evaluation to prevent unnecessary adrenalectomy or hypophysectomy and to allow earlier resections before these potentially curable malignancies metastasize. When the tumor is discovered, thorough exploration and complete lymph node mapping with resection must be performed.

  View details for Web of Science ID A1990DQ42000010

  View details for PubMedID 2164362

• PARATHYROID IMAGING BY TC/TL SCINTIGRAPHY EUROPEAN JOURNAL OF NUCLEAR MEDICINE Sandrock, D., MERINO, M. J., NORTON, J. A., Neumann, R. D. 1990; 16 (8-10): 607-613

  Abstract

  Between 1983 and 1988, a total of 224 99mTc/201Tl subtraction parathyroid scintigraphy studies were performed in 214 patients (136 women, 78 men, average age 50, +/- 15 years) with clinical and biochemical signs of hyperparathyroidism. Of the 214 patients, 113 underwent surgical exploration, and 127 benign parathyroid lesions were found, 48 of which were correctly localized by scintigraphy (sensitivity 38%). We detected 30 of 71 adenomas (42%) and 18 of 56 hyperplastic glands (32%). Additionally, the scans localized 2 of 6 parathyroid carcinomas in 5 patients. Overall, 83 parathyroid lesions were missed. There was no significant difference in size between detected and missed lesions. Previous neck surgery (65 of 113 patients) was not a significant detriment to scan sensitivity; but correct detection did depend upon the anatomic site of the lesion: 39% (n = 109) were detected in the typical site, 44% (n = 9) intrathyroidal, and 11% (n = 9) in the anterior and/or superior mediastinum. In conclusion, these results show only limited value for this 99mTc/201Tl subtraction scintigraphy protocol as the initial procedure for localization of abnormal parathyroid tissue prior to surgical exploration.

  View details for Web of Science ID A1990DH49300005

  View details for PubMedID 2166664

• UNDESCENDED PARATHYROID ADENOMA - AN IMPORTANT ETIOLOGY FOR FAILED OPERATIONS FOR PRIMARY HYPERPARATHYROIDISM MEETING OF THE INTERNATIONAL ASSOC OF ENDOCRINE SURGEONS FRAKER, D. L., DOPPMAN, J. L., Shawker, T. H., Marx, S. J., Spiegel, A. M., NORTON, J. A. SPRINGER VERLAG. 1990: 342–48

  Abstract

  From July, 1982 to April, 1989, a total of 145 patients with persistent or recurrent primary hyperparathyroidism (HPT) were explored; 105 patients had an adenoma as the cause of HPT, and in 9 patients (9%), the abnormal gland was located at or superior to the carotid bifurcation (undescended parathyroid gland). These 9 patients had 14 prior explorations for HPT including 4 median sternotomies and 5 thyroidectomies. Each of the 9 patients was symptomatic of HPT, including bone disease in 8 of 9 patients and renal stones in 4 of 9 patients. Seven patients had an undescended parathyroid adenoma correctly localized preoperatively by ultrasound (n = 5), angiography (n = 5), venous sampling (n = 1), or computed tomography scan (n = 4). These 7 patients with accurate preoperative localization were explored by an incision anterior to the sternocleidomastoid muscle high in the neck that avoided the previous operative field and allowed rapid resection of the parathyroid adenoma. In the 2 patients who did not have accurate preoperative localization, the undescended adenoma was found after long tedious exploration including median sternotomy in 1 patient. Each patient (n = 9) who had an undescended parathyroid adenoma removed was cured of hypercalcemia, and 5 patients required postoperative 1,25-dihydroxy vitamin D3 for hypocalcemia. We conclude that undescended parathyroid adenomas comprise a significant proportion (9%) of adenomas during reoperations for persistent HPT.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990DD83600010

  View details for PubMedID 2368436

• IMPACT OF TOLERANCE ON ANTITUMOR EFFICACY OF TUMOR-NECROSIS-FACTOR IN MICE CANCER RESEARCH FRAKER, D. L., Sheppard, B. C., NORTON, J. A. 1990; 50 (8): 2261-2267

  Abstract

  Repetitive sublethal doses of tumor necrosis factor (TNF) can induce tolerance or tachyphylaxis to the toxic effects of TNF. Because tumor-bearing (TB) mice are more sensitive to the toxic effects of TNF, this study investigates whether similar tolerance occurs in TB mice and whether it affects the antitumor response of TNF. Nontumor-bearing C3H/Hen mice were treated with twice daily i.p. sublethal escalating doses of human recombinant TNF (2, 2, 3, 3, 4, and 4 micrograms i.p. every 12 h for 6 days) and were challenged 2 days later with a lethal i.v. dose (40 micrograms) of TNF. TNF-pretreated mice had 100% survival as compared to 0% survival in control mice previously treated with saline (P less than 0.01). Tumor-bearing C57BL/6 mice bearing an MCA-106 or MCA-102 sarcoma were treated with an identical TNF-tolerizing regimen (2, 2, 3, 3, 4, and 4 micrograms i.p. every 12 h for 6 days) beginning 3 days following tumor inoculation and were similarly more resistant to a subsequent 100% lethal i.v. treatment dose of TNF than control TB mice. A significantly greater percentage of TNF-pretreated mice bearing the MCA-106 sarcoma survived treatment doses of 8, 12, and 16 micrograms of TNF i.v. than control TB mice. Similarly, a significantly greater percentage of TNF-pretreated mice bearing the MCA-102 sarcoma survived treatment doses of 6 and 9 micrograms of TNF i.v. than control TB mice. However, the ability to administer higher doses of TNF i.v. to TNF-pretreated TB mice did not improve therapeutic efficacy. In mice bearing the MCA-106 tumor the most efficacious treatment responses were seen in animals that were previously naive to TNF, and treatment toxicity (lethality) correlated directly with antitumor efficacy such that larger treatment doses of TNF in tolerant mice resulted in similar antitumor effects as smaller treatment doses in control TB mice. In mice bearing the MCA-102 tumor, equitoxic treatment doses of TNF produced similar antitumor effects in both control and tolerant TB mice. There were no differences in cure rate for TNF-tolerant or control TB mice bearing either tumor. The results suggest that TNF tolerance occurs in TB mice and reduces the toxicity as well as the therapeutic efficacy of TNF.

  View details for Web of Science ID A1990CZ34900009

  View details for PubMedID 2317813

• EFFECT OF PHOTODYNAMIC THERAPY ON TUMOR NECROSIS FACTOR PRODUCTION BY MURINE MACROPHAGES JOURNAL OF THE NATIONAL CANCER INSTITUTE Evans, S., Matthews, W., Perry, R., Fraker, D., Norton, J., PASS, H. I. 1990; 82 (1): 34-39

  Abstract

  Photodynamic therapy (PDT) involves the treatment of tumors in the presence of sensitizer, light, and oxygen, causing energy-dependent cytotoxicity. A vascular effect that causes hemorrhagic tumor necrosis has been described with PDT, but its basis remains undefined. To investigate the possible role of tumor necrosis factor (TNF) production in the generation of such a vascular effect and/or a direct tumor effect, we treated thioglycollate-elicited murine macrophages with PDT, and we measured the possible production of TNF using the L929 assay. An energy-dependent production of TNF by macrophage treated with PDT, stimulated or unstimulated with endotoxin, was demonstrated, and TNF production was inhibited at the highest treatment energy levels. These data represent the first description of cytokine production by PDT-treated macrophages, and may serve as another mechanism of PDT cytotoxicity in vivo, either directly by TNF-mediated tumor necrosis, or indirectly by vascular effects on tumor vessels.

  View details for Web of Science ID A1990CE84800012

  View details for PubMedID 2293654

• SPLENECTOMY IN THE MANAGEMENT OF SYSTEMIC MAST-CELL DISEASE SURGERY Friedman, B., Darling, G., Norton, J., HAMBY, L., Metcalfe, D. 1990; 107 (1): 94-100

  Abstract

  The records of 26 patients with systemic mast cell disease (SMCD) treated during the past decade at the National Institutes of Health were reviewed to determine the role of splenectomy in the management of SMCD. Seventeen (65%) patients had indolent SMCD, manifested primarily by urticaria pigmentosa and mast cell infiltration of the skin, bone marrow, or gastrointestinal tract. None of these patients underwent splenectomy. These patients required only symptomatic therapy. Nine (35%) patients, including those with associated hematologic disorders and those with a lymphoma-like illness termed lymphadenopathic mastocytosis with eosinophilia, had aggressive SMCD. Five of nine patients with aggressive SMCD underwent splenectomy. Of the five patients with splenectomy, three were alive at the time of this report, whereas none of the four who did not have a splenectomy was still alive. Length of survival without splenectomy was 26 months. With splenectomy, length of survival at the time of this report was 34 months. Patients without splenectomy died of bleeding caused by severe thrombocytopenia. Patients with splenectomy appeared better able to tolerate chemotherapy. We thus conclude that while splenectomy is of no value in the management of indolent mastocytosis, it should be considered in patients with aggressive SMCD.

  View details for Web of Science ID A1990CH21600014

  View details for PubMedID 2404352

• THE ROLE OF SURGERY IN THE MANAGEMENT OF ISLET CELL TUMORS GASTROENTEROLOGY CLINICS OF NORTH AMERICA FRAKER, D. L., NORTON, J. A. 1989; 18 (4): 805-830

  Abstract

  Endocrine tumors of the pancreas are rare disorders that can cause life-threatening symptoms related to the excessive hormonal secretion and the malignant nature of the neoplasm. In addition, these neoplasms can present as part of familial endocrinopathy syndromes, especially multiple endocrine neoplasia type 1 (MEN-1). The initial step in evaluation of a patient with an islet cell tumor is definitive diagnosis of the hormonal syndrome that usually can be achieved biochemically. The next step is to reverse the life-threatening hormonal syndrome medically to allow radiographic localization of the islet cell neoplasm and to prepare the patient for elective surgery. In general, the goal of surgery is to accurately stage the extent of disease and to totally resect the tumor resulting in complete correction of the excessive hormonal condition and freedom from malignant progression of the tumor. Resection of the neoplasm should encompass metastatic disease in select individuals in whom complete or nearly complete resection can be achieved. Surgery must be performed with acceptable morbidity and mortality because the medical management of the excessive hormonal secretion in most patients is adequate and the progression rate of malignant islet cell carcinomas is usually slow. Patients with MEN-1 should be identified during evaluation by careful history and should be managed differently. These patients always have multiple islet cell tumors and may have malignant islet cell carcinomas. Large (3 cm) imageable pancreatic neoplasms in patients with MEN-1 should be resected because nearly 50 per cent are malignant. Zollinger-Ellison syndrome in patients with MEN-1 and primary hyperparathyroidism is best managed initially by surgery directed at the hyperparathyroidism. It may be impossible to correct the biochemical abnormalities of Zollinger-Ellison syndrome by islet cell tumor resection in patients with MEN-1. However, insulinoma or VIPoma syndromes can often be corrected by islet cell tumor resection. Portal venous sampling for hormones may be helpful in determining what hormone a specific tumor is secreting.

  View details for Web of Science ID A1989CE88900009

  View details for PubMedID 2559034

• TUMOR NECROSIS FACTOR - IMMUNE ENDOCRINE INTERACTION SURGERY Darling, G., Goldstein, D. S., Stull, R., GORSCHBOTH, C. M., NORTON, J. A. 1989; 106 (6): 1155-1160

  Abstract

  Tumor necrosis factor (TNF), a peptide produced by macrophages in response to endotoxin, has been implicated as a mediator of septic shock. This study examined the effects of injections of recombinant (r) human TNF on circulating levels of metabolic substrates and hormones in conscious, unrestrained rats and the effects of TNF on cortisol secretion from human adrenocortical cells in vitro. Sublethal doses of rTNF--doses that did not produce hemodynamic changes in previous work--produced rapid (1 hour), significant increases in blood levels of glucose, lactate, and triglycerides and decreases in plasma levels of branched chain amino acids. Plasma levels of glucagon, corticosterone, ACTH, norepinephrine, and dihydroxyphenylglycol were also increased significantly. Incubation of adrenocortical cells with either 0.15 or 1.5 micrograms of rTNF increased cortisol secretion to the same extent as did 10(-10) mol/L ACTH. Administration of TNF produces a variety of metabolic and neuroendocrine effects including stimulation of anterior pituitary, adrenal cortical, and pancreatic secretion, and sympathoneural activation. These changes, and the in vitro results, are consistent with the view that immune cells can interact with endocrine cells through release of TNF.

  View details for Web of Science ID A1989CC24200034

  View details for PubMedID 2555929

• PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE - A LIGHT AND ELECTRON-MICROSCOPIC STUDY OF 8 CASES AMERICAN JOURNAL OF SURGICAL PATHOLOGY TRAVIS, W. D., Tsokos, M., DOPPMAN, J. L., Nieman, L., Chrousos, G. P., Cutler, G. B., Loriaux, D. L., NORTON, J. A. 1989; 13 (11): 921-930

  Abstract

  Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome, which is adrenocorticotropic hormone-independent and involves both adrenal glands. The characteristic pathological features include multiple pigmented cortical nodules and atrophy of the internodular cortex. The adrenal size ranges from small to normal or slightly enlarged. Review of the gross, light microscopic, and ultrastructural features of eight cases seen at the National Institutes of Health revealed several very unusual findings. We observed the following in our patients: macronodules up to 3.0 cm; microscopic foci of necrosis; mitoses; cortical hyperplasia rather than internodular atrophy; focal confluence of nodules giving a diffuse pattern of cortical involvement, and a focal trabecular growth pattern. The nodules were composed primarily of eosinophilic, lipid-poor cells similar to those of the zona reticularis. However, lipid-rich cells similar to those of the zona fasciculata were also demonstrated in the nodules by both light and electron microscopy. This suggests that the adrenal cortical nodules of PPNAD may be derived from not only the zona reticularis, but also the zona fasciculata.

  View details for Web of Science ID A1989AW36900002

  View details for PubMedID 2679153

• PREVENTION AND TREATMENT OF ENDOTOXIN AND SEPSIS LETHALITY WITH RECOMBINANT HUMAN-TUMOR NECROSIS FACTOR SURGERY Sheppard, B. C., FRAKER, D. L., NORTON, J. A. 1989; 106 (2): 156-162

  Abstract

  Tumor necrosis factor (TNF) is a macrophage product released in response to endotoxin that has been implicated as a cause of the toxicity and lethality seen in septic shock. Previous work suggests that tolerance to nutritional and lethal effects of TNF occur after repeated exposure to recombinant tumor necrosis factor (rTNF). In this study pretreatment of rats with a single low intravenous dose of rTNF prevented subsequent death when a lethal dose of rTNF was administered 24 hours later (tolerance or tachyphylaxis). Pretreatment with rTNF also afforded protection against the lethal effects of either endotoxin or cecal ligation and puncture when rats were challenged 24 hours later. Recombinant TNF injected 6 hours after cecal ligation and puncture initially resulted in a significant survival advantage for treated animals. When this experiment was repeated with a different lot of rTNF, however, the therapeutic benefit of rTNF was not obtained until the dose was decreased by a factor of 10. Protection against the lethal effects of cecal ligation and puncture did not occur when rTNF was given 24 hours after the insult. A single low dose of rTNF can result in tolerance or tachyphylaxis to the lethal effects of TNF. The results suggest that the early administration of low-dose rTNF may be useful in the prevention and treatment of the lethality of sepsis.

  View details for Web of Science ID A1989AJ36500007

  View details for PubMedID 2669193

• OVARIAN-CARCINOMA AS A CAUSE OF ZOLLINGER-ELLISON SYNDROME - NATURAL-HISTORY, SECRETORY PRODUCTS, AND RESPONSE TO PROVOCATIVE TESTS GASTROENTEROLOGY Maton, P. N., MACKEM, S. M., NORTON, J. A., Gardner, J. D., Odorisio, T. M., Jensen, R. T. 1989; 97 (2): 468-471

  Abstract

  Zollinger-Ellison syndrome is usually caused by a gastrin-secreting tumor in or near the pancreas. We describe a patient in whom an ovarian cystadenocarcinoma was the cause of the syndrome. The patient presented with a short history of peptic ulceration and development of a large pelvic mass. Investigations demonstrated a basal acid output of 37.8 mEq/h and a maximal acid output of 36.0 mEq/h, and the plasma concentration of gastrin was 830 pg/ml (normal less than 100). Secretin and calcium infusion tests were positive, and a meal test was compatible with Zollinger-Ellison syndrome. Imaging studies demonstrated a normal liver and pancreas but a large cystic right ovarian mass. Resection of the mass resulted in a marked reduction in gastric acid output, a fall in plasma gastrin concentration to normal, negative calcium and secretin tests, and a normal (positive) meal test. Histology of the mass showed it to be a mucinous cystadenocarcinoma. The tumor stained with immunoperoxidase technique was positive for gastrin, and the cyst fluid contained high concentrations of gastrin and calcitonin. One year later, the patient has no biochemical or imaging evidence of tumor. Ovarian, gastrin-producing tumors and pancreatic gastrinomas cannot be distinguished by provocative tests, and negative imaging studies do not exclude a pancreatic tumor. Patients with an ovarian mass and Zollinger-Ellison syndrome should have a bilateral oophorectomy and a careful exploration of the pancreatic area.

  View details for Web of Science ID A1989AG00700028

  View details for PubMedID 2663614

• CUSHING SYNDROME DUE TO PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE - FINDINGS AT CT AND MR IMAGING RADIOLOGY DOPPMAN, J. L., TRAVIS, W. D., Nieman, L., MILLER, D. L., Chrousos, G. P., Gomez, M. T., Cutler, G. B., Loriaux, D. L., NORTON, J. A. 1989; 172 (2): 415-420

  Abstract

  Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing syndrome in infants, children, and young adults. It is characterized by non-adrenocorticotropic hormone-dependent hypersecretion of cortisol by multiple, pigmented nodules of hyperplastic adrenocortical cells. With a single exception, adrenal glands have been described as normal with computed tomography (CT) in all previous series. Eight patients had Cushing syndrome due to surgically proved PPNAD. Four of the eight patients had stigmas of Carney complex (lentigines, calcified Sertoli cell tumors of the testes, and cardiac and soft-tissue myxomas). CT and/or magnetic resonance (MR) imaging demonstrated unilateral or bilateral nodularity in five of six patients examined. Macronodules (greater than 10 mm) were seen in the two oldest patients. As the clinical presentation of Cushing syndrome in this group of patients may be atypical (severe osteoporosis or short stature), the detection of multiple, small adrenocortical nodules with CT or MR imaging supports, or may even suggest, the diagnosis of PPNAD.

  View details for Web of Science ID A1989AF91700027

  View details for PubMedID 2748822

• CLONALITY OF PARATHYROID TUMORS IN FAMILIAL MULTIPLE ENDOCRINE NEOPLASIA TYPE-1 NEW ENGLAND JOURNAL OF MEDICINE FRIEDMAN, E., Sakaguchi, K., Bale, A. E., Falchetti, A., Streeten, E., Zimering, M. B., Weinstein, L. S., MCBRIDE, W. O., Nakamura, Y., Brandi, M. L., NORTON, J. A., AURBACH, G. D., Spiegel, A. M., Marx, S. J. 1989; 321 (4): 213-218

  Abstract

  Familial multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, endocrine pancreas, and anterior pituitary. Since the gene associated with MEN-1, located on chromosome 11 (11q13), may normally inhibit tumor proliferation, tumors could arise from inactivation of one or both of the alleles. However, parathyroid tumors in patients with MEN-1 have been considered to result from polyclonal hyperplasia. Using genetic probes, we tested parathyroid tumors for a monoclonal component, represented by a loss of alleles at any of eight loci along chromosome 11. Ten of 16 tumors from 14 patients with familial MEN-1 had losses of alleles from chromosome 11. Tumors with losses were larger than those without (1.6 vs. 0.2 g; P less than 0.002), suggesting that a monoclonal adenoma may develop after a phase of polyclonal hyperplasia. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included one copy of the MEN-1 locus. Of 34 sporadic adenomas from patients without MEN-1, 9 showed similar allelic losses in chromosome 11; in 7 the losses included the apparent MEN-1 locus. We conclude that many "hyperplastic" parathyroid tumors in familial MEN-1 are in fact monoclonal and may progress or even begin to develop by inactivation of the MEN-1 gene (at 11q13) in a precursor cell. Some sporadic adenomas have allelic losses on chromosome 11, which may also involve the MEN-1 gene.

  View details for Web of Science ID A1989AG41100002

  View details for PubMedID 2568586

• PRIMARY ADRENAL CAUSES OF CUSHINGS-SYNDROME - DIAGNOSIS AND SURGICAL-MANAGEMENT ANNALS OF SURGERY Perry, R. R., NIEMAN, L. K., Cutler, G. B., Chrousos, G. P., Loriaux, D. L., DOPPMAN, J. L., TRAVIS, W. D., NORTON, J. A. 1989; 210 (1): 59-68

  Abstract

  Cushing's syndrome is rare with only 20% of patients having a primary adrenal cause of hypercortisolism. We have developed a strategy to evaluate patients with suspected Cushing's syndrome and to localize the pathologic condition responsible for the hypercortisolism. This report reviews the last 11 consecutive patients who had a primary adrenal cause of hypercortisolism. Each patient had elevated 24-hour urine free cortisol and 17-hydroxycorticosteroid excretion consistent with hypercortisolism. All but one patient had undetectable plasma ACTH levels. No patient suppressed urinary steroid levels with high-dose dexamethasone and only one patient increased plasma ACTH or cortisol levels with oCRH, findings that were consistent with a pituitary-independent form of hypercortisolism. No patient had a pituitary tumor detected by computed tomography or magnetic resonance imaging, and eight patients had adrenal tumors accurately imaged. MRI of the adrenal glands correctly diagnosed adenoma in 5 of 6 patients with adenomas, carcinoma in 1 patient, and ACTH-producing pheochromocytoma in 1 patient. One tumor classified as carcinoma by MRI appeared on pathologic examination to be an adenoma. Three patients underwent petrosal sinus sampling for measurement of ACTH before and after oCRH administration, and each had petrosal sinus ACTH levels equal to peripheral levels, consistent with a primary adrenal cause of hypercortisolism. Two of these patients had typical bilateral pigmented micronodular adrenocortical disease and the third patient had macronodular adrenocortical hyperplasia. Each of the 11 patients was cured of hypercortisolism by unilateral or bilateral adrenalectomy and no patient has developed recurrent disease during the 7 to 29 month follow-up period. New modalities including the ovine CRH test, MRI, and petrosal sinus sampling have improved the evaluation of certain patients with Cushing's syndrome.

  View details for Web of Science ID A1989AE48800010

  View details for PubMedID 2742414

• ECTOPIC ADRENOCORTICOTROPIC HORMONE SYNDROME - LOCALIZATION STUDIES IN 28 PATIENTS RADIOLOGY DOPPMAN, J. L., Nieman, L., MILLER, D. L., PASS, H. I., Chang, R., Cutler, G. B., Schaaf, M., Chrousos, G. P., NORTON, J. A., ZIESSMAN, H. A., Oldfield, E. H., Loriaux, D. L. 1989; 172 (1): 115-124

  Abstract

  A variety of imaging procedures were performed in 28 patients with ectopic adrenocorticotropic hormone (ACTH) syndrome in an attempt to localize the ACTH-producing tumor. Diagnosis was made on the basis of removal of an ACTH-producing tumor or biopsy of metastases in the 19 patients with a proved source and the absence of ACTH gradients in bilateral samples of the inferior petrosal sinuses in the nine patients in whom an ACTH-secreting tumor had not been localized. Eleven bronchial carcinoids, two thymic carcinoids, three pheochromocytomas, and three islet-cell tumors constituted the proved sources. The condition has been cured in eight patients, six are alive with residual tumor, and five have died. Of the nine patients with undetected sites of ACTH production, one has died of pneumocystis pneumonia and eight are being treated medically or with bilateral adrenalectomy. Computed tomography (CT) of the chest and abdomen was the most helpful study in the detection of these tumors. Selective arteriography (bronchial and visceral), systemic and portal venous sampling, and iodine-131 meta-iodobenzylguanidine scintigraphy failed to demonstrate tumors when findings at CT were negative. Bronchial carcinoids constituted most of the ACTH-secreting tumors in this study (58%) and in a review of four large series (47%). To assure early detection of these potentially malignant tumors, pulmonary CT should be performed every 6 months, even after hypercortisolism has been medically or surgically controlled.

  View details for Web of Science ID A1989AB75000023

  View details for PubMedID 2544919

• REVERSAL OF THE TOXIC EFFECTS OF CACHECTIN BY CONCURRENT INSULIN ADMINISTRATION AMERICAN JOURNAL OF PHYSIOLOGY FRAKER, D. L., MERINO, M. J., NORTON, J. A. 1989; 256 (6): E725-E731

  Abstract

  Rats treated with recombinant human tumor necrosis factor-cachectin, 100 micrograms/kg ip twice daily for 5 consecutive days, had a 56% decrease in food intake, a 54% decrease in nitrogen balance, and a 23-g decrease in body weight gain vs. saline-treated controls. Concurrent neutral protamine hagedorn insulin administration of 2 U/100 g sc twice daily reversed all of these changes to control levels without causing any treatment deaths. The improvement seen with insulin was dose independent. Five days of cachectin treatment caused a severe interstitial pneumonitis, periportal inflammation in the liver, and an increase in wet organ weight in the heart, lungs, kidney, and spleen. Concurrent insulin treatment led to near total reversal of these histopathologic changes. Cachectin treatment did not significantly change blood glucose levels from control values of 130-140 mg/dl, but insulin plus cachectin caused a significant decrease in blood glucose from 1 through 12 h after injection. Administration of high-dose insulin can near totally reverse the nutritional and histopathologic toxicity of sublethal doses of cachectin in rats.

  View details for Web of Science ID A1989AC79200027

  View details for PubMedID 2660586

• GASTRINOMAS - COMPARISON OF MR IMAGING WITH CT, ANGIOGRAPHY, AND US RADIOLOGY Frucht, H., DOPPMAN, J. L., NORTON, J. A., MILLER, D. L., Dwyer, A. J., Frank, J. A., Vinayek, R., Maton, P. N., Jensen, R. T. 1989; 171 (3): 713-717

  Abstract

  In this prospective study, magnetic resonance (MR) imaging was used to localize gastrinoma in 24 patients with Zollinger-Ellison syndrome. The results were confirmed by means of either surgery or percutaneous liver biopsy and compared with results of computed tomographic (CT) scanning, selective abdominal angiography, and abdominal ultrasound (US). For primary extrahepatic gastrinoma (intra-or extrapancreatic), MR imaging had a sensitivity of 20% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 11%. For metastatic gastrinoma in the liver, MR imaging had a sensitivity of 43% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 81%. The ability of MR imaging to depict extrahepatic gastrinomas was directly related to tumor size; no tumors smaller than 1 cm were detected, and 50% of tumors 3 cm or larger were detected. MR imaging was as effective as abdominal US but less effective than either CT scanning or selective abdominal angiography for the detection of extrahepatic gastrinoma. In seven patients with hepatic gastrinoma, three gastrinomas were detected with MR imaging and with abdominal US, while five were detected with CT scanning and with selective abdominal angiography. These results indicate that, at the present time, MR imaging is generally not useful in the initial attempt to localize gastrinomas.

  View details for Web of Science ID A1989U594000026

  View details for PubMedID 2655004

• ALTERED MACROPHAGE ACTIVITY AND TUMOR NECROSIS FACTOR - TUMOR NECROSIS AND HOST CACHEXIA JOURNAL OF SURGICAL RESEARCH STOVROFF, M. C., FRAKER, D. L., TRAVIS, W. D., NORTON, J. A. 1989; 46 (5): 462-469

  Abstract

  Tumor necrosis factor (TNF) may be a mediator of cancer cachexia. This study evaluates the activity of macrophages from non-tumor-bearing (NTB) and tumor-bearing (TB) rats by measuring TNF production in response to endotoxin (LPS), both in vitro and in vivo, and correlates macrophage activity with tumor burden and parameters of host cachexia. Isolated macrophages from rats with small tumors, normal food intake, and weight gain secreted more TNF in response to 10 micrograms/ml LPS than macrophages from control NTB rats and behaved similar to activated macrophages from rats previously treated with thioglycollate. Heightened macrophage activity (increased production of TNF in response to LPS) in TB rats increased further as tumor burden increased (r = 0.889, P less than 0.001). Tumor resection reversed the heightened macrophage activity as LPS-induced levels of TNF secreted by macrophages from resected TB rats were not different from those of sham-operated NTB control rats. TB rats had serum levels of TNF activity following an iv bolus of 10 mg/kg LPS greater than those of NTB rats (P less than 0.05). In addition, peak serum TNF activity levels following iv LPS increased directly as tumor burden increased (r = 0.91, P less than 0.001). Supernatants from tissue cultures of the tumor (MCA sarcoma) failed to have any detectable TNF activity. However, large tumors in vivo had increased amounts of necrosis (78 +/- 8%), increased numbers of infiltrating macrophages, and increased levels of TNF (480 +/- 68 U/ml) compared to small tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1989U651900011

  View details for PubMedID 2716304

• TOLERANCE TO TUMOR NECROSIS FACTOR NUTRITION NORTON, J. A., FRAKER, D. L. 1989; 5 (2): 131-135

  View details for Web of Science ID A1989AP18300015

  View details for PubMedID 2520273

• CACHECTIN ACTIVITY IN THE SERUM OF CACHECTIC, TUMOR-BEARING RATS ARCHIVES OF SURGERY STOVROFF, M. C., FRAKER, D. L., NORTON, J. A. 1989; 124 (1): 94-99

  Abstract

  Cachectin/tumor necrosis factor has been postulated to be a possible mediator of cancer cachexia. Using a sensitive bioassay, we attempted to detect circulating cachectin activity in the serum of sarcoma-bearing rats and to correlate levels with measurements of cachexia and the extent of disease. In addition, we resected the tumor to determine the time course of reversal of cachexia and the disappearance of cachectin activity in the serum. Circulating cachectin activity was not detectable in the serum of non-tumor-bearing rats or in tumor-bearing rats until 28 days after implantation. With evidence of food intake and body weight decline, cachectin activity became detectable in the serum and levels increased as cachexia and tumor burden increased. Serum cachectin activity levels correlated directly with tumor burden and inversely with food intake and body weight change. After resection of the tumor, food intake and body weight increased and serum cachectin activity became undetectable. Serum triglyceride levels were higher in cachectic tumor-bearing rats than in pair-fed non-tumor-bearing controls, and levels decreased after tumor resection as cachectin activity decreased. The results suggest that cachectin is a humoral mediator of cachexia in this rat-tumor model.

  View details for Web of Science ID A1989R703100018

  View details for PubMedID 2910253

• A SIMPLIFIED LOW IODINE DIET IN I-131 SCANNING AND THERAPY OF THYROID-CANCER CLINICAL NUCLEAR MEDICINE Lakshmanan, M., Schaffer, A., Robbins, J., Reynolds, J., Norton, J. 1988; 13 (12): 866-868

  Abstract

  A simplified, low iodine diet was developed for outpatient use prior to I-131 scanning and therapy in thyroid cancer. Iodine intake of five subjects on the diet was approximately 50 micrograms a day and this level was maintained for four weeks. The diet required only minimal instruction to be followed reliably. This level of iodine intake may increase radioiodine uptake in thyroid carcinomas.

  View details for Web of Science ID A1988R698200003

  View details for PubMedID 3246114

• CHANGING CONCEPTS OF ISLET CELL DYSPLASIA IN NEONATAL AND INFANTILE HYPERINSULINISM - INVITED COMMENTARY WORLD JOURNAL OF SURGERY NORTON, J. A., STOVROFF, M. C. 1988; 12 (5): 608-609

  View details for Web of Science ID A1988Q078800008

• CACHECTIN TUMOR NECROSIS FACTOR - A POSSIBLE MEDIATOR OF CANCER ANOREXIA IN THE RAT CANCER RESEARCH STOVROFF, M. C., FRAKER, D. L., SWEDENBORG, J. A., NORTON, J. A. 1988; 48 (16): 4567-4572

  Abstract

  Cachectin/tumor necrosis factor (TNF) is a macrophage product which may have a role in cancer cachexia. Recombinant human cachectin/TNF (Cetus Corporation) was administered i.p. twice daily to male F344 rats at varying, nonlethal dosages for either 5 or 10 days, and daily rat food intake and body weight were measured. There was a dose-dependent cachectin/TNF-induced decline in food intake and body weight gain over the treatment period. However, after 1 day rats became tolerant to these effects and increased food intake and gained body weight despite receiving cachectin/TNF. Rats were subsequently inoculated with a transplantable methylcholanthrene-induced sarcoma, and survival was measured. Rats previously treated with high-dose (either 100 or 200 micrograms/kg/day) cachectin/TNF survived significantly longer following tumor inoculation than did control rats given saline or rats given 10 micrograms/kg/day of cachectin/TNF. Analysis of tumor growth curves and tumor weight indicated that high-dose cachectin pretreatment did not retard tumor growth. Analysis of food intake and tumor burden following tumor inoculation indicated that high-dose cachectin pretreatment decreased the reduction in food intake associated with progressive tumor growth and allowed rats to withstand a greater tumor burden at death. Rats immunized with low-dose human cachectin/TNF developed high IgG titers against human TNF, but failed to demonstrate the same protection against a methylcholanthrene-induced tumor challenge as rats made tolerant with repetitive twice daily high-dose cachectin/TNF. The observation of reduced cancer-associated anorexia and increased survival of tumor-bearing rats associated with previous tolerance to exogenous cachectin/TNF strengthens the contention that endogenously produced cachectin may be a factor in the pathogenesis of cancer anorexia in the tumor-bearing rat. The mechanism of this tolerance is unclear but does not appear to be a humoral immune response.

  View details for Web of Science ID A1988P580300024

  View details for PubMedID 3165053

• LOCALIZATION AND RESECTION OF INSULINOMAS AND GASTRINOMAS JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION FRAKER, D. L., NORTON, J. A. 1988; 259 (24): 3601-3605

  View details for Web of Science ID A1988N776400030

  View details for PubMedID 2836638

• PROSPECTIVE-STUDY OF CHEMOTHERAPY IN PATIENTS WITH METASTATIC GASTRINOMA GASTROENTEROLOGY VONSCHRENCK, T., Howard, J. M., DOPPMAN, J. L., NORTON, J. A., Maton, P. N., Smith, F. P., Vinayek, R., Frucht, H., Wank, S. A., Gardner, J. D., Jensen, R. T. 1988; 94 (6): 1326-1334

  Abstract

  Ten consecutive patients with metastatic gastrinoma that increased in size over time were studied prospectively during treatment with monthly cycles of streptozotocin (3 g/m2), 5-fluorouracil (1.2 g/m2), and adriamycin (40 mg/m2) to determine the response rate and time-courses of changes during chemotherapy and to assess various methods of evaluating the effect of chemotherapy. Forty percent of patients demonstrated an initial objective response (greater than or equal to 25% decrease in tumor size with no new lesions) and 60% failed chemotherapy (greater than or equal to 25% increase in tumor size or appearance of new lesions). The mean dose of streptozotocin was 27 g/m2 with objective responses occurring at 3.7 +/- 0.7 mo and failures at 4.5 +/- 0.7 mo. Responses lasted 9.7 +/- 2.8 cycles and no complete responses occurred. Survival was not significantly different in responders versus nonresponders (26 +/- 11 vs. 15 +/- 4.8 mo, p greater than 0.1). Changes in serum gastrin concentration, basal acid output, or sensitivity to a given dose of histamine H2-receptor antagonist did not reflect changes in tumor size. Computed tomography and angiography were the best methods to assess changes in tumor size during chemotherapy, whereas liver-spleen scan and ultrasound were relatively insensitive. All patients developed side effects with chemotherapy: 100% had vomiting, 80% alopecia, 40% transient proteinuria, and 20% leukopenia. The present results indicate that chemotherapy with streptozotocin, 5-fluorouracil, and adriamycin is much less effective in patients with extensive metastatic gastrinoma than previously reported. Computed tomography scanning is the method of choice to assess changes in tumor size. Changes in serum gastrin concentration, acid secretion, or tumor size assessed by liver-spleen scan or ultrasound are not sensitive indicators of the tumor response during chemotherapy.

  View details for Web of Science ID A1988N454600011

  View details for PubMedID 2966088

• GLUCOCORTICOID RECEPTOR-MEDIATED EFFECTS ON RAT FIBRO-SARCOMA GROWTH CANCER RESEARCH Laue, L., Peacock, J., Brandon, D. D., GALLUCCI, W. T., Cutler, G. B., Loriaux, D. L., Chrousos, G. P., NORTON, J. A. 1988; 48 (10): 2703-2706

  Abstract

  Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.

  View details for Web of Science ID A1988N269700012

  View details for PubMedID 3359431

• BODY-COMPOSITION CHANGES IN RATS WITH EXPERIMENTAL CANCER CACHEXIA - IMPROVEMENT WITH EXOGENOUS INSULIN CANCER RESEARCH Moley, J. F., Morrison, S. D., GORSCHBOTH, C. M., NORTON, J. A. 1988; 48 (10): 2784-2787

  Abstract

  Exogenous insulin treatment has been shown to improve food intake and host weight of cachectic tumor-bearing (TB) rats, but the composition of the host weight gain has not been quantitated. Sixty-six Fischer 344 rats were randomized to seven groups: early nontumor-bearing (NTB) (n = 10) who underwent compositional analysis (CA) on the day the methylcholanthrene sarcoma was implanted in TB rats; pretreatment-NTB (n = 10) and pretreatment-TB (n = 10) who underwent CA 25 days later when rats began treatment with saline or insulin; and finally saline-treated NTB (n = 9), saline-treated TB (n = 9), insulin-treated NTB (n = 9), and insulin-treated TB (n = 9), who underwent CA following 5 days of treatment with daily saline or neutral protamine hagedorn insulin 2 units/100 g. Body weight and food intake were measured daily. For compositional analysis, the tumor was separated from the host in TB rats and the entire rat in NTB animals was homogenized, lyophilized and analyzed for fat, water, protein, potassium, chloride, and sodium. The tumor was processed in a similar fashion. In response to insulin, NTB rats ate significantly more food, and had an increase in body weight gain. Compositional analysis of insulin-treated NTB rats indicated a slight, but insignificant, increase in body fat and a similar insignificant decrease in body protein. TB rats ate significantly less than NTB rats during the 5-day experimental period, and insulin treatment significantly increased food intake to levels similar to NTB animals. Compositional analysis indicated that the tumor-bearing state resulted in a significant decrease in total host water, protein, fat, potassium, sodium, and chloride. Insulin administration resulted in preservation of host nitrogen, fat, potassium, sodium, and chloride in cachectic tumor-bearing rats. Insulin treatment did not affect tumor dry weight or composition. The results suggest that exogenous insulin, can preserve normal host composition of TB rats during cachectic decline.

  View details for Web of Science ID A1988N269700029

  View details for PubMedID 3282649

• IMPACT OF INSULIN ON SURVIVAL OF CACHECTIC TUMOR-BEARING RATS JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Peacock, J. L., NORTON, J. A. 1988; 12 (3): 260-264

  Abstract

  The present study was performed to determine if a host nutritional treatment, insulin, in the absence of antitumor treatment could improve survival of cachectic tumor-bearing (TB) rats. Initially food intake and host weight were correlated with survival of untreated rats with similar size sarcomas (45-50 cm3). TB rat food intake (r = 0.69, p less than 0.0001) and host weight (r = 0.47, p less than 0.004) correlated positively with subsequent survival. Once daily neutral protamine hagedorn (NPH) insulin treatment (2 units/100 g) significantly improved food intake (p less than 0.01) and host weight (p less than 0.01) of cachectic TB rats without increasing tumor growth. Twice daily NPH insulin (2 units/100 g) maintained normal food intake of cachectic TB rats and turned a host weight loss into a host weight gain which was significantly greater than untreated controls (p less than 0.001) and all other methods of insulin administration including once daily (p less than 0.001). Twice daily NPH insulin maintained mild hypoglycemia (glucose = 84 +/- 12 mg/dl) compared to once daily NPH insulin which resulted in hyperglycemia (glucose = 140 +/- 8 mg/dl, p less than 0.001) prior to next dose. In addition, twice daily NPH insulin did not increase tumor growth. Once daily NPH insulin for 5 days during cachectic decline was well tolerated (no treatment deaths), and improved median survival of TB rats randomized to insulin (15 days) compared to controls (13 days, p = 0.06). However, twice daily NPH insulin during cachectic decline failed to improve survival because of treatment deaths.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1988N457900006

  View details for PubMedID 3392822

• CANCER CACHEXIA JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Kern, K. A., NORTON, J. A. 1988; 12 (3): 286-298

  Abstract

  Cancer cachexia describes a syndrome of progressive weight loss, anorexia, and persistent erosion of host body cell mass in response to a malignant growth. Although often associated with preterminal patients bearing disseminated disease, cachexia may be present in the early stages of tumor growth before any signs or symptoms of malignancy. A decline in food intake relative to energy expenditure (which may be increased, normal, or decreased) is the fundamental physiologic derangement leading to cancer-associated weight loss. In addition, abnormalities of host carbohydrate, protein, and fat metabolism lead to continued mobilization and ineffective repletion of host tissue, despite adequate nutritional support. Mediators of cancer anorexia and associated abnormalities are unknown. Cachectin/TNF or other host-derived cytokines (produced as a defense against malignancy) have been implicated as signal molecules in cachexia, based upon similar metabolic derangements produced by these cytokines in other chronic wasting illnesses. Nutritional support is effective in maintaining body weight of cachectic cancer patients, but ineffective in maintaining lean body mass. Although in one study parenteral nutritional support has improved operative morbidity and mortality in cancer patients, it has not yet improved response to chemotherapy or radiation therapy. Because of metabolic derangements seen in cancer cachexia, effective nutritional treatment regimens will probably require manipulation of host intermediary metabolism in addition to feeding. Insulin therapy or exercise are two such methods which appear to preserve host composition by preferential feeding of the host at the expense of the tumor. Future studies which more clearly define the role of signal molecules in producing cancer cachexia syndrome may lead to new treatment strategies, possibly involving modulation of the effects of such molecules on host metabolism.

  View details for Web of Science ID A1988N457900011

  View details for PubMedID 3292798

• INTRAOPERATIVE ULTRASONOGRAPHIC LOCALIZATION OF ISLET CELL TUMORS - A PROSPECTIVE COMPARISON TO PALPATION ANNALS OF SURGERY NORTON, J. A., CROMACK, D. T., Shawker, T. H., DOPPMAN, J. L., Comi, R., GORDEN, P., Maton, P. N., Gardner, J. D., Jensen, R. T. 1988; 207 (2): 160-168

  Abstract

  The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

  View details for Web of Science ID A1988L978700008

  View details for PubMedID 2829761

• EFFECT OF PROSTAGLANDIN-F2ALPHA ON HUMAN PARATHYROID ADENOMAS - EVIDENCE FOR UNCOUPLING OF PARATHYROID-HORMONE SECRETION AND CAMP ACCUMULATION JOURNAL OF BONE AND MINERAL RESEARCH Fitzpatrick, L. A., Norton, J., Martin, C., Sharp, M., AURBACH, G. D. 1988; 3 (1): 81-86

  Abstract

  Human parathyroid adenomas are aberrantly regulated by extracellular calcium. We tested pertussis toxin, which ADP-ribosylates and inactivates several guanine nucleotide regulatory proteins, to test the role of these proteins in the secretory control of adenomatous parathyroid tissue. Pertussis toxin did not affect basal cAMP accumulation in 12 adenomas and enhanced parathyroid hormone (PTH) release in 6 of 10 adenomas. Prostaglandin F2 alpha (PGF2 alpha) inhibited cAMP in three of six adenomas, and pertussis toxin pretreatment did not affect this result. PTH release in 7 of 10 adenomas was inhibited by PGF2 alpha, and pertussis toxin did not significantly alter PTH release. Pertussis toxin catalyzed ADP-ribosylation of a 40-kDa protein in all adenomas tested (n = 8). We conclude that cAMP accumulation was not affected by pertussis toxin but that in 6 of 10 adenomas, the toxin enhanced PTH release. We suggest that cAMP accumulation and PTH release may be uncoupled from negative control by inhibitory ligands in adenomatous tissue or that the G-proteins involved do not couple to regulatory receptors or to effector.

  View details for Web of Science ID A1988M256300011

  View details for PubMedID 2850725

• METABOLIC IMAGING OF HUMAN EXTREMITY MUSCULOSKELETAL TUMORS BY PET JOURNAL OF NUCLEAR MEDICINE Kern, K. A., Brunetti, A., NORTON, J. A., Chang, A. E., Malawer, M., Lack, E., Finn, R. D., Rosenberg, S. A., Larson, S. M. 1988; 29 (2): 181-186

  Abstract

  The measurement of glucose utilization rate (GUR) by positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) is a valuable method to assess the grade of malignancy of brain tumors. We have designed a feasibility trial to determine whether PET could be used to image and predict the grade of malignancy of human extremity musculoskeletal tumors. Five patients with extremity tumors (four soft-tissue tumors and one osteogenic tumor) were studied. Peak and mean apparent GURs were determined in the tumor region. All tumors were subsequently resected and graded in a standard fashion using the NCI grading system. Peak apparent GURs ranged from 3.3 mg/100 g/min to 15.2 mg/100 g/min, with the highest values found in the high grade tumors. Although the number of patients studied was small, a good correspondence was shown between GURs and histopathologic grading. Our results indicate that PET can be used to image and evaluate the metabolic activity of human musculoskeletal tumors.

  View details for Web of Science ID A1988L889000005

  View details for PubMedID 2831318

• STRAIN RATE DEPENDENCY OF WOUND BREAKING STRENGTH FOR THE DERMAL WOUND MODEL 1989 ANNUAL INTERNATIONAL CONF OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOC Talbot, T. L., CROMACK, D. T., NORTON, J. A., TIPTON, H. W. I E E E. 1988: 687–687

  View details for Web of Science ID A1988BP88P00355

• PASSAGE OF SOMATOSTATIN ANALOG ACROSS HUMAN AND MOUSE SKIN SURGERY Weber, C. J., Jicha, D., Matz, S., SIVERLY, J., Odorisio, T., Strausberg, L., LAURENCOT, J., McLarty, A., Norton, J., Kazim, M., Reemtsma, K. 1987; 102 (6): 974-981

  Abstract

  Recent studies have documented beneficial effects of the somatostatin analogue, SMS 201-995 (hereafter referred to as SMS), when administered subcutaneously to patients with a variety of disorders. Since SMS is a small peptide, we tested the ability of two penetrant enhancers--dimethylsulfoxide and N-decylmethylsulfoxide (C10MS)--to promote transcutaneous passage of SMS. Samples of skin from human cadavers and hairless mice were tested in a static diffusion chamber. Application of SMS in conjunction with 1% C10MS resulted in rapid transdermal passage of SMS. These data were confirmed for hairless mouse skin in experiments with a modified diffusion chamber having continuous flow-through of receptor fluid in the subdermal reservoir. In this system, the cumulative amount of SMS that permeated hairless mouse skin was 20 micrograms/cm2/24 hours. Topical application of SMS with C10MS beneath a patch to mice confirmed in vitro data. Topical application of 10 micrograms of SMS resulted in plasma SMS levels of greater than 8,000 pg/ml within 2 hours. We conclude that SMS will cross both human and mouse skin, with a clinically significant flux, when administered topically with C10MS. The data support the feasibility of in vivo human trials of topical SMS therapy.

  View details for Web of Science ID A1987L164600013

  View details for PubMedID 2891203

• DIFFERENTIATION OF ADRENAL MASSES BY MAGNETIC-RESONANCE-IMAGING SURGERY DOPPMAN, J. L., REINIG, J. W., Dwyer, A. J., Frank, J. P., Norton, J., Loriaux, D. L., KEISER, H. 1987; 102 (6): 1018-1026

  Abstract

  Eighty-one adrenal masses in 68 patients were examined with magnetic resonance imaging (MRI). Masses included nonfunctioning adenomas (17), metastases (25), adrenocortical carcinomas (10), and pheochromocytomas (23). T1-weighted pulse sequences depicted the anatomy with a resolution comparable to that of computed tomography (CT). T2-weighted pulse sequences provided some histologic specificity separating nonfunctioning adenomas with low signal-intensity from metastases with intermediate signal-intensity and pheochromocytomas with high signal-intensity. Pheochromocytomas could always be distinguished from other adrenal masses. In 20% of the cases, metastases with low signal-intensity could not be distinguished from nonfunctioning adenomas.

  View details for Web of Science ID A1987L164600018

  View details for PubMedID 3686342

• GLUCONEOGENESIS IN THE TUMOR-INFLUENCED RAT HEPATOCYTE - IMPORTANCE OF TUMOR BURDEN, LACTATE, INSULIN, AND GLUCAGON JOURNAL OF THE NATIONAL CANCER INSTITUTE Inculet, R. I., Peacock, J. L., GORSCHBOTH, C. M., NORTON, J. A. 1987; 79 (5): 1039-1046

  Abstract

  In an attempt to define the relationship between tumor burden (cachexia) and host hepatocyte gluconeogenesis, the following experiments were performed with the use of an F344 male rat bearing a transplantable sarcoma. Food intake of tumor-bearing (TB) rats was constant until day 24 following implant and a tumor burden of 18 +/- 5.2% (mean +/- SD), at which time food intake progressively declined daily. Tumor burden was arbitrarily divided at 12.8% to determine if any measured changes occurred prior to or following the approximate time when a significant decline in food intake occurred. Plasma glucose levels decreased with tumor burden. Whole-blood lactate levels increased with tumor burden. Fasting plasma alanine levels decreased with tumor burden. Plasma 3-methylhistidine levels increased with tumor burden. Plasma glucagon levels increased with tumor burden, whereas plasma insulin levels decreased. Hormone changes were noted at small tumor burdens prior to a decline in food intake. Viable hepatocytes were isolated from 4 groups: non-tumor-bearing (NTB), small tumor burden [(STB) 3.5% total body weight (TBW)], moderate tumor burden [(MTB) 14% TBW], and large tumor burden [(LTB) 23% TBW]. As expected in NTB rats, hepatocytes produced significantly more glucose with 20 mM lactate than 20 mM alanine or than Hanks' balanced salt solution (HBSS) alone. Hepatocytes from STB rats demonstrated the same basic relationship for lactate, alanine, and HBSS, but they produced significantly more glucose from lactate and HBSS alone than NTB hepatocytes. With alanine as substrate, the rates of glucose production by hepatocytes were not affected by the presence or size of tumor. However, with lactate as substrate, hepatocytes from MTB and LTB rats produced progressively less glucose as tumor burden increased (r = -0.85, p less than .001), which may partly explain the reduction in blood glucose and elevation in blood lactate levels observed. Elevated gluconeogenesis in TB rats occurred early prior to a decline in food intake. The key precursor appeared to be lactate. The balance between glucagon and insulin appeared to promote the abnormal host carbohydrate metabolism observed.

  View details for Web of Science ID A1987K990900015

  View details for PubMedID 3316783

• THE USE OF HIGH-RESOLUTION INTRAOPERATIVE ULTRASOUND TO LOCALIZE GASTRINOMAS - AN INITIAL REPORT OF A PROSPECTIVE-STUDY WORLD JOURNAL OF SURGERY CROMACK, D. T., NORTON, J. A., Sigel, B., Shawker, T. H., DOPPMAN, J. L., Maton, P. N., Jensen, R. T. 1987; 11 (5): 648-653

  View details for Web of Science ID A1987K061100015

  View details for PubMedID 3314183

• THE USE OF HIGH-RESOLUTION ULTRASOUND TO LOCATE PARATHYROID TUMORS DURING REOPERATIONS FOR PRIMARY HYPERPARATHYROIDISM WORLD JOURNAL OF SURGERY Kern, K. A., Shawker, T. H., DOPPMAN, J. L., MILLER, D. L., Marx, S. J., Spiegel, A. M., AURBACH, G. D., NORTON, J. A. 1987; 11 (5): 579-585

  View details for Web of Science ID A1987K061100004

  View details for PubMedID 3314177

• RESTING ENERGY-EXPENDITURE AND BODY CELL MASS ALTERATIONS IN NONCACHECTIC PATIENTS WITH SARCOMAS SURGERY Peacock, J. L., Inculet, R. I., CORSEY, R., Ford, D. B., RUMBLE, W. F., Lawson, D., NORTON, J. A. 1987; 102 (3): 465-472

  Abstract

  Resting energy expenditure (REE), body cell mass (BCM), and body fat (BF) were measured in six male and seven female volunteers and in a homogeneous group of noncachectic patients with sarcoma, (n = 7). The patients all had large localized tumors, no history or clinical evidence of decreased food intake or weight loss, and had received no prior treatment for cancer. Indirect calorimetry (for REE), K40 analysis (for BCM), and anthropometric measurements (for BF) were performed in accordance with established methods. Physical activity and nutritional status were also assessed. As expected, female control subjects had 50% greater percent BF (p less than 0.001) and 13% less percent BCM (p less than 0.01) than male controls. Male patients with sarcoma had equivalent percent BF, but significantly less percent BCM than controls matched for age, sex, and body surface area (BSA) (p less than 0.05). The REE corrected for BSA was similar in male and female controls but was 25% greater in male sarcoma patients than in male controls (p less than 0.05). This difference was doubled when REE was corrected for BCM (p less than 0.01). In patients with sarcomas, REE/BSA varied inversely with percent BCM (r = -0.782; p less than 0.05) while a similar relationship was not observed in healthy volunteers. We conclude that both REE and vital, functional BCM can be significantly altered in sarcoma patients before any overt signs of cachexia develop. The results support the contention that sarcoma alters host energy metabolism and causes abnormal body composition.

  View details for Web of Science ID A1987J950300006

  View details for PubMedID 3629474

• ALTERED LEUCINE METABOLISM IN NONCACHECTIC SARCOMA PATIENTS CANCER RESEARCH Inculet, R. I., Stein, T. P., Peacock, J. L., Leskiw, M., Maher, M., GORSCHBOTH, C. M., NORTON, J. A. 1987; 47 (17): 4746-4749

  Abstract

  Leucine and whole body protein metabolism were quantitated in 26 human subjects (6 sarcoma patients, 20 age-matched normal controls) using a primed, continuous infusion of [13C]leucine. Plasma samples were analyzed every 15 min for enrichment of [13C]leucine. Plateau enrichment levels were then used to calculate whole-body protein turnover, synthesis, and breakdown rates. Exhaled gas samples were analyzed every 15 min for enrichment of 13CO2, and plateau enrichment levels (as well as CO2 production rates) were used to calculate leucine oxidation rates. Fasting plasma amino acid levels, serum albumin, and total protein levels were also determined. The 6 patients were otherwise healthy but had a large, localized high-grade sarcoma which had not been previously treated. No patient had weight loss. Amino acid, albumin, and total protein levels were equivalent in patients and controls. Whole-body protein turnover rates were significantly greater in sarcoma patients than age-matched controls (15%). Increased protein turnover rates resulted in increased whole-body protein synthesis and breakdown rates in sarcoma patients compared to controls. Leucine oxidation rates were not different in the 2 groups. The results suggest that in humans with high-grade sarcomas leucine metabolic abnormalities are specific to tumor growth and not malnutrition because abnormalities of turnover, synthesis, and breakdown occur prior to any weight loss or measurable change in blood amino acid or protein level.

  View details for Web of Science ID A1987J771800040

  View details for PubMedID 3621173

• AUTORADIOGRAPHIC IMAGING OF RAT SARCOMA IN DIFFERENT ANATOMICAL SITES USING 2-[C-14]DEOXYGLUCOSE CANCER RESEARCH Kern, K. A., NORTON, J. A. 1987; 47 (17): 4706-4708

  Abstract

  As sarcomas are known to have accelerated glycolysis, we used the radiolabeled glucose analogue 2-deoxy-d-[U-14C]glucose in autoradiographic imaging studies of a methylcholanthrene-induced rat fibrosarcoma placed in an i.m. site, and in models of pulmonary and hepatic metastases. Fifty muCi of 2-deoxy-d-[U-14C]glucose were injected i.p. into groups of rats bearing tumors in these three sites; sacrifice of animals for imaging was carried out 45 min later. Excellent imaging of sarcoma tissue in all three anatomical sites was obtained, with high visual contrast compared to the normal tissue background. Using densitometry of autoradiographs, tumor/tissue ratios were 7.1 for i.m. tumors, 3.8 for pulmonary metastases, and 2.8 for hepatic metastases. Autoradiographic imaging of sarcomas may be obtained based upon avidity of neoplastic tissue for the glucose analogue 2-deoxy-d-[U-14C] glucose. Such imaging is not dependent upon anatomical site and reproducibly images rat sarcomas in muscle, lung, and liver.

  View details for Web of Science ID A1987J771800032

  View details for PubMedID 3621165

• IMPACT OF INSULIN ON DOXORUBICIN-INDUCED RAT HOST TOXICITY AND TUMOR-REGRESSION CANCER RESEARCH Peacock, J. L., GORSCHBOTH, C. M., NORTON, J. A. 1987; 47 (16): 4318-4322

  Abstract

  To test whether the anorexia and host depletion following doxorubicin chemotherapy can be improved by concomitant insulin therapy, 70 F344 rats were divided equally between tumor-bearing (TB) and non-tumor-bearing (NTB) groups and studied for food intake, host weight, and tumor size changes. Sarcoma fragments were implanted s.c. in TB rats and 18 days later all rats received an i.v. dose of doxorubicin (8 mg/kg). The following day TB and NTB rats were randomized to receive neutral protaminehagedorn insulin (2 units/100 g/24 h) or normal saline until food intake returned to normal. Following doxorubicin administration food intake and host weight declined in an identical pattern in both NTB and TB rats treated with saline. However, beginning on day 6 insulin-treated TB and NTB rats ate significantly more than saline-treated controls. Insulin-treated animals returned to normal food intake levels in 50% less time than controls. This improved food intake resulted in an improved host mass beginning also on day 6 for both TB and NTB rats. In addition, it appeared that insulin treatment significantly improved the tumor shrinkage initiated by doxorubicin. Following doxorubicin, insulin-treated TB rats had a greater reduction of tumor size (10.6 +/- 1.2 cm3) compared to saline-treated rats (6.6 +/- 0.8 cm3, P less than 0.01). To further characterize the effect of insulin and/or doxorubicin on tumor growth, the experiment was repeated in the same manner except for two additional TB groups: saline- and insulin-treated tumor bearers with treatment beginning 19 days after tumor implant. Rats treated with doxorubicin had a significant reduction in tumor size compared to rats not treated with doxorubicin (P less than 0.001). Insulin alone did not affect tumor growth, but insulin plus doxorubicin significantly decreased tumor size compared to doxorubicin alone (P less than 0.01). In a second experiment using 80 rats insulin treatment had no apparent effect on reduction of peripheral blood counts including white blood cells, neutrophils, lymphocytes, platelets, and hematocrit induced by doxorubicin in either NTB or TB rats. Insulin given 24 h previously had minimal effect on plasma glucose. The marked improvement in food intake and host weight, as well as additional tumor reduction with exogenous insulin following doxorubicin, suggests that insulin may have a role in reversal of doxorubicin host nutritional toxicity and perhaps improvement of antitumor efficacy.

  View details for Web of Science ID A1987J588400016

  View details for PubMedID 3300963

• INHIBITION OF ESTABLISHED RAT FIBROSARCOMA GROWTH BY THE GLUCOSE ANTAGONIST 2-DEOXY-D-GLUCOSE SURGERY Kern, K. A., NORTON, J. A. 1987; 102 (2): 380-385

  Abstract

  Sarcoma cells exhibit higher rates of glycolysis than normal tissues and may be dependent on glucose utilization for growth. Accordingly, we tested the ability of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) to inhibit the growth of an established methylcholanthrene-induced rat fibrosarcoma in three groups of F344 rats with increasing subcutaneous inoculations of tumor (2 X 10(6) cells, 1 X 10(7) cells, and 1 mm tumor fragments). Rats were randomized to receive 2-DG or saline solution at doses of 0.75 gm/kg, 1.5 gm/kg, or 1.75 gm/kg, beginning 3 days after tumor implantation and continuing for 10 days. Tumors were removed and weighed on day 14. We measured tissue [14C]-2-DG levels in tumor, brain, liver, and muscle after intraperitoneal injection of radiolabeled 2-DG. In these same tissues we determined the activity of glucose-6-phosphatase (G-6-Pase), an enzyme which dephosphorylates the intracellular glycolytic inhibitor 2-DG-6-phosphate, thus reversing the antitumor effect of 2-DG. All groups treated with 2-DG had a significant reduction in tumor weight of 50% to 70% when compared with saline solution-treated controls. Toxicity was substantial at the highest dose of 2-DG, but minimal toxicity was noted at intermediate and low doses. Tumor had the greatest uptake of [14C]-2-DG, with low levels of G-6-Pase leading to prolonged retention and highest tissue levels of radiolabeled 2-DG. Use of 2-DG inhibits established sarcoma growth because it is rapidly transported into tumors, cannot be metabolized after phosphorylation, and is dephosphorylated and released slowly from tumor cells. Rat sarcoma growth is dependent on glucose utilization and can be effectively inhibited by glucose antagonism.

  View details for Web of Science ID A1987J463900037

  View details for PubMedID 3039679

• PREOPERATIVE INSULIN REVERSES CACHEXIA AND DECREASES MORTALITY IN TUMOR-BEARING RATS JOURNAL OF SURGICAL RESEARCH Moley, J. F., Morrison, S. D., NORTON, J. A. 1987; 43 (1): 21-28

  Abstract

  As a model of surgical stress in the cancer-bearing animal, we resected large flank sarcomas from cachectic rats under ether anesthesia and closed wounds primarily. The metabolic cost of tumor resection was measured using a long-term continuous indirect calorimeter. In the immediate postresection period energy balance decreased and host energy expenditure increased significantly (P less than 0.005). In animals with similar tumor weights, mortality following resection was determined by the degree of cachectic depletion. We then considered whether improvement of preoperative host nutritional status with insulin treatment might improve a subsequent surgical outcome. Insulin, when administered exogenously to cachectic tumor-bearing rats, has been shown to stimulate food intake and preserve host weight and does not stimulate tumor growth. When individual rats bearing a cachexia-producing flank sarcoma demonstrated a decline in food intake to less than 75% of predicted (approximately 25 days after tumor implantation), they were randomized to receive either daily injections of NPH insulin (2 units/100 g/day) for 5 days or no treatment for 5 days. Animals then underwent tumor resection and 14-day survival was measured. All resections were performed in an unbiased manner without the surgeon's knowledge of each rat's treatment status. In an experiment using 59 rats, insulin-treated rats had a threefold higher 5-day preoperative food intake and did not lose weight in the preoperative period, while untreated rats lost 17 g (P less than 0.001). Mortality in the insulin-treated group was 10% versus 28% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1987J255500004

  View details for PubMedID 3599982

• TRANSFORMING GROWTH-FACTOR BETA-LEVELS IN RAT WOUND CHAMBERS JOURNAL OF SURGICAL RESEARCH CROMACK, D. T., Sporn, M. B., ROBERTS, A. B., MERINO, M. J., DART, L. L., NORTON, J. A. 1987; 42 (6): 622-628

  Abstract

  Exogenous TGF-beta accelerates healing in both normal and doxorubicin-treated rats, but whether it plays an intrinsic role in the natural healing process is unknown. Subcutaneous wound chambers in 16 F344 rats were aspirated from postwounding Day 3 through Day 16 for TGF-beta levels and cytology. A soft agar assay and a competitive radioreceptor binding assay were used to determine TGF-beta levels. Papanicolau staining and differential cell counts were used to determine cytology. Results were similar using either method for the determination of TGF-beta levels. With the sensitive radioreceptor assay, low TGF-beta levels on postwounding Day 4, mean 2.6 ng/ml, rose to a peak mean level of 20.4 ng/ml on Day 7 and fell significantly from peak level to a level of 5.4 ng/ml of Day 16. All TGF-beta levels for postwounding Days 6 through 14 were significantly increased over the baseline TGF-beta levels of Days 4 and 5 (P less than 0.05). Day 16 TGF-beta levels were not different from baseline. Cytologic changes were characterized by a liner decrease in total neutrophil count over the exam period and a concurrent linear increase in total lymphocyte and macrophage counts. TGF-beta levels changed in a bell-shaped temporal sequence during healing, apparently unrelated to percentage lymphocyte, macrophage, or neutrophil count. Peak TGF-beta levels occurred during the fibroblast proliferation and collagen synthesis phase of healing. This study presents the first evidence that TGF-beta is present in a healing wound and suggests that it may be an intrinsic mediator of the healing process.

  View details for Web of Science ID A1987J143000005

  View details for PubMedID 3473269

• RESPONSES OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AND RENIN-ANGIOTENSIN AXES AND THE SYMPATHETIC SYSTEM DURING CONTROLLED SURGICAL AND ANESTHETIC STRESS JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Udelsman, R., NORTON, J. A., JELENICH, S. E., Goldstein, D. S., Linehan, W. M., Loriaux, D. L., Chrousos, G. P. 1987; 64 (5): 986-994

  Abstract

  We studied the responses of plasma CRH, ACTH, cortisol, norepinephrine, epinephrine, and renin activity in 11 patients undergoing parathyroid or thyroid surgery after identical preoperative sedation and during isoflurane (Forane) anesthesia. During surgical exploration, plasma CRH levels [10 +/- 2 (+/- SEM) pg/mL] remained at basal (unstimulated) levels, and plasma ACTH (11.5 +/- 1.4 pg/mL), cortisol (24 +/- 4 micrograms/dL), and epinephrine (35 +/- 10 pg/mL) concentrations remained within their normal morning ranges. The majority of the patients had no evidence of pulsatile ACTH secretion during the operation, but, rather, secreted ACTH and cortisol continuously. There was a small elevation of plasma norepinephrine and PRA which was associated with a small increase in heart rate and decrease in blood pressure. Anesthesia reversal, endotrachial extubation, and the early recovery period were associated with marked mean peak increases in plasma ACTH (173 +/- 45 pg/mL), cortisol (35 +/- 6 micrograms/dL), and epinephrine (220 +/- 56 pg/mL) and the return of plasma norepinephrine and PRA to basal levels. All hormones returned to basal levels by the first post-operative day. The data suggest that with modern anesthetic techniques patients undergoing neck surgery had mildly elevated plasma ACTH, cortisol, and epinephrine levels. Glucocorticoid secretion during the operation was maintained primarily by continuous rather than pulsatile ACTH secretion. The immediate postoperative period was associated with profound elevations of plasma ACTH, cortisol, and epinephrine. The major determinant of ACTH, cortisol, and epinephrine secretion was anesthesia reversal and recovery and not surgical trauma.

  View details for Web of Science ID A1987G950300021

  View details for PubMedID 3031124

• BODY CELL MASS IN CANCER-BEARING AND ANOREXIC PATIENTS JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Moley, J. F., Aamodt, R., RUMBLE, W., Kaye, W., NORTON, J. A. 1987; 11 (3): 219-222

  Abstract

  We used a sensitive whole body counter which measures potassium-40 (40K) to determine total body potassium and to estimate body cell mass (BCM) in 104 previously untreated patients with upper gastrointestinal malignancies, 233 normal volunteers, and 18 patients with anorexia nervosa. BCM was greater in normal males than in females. In both normal males and females, the BCM tended to decrease with age, both as an absolute measure and as a percentage of body weight. Anorexia nervosa patients experienced marked weight loss (30.5%), and had significant depletion of absolute BCM, but exhibited relative sparing of BCM as indicated by a rise in BCM as a percentage of body weight. This may reflect a normal adaptation and predominant fat utilization in chronic malnutrition. The cancer patients, on the other hand, had significant weight loss (12.7% for females, 13.9% for males) and demonstrated a proportional decline in BCM, with no change in BCM as a percentage of body weight. These findings support the contention that, in the cancer-bearing patient, weight loss consists of a significant depletion of both fat and BCM. The challenge to the clinicians caring for cancer patients is repletion of this supremely functional body compartment.

  View details for Web of Science ID A1987H350500002

  View details for PubMedID 3474427

• WOUND-HEALING IN SARCOMA-BEARING RATS - TUMOR EFFECTS ON CUTANEOUS AND DEEP WOUNDS JOURNAL OF SURGICAL ONCOLOGY Lawrence, W. T., NORTON, J. A., Harvey, A. K., GORSCHBOTH, C. M., Talbot, T. L., GROTENDORST, G. R. 1987; 35 (1): 7-12

  Abstract

  Many surgeons think that cancer causes a higher incidence of wound complications. Wound healing was examined in a cutaneous and deep model in control and sarcoma-bearing rats to evaluate this concept. In a dorsal incisional wound, a significant decrease in wound breaking strength was observed from 19 days after tumor implantation onward. The amount of the breaking strength deficit increased with the size of tumor and the day post-tumor implant. In a deeper wound chamber, hydroxyproline levels, 3H-thymidine incorporation into DNA, histology, and collagen types were examined, and tumor produced no significant change in any parameter. The presence of tumor appeared to inhibit wound healing in cutaneous wounds but had no apparent effect on deeper wounds. This difference in healing in the two wound models is important to surgical oncologists. Because there is no demonstrable tumor-induced healing deficit in deep wounds, cancer-bearing organisms probably still heal these wounds normally.

  View details for Web of Science ID A1987H389300002

  View details for PubMedID 3573776

• WATER-SOLUBLE VITAMINS IN CANCER-PATIENTS ON PARENTERAL-NUTRITION - A PROSPECTIVE-STUDY JOURNAL OF PARENTERAL AND ENTERAL NUTRITION Inculet, R. I., NORTON, J. A., NICHOALDS, G. E., Maher, M. M., White, D. E., Brennan, M. F. 1987; 11 (3): 243-249

  Abstract

  Forty-three patients with mild weight loss were studied prospectively to determine whether the parenteral water-soluble vitamin doses in a commercially available preparation (MVI concentrate; USV Laboratories, Tarrytown, NY) maintained serum, red blood cell (RBC), and urinary concentrations of water-soluble vitamins in stressed cancer patients receiving total parenteral nutrition (TPN). Patients were divided into three groups: (1) oral diet, no intravenous vitamins given; (2) TPN plus 5 ml MVI; and (3) TPN plus 10 ml MVI. Vitamins C, B1, B2, B3, B6, and niacin were measured initially and weekly during a 6-week study period. Caloric and nitrogen balances were quantified. Most of the patients in all three groups had normal blood or urine levels of all water-soluble vitamins. No clinical evidence of vitamin deficiency or MVI toxicity was detected. The recommended parenteral dosages of vitamin C (100 mg/day) and B3 (15 mg/day) provided measurably adequate levels in all patients. Levels of vitamins B1, B2, B6, and niacin that were less than the normal range were noted in 4-40% of patients receiving the recommended daily dosages of 3 mg, 3.6 mg, 4 mg, and 40 mg, respectively. These deficiencies appeared to improve in group III patients who received twice the recommended parenteral vitamin dosages, although they did not completely disappear. Niacin deficiency appeared to be the most prevalent, occurring in 40% of patients studied. Since intravenous doses of B1, B2, B6, and niacin are safe and well tolerated, it appears that increased daily amounts of these vitamins should be given to cancer patients on parenteral nutrition.

  View details for Web of Science ID A1987H350500006

  View details for PubMedID 3110440

• INFERIOR THYROID ARTERY ARISING FROM COMMON CAROTID-ARTERY WITH ABERRANT RIGHT SUBCLAVIAN ARTERY CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY Simmons, J. T., DOPPMAN, J. L., Norton, J. 1987; 10 (3): 150-152

  Abstract

  We describe an unusual variant in the blood supply to the inferior portion of the right thyroid gland encountered during parathyroid localization studies. A brief review of other possible variants is given.

  View details for Web of Science ID A1987H777900007

  View details for PubMedID 3111696

• CANCER CACHEXIA CRC CRITICAL REVIEWS IN ONCOLOGY/HEMATOLOGY NORTON, J. A., Peacock, J. L., Morrison, S. D. 1987; 7 (4): 289-327

  Abstract

  Cancer cachexia is a complex syndrome that includes host tissue wasting, anorexia, asthenia, and abnormal host intermediary metabolism. It is present in approximately 50% of cancer patients during treatment and nearly 100% of treated cancer patients at death. Cachexia has a detrimental impact on cancer therapy. The central problem of cancer cachexia is that energy balance is not maintained, and the host has a relative hypophagia which results in host tissue wasting. The tumor by its nature and obligate growth can continue to consume glucose, amino acids, and lipids at the expense of the host. This produces abnormal host intermediary metabolism including elevated glucose production and recycling, decreased muscle protein synthesis, and increased muscle and fat breakdown. The exact mechanisms of cancer cachexia have been only partially elucidated. The identification of signal molecules like cachectin which mediate these changes may be on the horizon. Nutritional support can reverse some of the derangements seen with cachexia, and there is evidence that functional lean body mass or body cell mass can be restored in some (but not all) patients. However, nutritional support has not yet improved response to chemotherapy or radiation therapy, nor has it improved host tolerance of chemotherapy. It has improved operative mortality and morbidity in cachectic cancer patients undergoing major surgical procedures. Optimum host nutritional support appears to be dependent on high insulin concentrations in both humans and rats. Insulin and exercise may be methods to preserve host lean tissue and feed the host rather than the tumor. Future studies depend on better definition of tumor-bearing host metabolism, altering the relationship between neoplasm and host to preferentially feed the host, and making the neoplasm more susceptible to effective treatment.

  View details for Web of Science ID A1987Q613500002

  View details for PubMedID 3123081

• LOCALIZATION OF PARATHYROID ADENOMAS IN PATIENTS WHO HAVE UNDERGONE SURGERY .2. INVASIVE PROCEDURES RADIOLOGY MILLER, D. L., DOPPMAN, J. L., Krudy, A. G., Shawker, T. H., NORTON, J. A., Vucich, J. J., MORRISH, K. A., Marx, S. J., Spiegel, A. M., AURBACH, G. D. 1987; 162 (1): 138-141

  Abstract

  The authors studied intraarterial digital subtraction angiography (DSA), conventional selective angiography, parathyroid venous sampling (PVS), and intraoperative ultrasound (US) as localization procedures for parathyroid adenomas in 53 patients with proved parathyroid adenomas and previous unsuccessful parathyroid surgery. PVS had the highest overall sensitivity as a single study (80%), followed by intraoperative US (78%), angiography (60%), and DSA (49%). Invasive procedures permitted successful localization of adenomas in 41 of 43 patients studied (95%). False-positive studies were uncommon. The optimum sequence of invasive localization procedures is determined by clinical factors and not by the sensitivity of individual tests. The authors recommend DSA be performed first, followed by angiography, PVS, and intraoperative US, in that order.

  View details for Web of Science ID A1987F351700026

  View details for PubMedID 3538146

• LOCALIZATION OF PARATHYROID ADENOMAS IN PATIENTS WHO HAVE UNDERGONE SURGERY .1. NONINVASIVE IMAGING METHODS RADIOLOGY MILLER, D. L., DOPPMAN, J. L., Shawker, T. H., Krudy, A. G., NORTON, J. A., Vucich, J. J., MORRISH, K. A., Marx, S. J., Spiegel, A. M., AURBACH, G. D. 1987; 162 (1): 133-137

  Abstract

  The authors evaluated computed tomography (CT), ultrasound (US), technetium/thallium scintigraphy, and magnetic resonance (MR) imaging as localization procedures in 53 patients with proved parathyroid adenomas and previous unsuccessful parathyroid surgery. CT had the highest overall sensitivity (47%), followed by US (36%) and scintigraphy (27%). There is still too little data to assess MR imaging. Adenoma size affected the sensitivity of CT, scintigraphy, and MR imaging but not US. When all three studies were used, at least one study depicted a lesion in 78% of patients, but definitive localization (two positive studies) was achieved in only 31%.

  View details for Web of Science ID A1987F351700025

  View details for PubMedID 3538145

• SELECTIVE VENOUS SAMPLING FOR GASTRIN TO LOCALIZE GASTRINOMAS - A PROSPECTIVE ASSESSMENT ANNALS OF INTERNAL MEDICINE CHERNER, J. A., DOPPMAN, J. L., NORTON, J. A., MILLER, D. L., Krudy, A. G., Raufman, J. P., COLLEN, M. J., Maton, P. N., Gardner, J. D., Jensen, R. T. 1986; 105 (6): 841-847

  Abstract

  In 27 consecutive patients with Zollinger-Ellison syndrome, we prospectively evaluated the ability of selective venous sampling for gastrin to localize gastrinomas, then compared the results with those from imaging studies and with findings at surgery. All patients had a gastrin gradient, but in only 20 patients was it significant. Neither the magnitude of the gastrin gradient nor its presence or absence correlated with the frequency with which gastrinoma was found at surgery. A gastrinoma was found at surgery in 15 patients, of whom 12 had positive imaging studies, 11 had a significant gastrin gradient, 14 had both tests positive, and 1 had both tests negative. A gastrinoma was not found at surgery in 12 patients, of whom 8 had a significant gradient and none had a positive imaging study. Gastrin sampling has equal sensitivity with imaging studies in localizing gastrinoma, but imaging studies have higher positive and negative predictive values and higher specificity. Thus, selective venous sampling for gastrin is much less useful in localizing gastrinoma than has been suggested and should not be routinely done preoperatively in patients with Zollinger-Ellison syndrome.

  View details for Web of Science ID A1986F162500004

  View details for PubMedID 3535602

• HOME PARENTERAL-NUTRITION FOR PATIENTS WITH ADVANCED INTRAPERITONEAL CANCERS AND GASTROINTESTINAL DYSFUNCTION JOURNAL OF SURGICAL ONCOLOGY Moley, J. F., August, D., NORTON, J. A., Sugarbaker, P. H. 1986; 33 (3): 186-189

  Abstract

  The use of total parenteral nutrition (TPN) in patients with advanced, untreatable cancer is controversial. Occasionally, however, damage to bowel by tumor, radiation, or surgery renders these patients unable to eat and TPN may be indicated to prevent premature death from starvation. We have used Home Parenteral Nutrition (HPN) to support three patients with advanced, untreatable abdominal cancer and inability to eat. Morbidity was minimal and survival times were 24, 6 and 1.5 months. Payment was covered by third party agencies. All patients and their families were gratified by the ability to return home with nutritional support. HPN can be used to support terminal cancer patients with bowel obstruction and may afford them longer survival. Ideally, patients considered for this should be well motivated, with good support systems, and with survival estimated to be at least months.

  View details for Web of Science ID A1986E975900007

  View details for PubMedID 3095593

• PROSPECTIVE-STUDY OF GASTRINOMA LOCALIZATION AND RESECTION IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME ANNALS OF SURGERY NORTON, J. A., DOPPMAN, J. L., COLLEN, M. J., Harmon, J. W., Maton, P. N., Gardner, J. D., Jensen, R. T. 1986; 204 (4): 468-479

  Abstract

  In 1982, a prospective study was initiated of 52 consecutive patients with proven Zollinger-Ellison syndrome (ZES), involving surgical exploration with the goal of removing the gastrinoma after an extensive protocol to localize the tumor. Each patient underwent ultrasound, computed tomography (CT) with oral/intravenous (IV) contrast, and selective arteriography. Eighteen patients had metastatic disease identified by imaging studies and confirmed by percutaneous biopsies, and two patients had multiple endocrine neoplasia type I (MEN-I) with negative imaging studies; therefore, these 20 patients did not undergo laparotomy. Each of the remaining 32 patients (3 with MEN-I and positive imaging studies) underwent laparotomy, and gastrinomas were removed in 20 patients. Preoperative ultrasound localized tumors in 20% of patients, CT in 40%, arteriography in 60%, and any of the modalities in 70% of patients. Infusion CT and arteriography were 100% specific. In 18 patients with either negative imaging (17) or false-positive imaging (1 ultrasound), gastrinomas were found and removed in six patients (33%). Twenty-four gastrinomas were found in 20 patients at laparotomy: eight in lymph nodes around the pancreatic head, four in the pancreatic head, one in the pancreatic body, three in the pancreatic tail, three in the pyloric channel, one in the duodenal wall, two in the jejunum at the ligament of Treitz, one in the ovary, and multiple liver metastases in one patient. If one excludes patients with MEN-I or liver metastatic disease, 12/28 (43%) of patients were biochemically "cured" immediately after operation. This result decreased to 7/23 (30%) with greater than 6 months follow-up. No patients with gastrinomas resected have developed recurrent gastrinoma on follow-up imaging studies (longest follow-up: 4 years). This study indicates that 95% of metastatic gastrinoma can be diagnosed before operation and that, by a combination of careful imaging studies and thorough exploration at surgery, 30% of patients with gastrinomas may be curable.

  View details for Web of Science ID A1986E249800015

  View details for PubMedID 3532971

• INTRAOPERATIVE ULTRASOUND AND REOPERATIVE PARATHYROID SURGERY - AN INITIAL EVALUATION WORLD JOURNAL OF SURGERY NORTON, J. A., Shawker, T. H., Jones, B. L., Spiegel, A. M., Marx, S. J., Fitzpatrick, L., AURBACH, G. D., DOPPMAN, J. L. 1986; 10 (4): 631-639

  View details for Web of Science ID A1986D347000013

  View details for PubMedID 3529650

• PREOPERATIVE OF POSTOPERATIVE DOXORUBICIN HYDROCHLORIDE (ADRIAMYCIN) - WHICH IS BETTER FOR WOUND-HEALING SURGERY Lawrence, W. T., Talbot, T. L., NORTON, J. A. 1986; 100 (1): 9-13

  Abstract

  The purpose of this study was to determine if any interval between preoperative or postoperative administration of doxorubicin hydrochloride (Adriamycin) and wounding would limit the impairment in healing induced by Adriamycin. The question was evaluated in 7 cm incisional wounds on the dorsal midline of rats. Preoperative Adriamycin was administered 42, 28, 21, 14, and 7 days before wounding, and wound breaking strengths (WBS) of the incisional wounds were measured 7, 18, and 28 days after wounding. Postoperative Adriamycin was administered 0, 7, 14, 21, and 28 days after wounding, and WBS were measured 7, 14, 28, 35, and 42 days after wounding. A similar and significant degree of impairment was induced in healing by all preoperative Adriamycin regimens evaluated. Postoperative Adriamycin administered up to 21 days after wounding induced a healing deficit that manifested 1 to 2 weeks after Adriamycin administration. Adriamycin administered 28 days after surgery induced no demonstrable impairment in WBS. In addition, Adriamycin never decreased the WBS of a wound after a certain degree of strength had been obtained. These results lead us to warn against the use of preoperative Adriamycin and support the use of postoperative Adriamycin administered 28 days after a surgical procedure.

  View details for Web of Science ID A1986D078700002

  View details for PubMedID 3726767

• ADAPTATION DURING SURGICAL STRESS - A REEVALUATION OF THE ROLE OF GLUCOCORTICOIDS JOURNAL OF CLINICAL INVESTIGATION Udelsman, R., Ramp, J., GALLUCCI, W. T., Gordon, A., Lipford, E., NORTON, J. A., Loriaux, D. L., Chrousos, G. P. 1986; 77 (4): 1377-1381

  Abstract

  Pharmacologic doses of glucocorticoids are administered to patients with adrenal insufficiency during operative procedures to prevent hemodynamic instability, cardiovascular collapse, and death. Since these supraphysiologic doses might not be necessary and might have adverse effects, we examined the effects of different doses of glucocorticoids on hemodynamic adaptation during surgical stress in adrenalectomized primates. Sham-adrenalectomized placebo-treated animals served as controls. Adrenalectomized monkeys were maintained for 4 mo on physiologic glucocorticoid and mineralocorticoid replacement. The adrenalectomized monkeys were then stratified into three groups receiving, respectively, subphysiological (one-tenth the normal cortisol production rate), physiological, or supraphysiological (10 times the normal cortisol production rate) cortisol (hydrocortisone) treatment. 4 d later a cholecystectomy was performed. The intraoperative hemodynamic and metabolic parameters, perioperative survival rates, and postoperative wound healing were compared. The subphysiologically treated group was hemodynamically unstable before, during, and after surgery and had a significantly higher mortality rate than control. In this group, arterial blood pressure was low, and the cardiac index, systemic vascular resistance index, and left ventricular stroke work index were all reduced, suggesting decreased cardiac contractility and blood vessel tone. In contrast, the physiologically replaced group was indistinguishable from either supraphysiologically treated animals or sham-operated controls. All groups had similar metabolic profiles and normal wound healing. These findings suggest that the permissive actions of physiologic glucocorticoid replacement are both necessary and sufficient for primates to tolerate surgical stress. Supraphysiological glucocorticoid treatment has no apparent advantage during this form of stress in the primate.

  View details for Web of Science ID A1986A831700041

  View details for PubMedID 3958189

• VOCAL CORD PARALYSIS AND REOPERATIVE PARATHYROIDECTOMY - A PROSPECTIVE-STUDY ANNALS OF SURGERY Patow, C. A., NORTON, J. A., Brennan, M. F. 1986; 203 (3): 282-285

  Abstract

  One hundred sixty-three patients undergoing reoperative parathyroidectomy were evaluated before and after operation to determine the incidence of, risk factors for, and morbidity of vocal cord paralysis. These patients were compared to 77 patients undergoing initial parathyroid operation, only one of whom had vocal cord paralysis on postoperative indirect laryngoscopy (1.3%). Preoperative examination of the reoperative patients revealed vocal cord paralysis from initial exploration in 11 patients who were excluded from this study. After re-exploration, 10 patients (6.6%) had vocal cord paralysis, eight unilateral and two bilateral. Right vocal cords were paralyzed twice as often as left. In 90%, vocal cord paralysis was associated with removal or biopsy of an ipsilateral gland. Vocal cord paralysis occurred despite intraoperative visualization of the recurrent laryngeal nerves. Preoperative localization, parathyroid gland pathology, and concomitant thyroidectomy were not associated with increased risk of vocal cord paralysis. Hoarseness was the major symptom. Tracheostomy was required for two patients, one was permanent. One patient was treated for aspiration with a temporary gastrostomy. Nine of 10 patients had return of normal voice quality in an average of 4 months time. On examination 4 years or more after surgery, two of five patients had normal vocal cord motion. The oblique anatomic course of the right recurrent laryngeal nerve may account for the greater frequency of right vocal cord paralysis.

  View details for Web of Science ID A1986A431100011

  View details for PubMedID 3954480

• THE REVERSAL OF AN ADRIAMYCIN INDUCED HEALING IMPAIRMENT WITH CHEMOATTRACTANTS AND GROWTH-FACTORS ANNALS OF SURGERY Lawrence, W. T., NORTON, J. A., Sporn, M. B., GORSCHBOTH, C., GROTENDORST, G. R. 1986; 203 (2): 142-147

  Abstract

  Rats treated with 8 mg/kg Adriamycin intravenously 4 days prior to chamber implantation develop impaired wound healing in a wound chamber model. In this study, the effects on healing of supplemental platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), and insulin were evaluated in chambers extracted from Adriamycin-treated rats 10 and 20 days after implantation. The effects of individual factors, combinations of factors, and different concentrations of TGF-beta were evaluated. The parameters evaluated included collagen content, protein content, cellular proliferation rate, chamber histology, and collagen types. Supplemental TGF-beta alone reversed much of the healing deficit noted. A minimum concentration of 100 ng/ml TGF-beta was required to significantly reverse this deficit. PDGF and EGF alone had no effect. Addition of PDGF and TGF-beta in combination stimulated a significantly higher level of collagen deposit than TGF-beta alone. Addition of EGF in combination with PDGF and TGF-beta restored collagen deposition to 86% of normal. No synergism was seen between TGF-beta and EGF unless PDGF was also present. These data suggest that growth factors contained in platelets may play key roles in initiating the wound healing response and may have clinical utility in healing deficit states.

  View details for Web of Science ID A1986AZB3200006

  View details for PubMedID 3511865

• DOXORUBICIN-INDUCED IMPAIRMENT OF WOUND-HEALING IN RATS JOURNAL OF THE NATIONAL CANCER INSTITUTE Lawrence, W. T., NORTON, J. A., Harvey, A. K., GORSCHBOTH, C. M., Talbot, T. L., GROTENDORST, G. R. 1986; 76 (1): 119-126

  Abstract

  The mortality rate induced by 3 doses of iv doxorubicin was evaluated in F344 rats, and a dose of 8 mg doxorubicin/kg body weight was the maximum dose tolerated with an acceptable mortality rate. Rats treated with 8 mg doxorubicin/kg prior to or on the day of wounding demonstrated decreased wound breaking strength in incisional wounds at all intervals after wounding. Decreased amounts of collagen and DNA and less cellularity were noted in wound chambers from rats treated in the same manner. In both the incisional wound and wound chamber models, rats treated with doxorubicin 7 days after wounding showed a less dramatic healing impairment. No difference in collagen types was noted between chambers from the doxorubicin-treated and untreated rats. Doxorubicin also produced a significant reduction in platelet and white blood cell counts 1 week after it was administered. The data indicate that doxorubicin impedes healing by decreasing wound cellularity and collagen synthesis.

  View details for Web of Science ID A1986AXQ2500017

  View details for PubMedID 3455735

• DEMONSTRATION OF AN ANGIOGRAPHICALLY HYPOVASCULAR INSULINOMA WITH INTRAARTERIAL DYNAMIC CT AMERICAN JOURNAL OF ROENTGENOLOGY FINK, I. J., Krudy, A. G., Shawker, T. H., NORTON, J. A., GORDEN, P., DOPPMAN, J. L. 1985; 144 (3): 555-556

  View details for Web of Science ID A1985ACG1100021

  View details for PubMedID 2982249

• MEDIAN STERNOTOMY IN REOPERATIONS FOR PRIMARY HYPERPARATHYROIDISM WORLD JOURNAL OF SURGERY NORTON, J. A., Schneider, P. D., Brennan, M. F., Rothmund, M. 1985; 9 (5): 807-813

  View details for Web of Science ID A1985ARU6000022

  View details for PubMedID 4060751

• FASTING PLASMA AMINO-ACID LEVELS IN CANCER-PATIENTS CANCER NORTON, J. A., GORSCHBOTH, C. M., Wesley, R. A., Burt, M. E., Brennan, M. F. 1985; 56 (5): 1181-1186

  Abstract

  The concentration in plasma of 15 fasting amino acids were measured in 14 control volunteers and 55 cancer patients. In addition, 16 patients (7 with, 9 without total parenteral nutrition [TPN] ) with metastatic sarcoma had sequential amino acid profiles measured during 6 weeks of ablative chemotherapy. In four cancer patient groups (lymphoma, sarcoma, osteosarcoma and metastatic sarcoma) with no or minimal weight loss, most plasma amino acid levels were similar to controls. Proline levels were significantly reduced in the lymphoma and sarcoma patients. Esophageal cancer patients with 20% body weight loss had a marked reduction in total and individual amino acid levels (except branched chain amino acids) compared to controls and all others. The metastatic sarcoma patients who received parenteral nutrition had higher levels of plasma lysine and tyrosine during chemotherapy than controls; however, TPN failed to change the majority of amino acid levels. It appears that plasma amino acid levels except proline were well maintained in cancer patients without weight loss. Esophageal cancer patients with weight loss demonstrated marked reduction in all circulating amino acids except branched chain. Parenteral nutrition did not significantly alter the amino acid profile of cancer patients undergoing chemotherapy.

  View details for Web of Science ID A1985ANQ4300034

  View details for PubMedID 3926295

• REVERSAL OF AN ADRIAMYCIN-INDUCED HEALING IMPAIRMENT WITH GROWTH-FACTORS SURGICAL FORUM Lawrence, W. T., GROTENDORST, G. R., NORTON, J. A. 1985; 36: 575-577

  View details for Web of Science ID A1985AVR3900243

• REOPERATION FOR PERSISTENT AND RECURRENT HYPERPARATHYROIDISM ANNALS OF SURGERY Brennan, M. F., NORTON, J. A. 1985; 201 (1): 40-44

  Abstract

  As a consequence of an experience with 175 patients undergoing reoperation for persistent or recurrent hyperparathyroidism, the authors have evolved an approach to management. The emphasis is on the confirmation of the diagnosis; the critical evaluation of invasive and noninvasive localization tests, techniques of intraoperative assessment as to the adequacy of the reexploration; the avoidance of postoperative complications; the treatment with cryopreserved autografts of persistent hypocalcemia. With this approach, the authors have had a success rate of greater than 90% for reexploration in patients with persistent and recurrent hyperparathyroidism.

  View details for Web of Science ID A1985AAB3000005

  View details for PubMedID 2981520

• PARABIOTIC TRANSFER OF CANCER ANOREXIA CACHEXIA IN MALE-RATS CANCER RESEARCH NORTON, J. A., Moley, J. F., Green, M. V., Carson, R. E., Morrison, S. D. 1985; 45 (11): 5547-5552

  Abstract

  To demonstrate that the anorexia and depletion of cachexia reverses on tumor removal, F344 rats underwent sarcoma resection when their food intake fell to 0 g/day. In survivors of surgery, reversal in food intake was apparent within 3 days postoperatively, followed after 2 days by gain in host weight. To detect whether the transmission of anorexia/cachexia in these tumor-bearing (TB) rats was via the circulation, four groups were studied: single non-tumor bearing (NTB); single TB; parabiotic NTB; and parabiotic TB. The measured blood exchange rate between parabiotic halves was 1.2-1.5%/min. No cachectic effect was detected in either half of the NTB parabionts. There was no evidence of sarcoma metastases in the tumor-free half of the parabiotic TB pair. All the rats associated with the presence of tumor showed cachectic effects but the degree and timing of effect varied among the three conditions, single TB, parabiotic TB half, and parabiotic tumor-free half. In all variables examined (fall in food intake, time of first fall in food intake, host weight loss, elevation of blood urea nitrogen) the severities were always in the same sequence: single TB greater than parabiotic TB half greater than parabiotic tumor-free half greater than NTB. In addition, the TB parabiotic pair had a significantly longer survival time and grew a significantly larger tumor than did the single TB animal. The parabiotic tumor had a slower initial growth rate and a slower deceleration rate than the singlet tumor. These results provide evidence for the humoral mediation of cancer-associated cachexia.

  View details for Web of Science ID A1985ATM2700057

  View details for PubMedID 3863707

• CARDIAC AND RED BLOOD-CELL GLUTATHIONE-PEROXIDASE - RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL IN PATIENTS ON TOTAL PARENTERAL-NUTRITION CANCER RESEARCH BATIST, G., Norton, J., Katki, A. G., Wagman, L., Ferrans, V. J., Maher, M., Myers, C. E. 1985; 45 (11): 5900-5903

  Abstract

  Oxygen derived free radicals and peroxides result from many antitumor treatments, including radiation and anthracyclines. Doxorubicin cardiotoxicity is thought to result from free radical induced lipid peroxidation. The heart has less active detoxification enzymes than does the liver and depends on selenium dependent glutathione peroxidase (GSH-PX) for this function. We did a sequential prospective trial in patients with totally controlled parenteral diets to examine the activity of red blood cell GSH-PX in patients with and without malignant disease. Decreased GSH-PX activity was found in 54% of the patients on parenteral nutrition and was more common in the older of these patients and in those with the greatest weight loss. In the absence of selenium supplementation, the RBC GSH-PX activity declines steadily, but with supplementation this was prevented or reversed. Because selenium deficiency can manifest as a cardiomyopathy, we measured the enzyme activity in the hearts of five patients who had died. The cardiac enzyme activity correlated strongly with the RBC levels. Significantly decreased GSH-PX has been shown in animals to be associated with changes in other enzymes critical both to activation and detoxification of carcinogens as well as antitumor drugs. Abnormality of selenium status might be a previously unsuspected contributor to interpatient variation in drug effects.

  View details for Web of Science ID A1985ATM3000051

  View details for PubMedID 3931910

• INSULIN REVERSAL OF CANCER-INDUCED PROTEIN LOSS SURGICAL FORUM Moley, J. F., Peacock, J. E., Morrison, S. D., NORTON, J. A. 1985; 36: 416-419

  View details for Web of Science ID A1985AVR3900173

• INSULIN REVERSAL OF CANCER CACHEXIA IN RATS CANCER RESEARCH Moley, J. F., Morrison, S. D., NORTON, J. A. 1985; 45 (10): 4925-4931

  Abstract

  The anabolic effects of exogenous neutral protamine hagedorn insulin on tumor-bearing (TB) and non-tumor-bearing (NTB) rats were examined. Exogenous insulin (2 units/100 g/day) produced similar hypoglycemia in TB and NTB rats. Food intake and body weight gain were significantly increased by insulin in NTB rats. In TB rats in an early stage of cachexia, insulin increased food intake and host weight (total body weight minus tumor weight). In TB rats with severe cachexia, insulin increased food intake and stabilized host weight when untreated TB controls were not eating and were losing weight. When daily insulin administration was started at an early stage of tumor growth and continued until death, there was again significant enhancement of host weight and food intake. Heart and adrenal weights were significantly reduced in insulin-treated TB animals. Tumor growth was not stimulated by insulin treatment. Survival time was slightly reduced in TB rats treated with long-term insulin. Survival time in TB rats randomized to insulin during late cachectic decline was not different from untreated TB controls. Insulin did not have any measurable effect on energy expenditure or the motor activity compartment of energy expenditure in either TB or NTB rats. Insulin treatment can reverse experimental cancer cachexia. It is a nutritional therapy which preferentially feeds the host over the tumor. As yet, its beneficial effects have not prolonged survival of tumor-bearing animals.

  View details for Web of Science ID A1985ARH6200038

  View details for PubMedID 3896470

• PARATHYMIC PARATHYROID - CT, US, AND ANGIOGRAPHIC FINDINGS RADIOLOGY DOPPMAN, J. L., Shawker, T. H., Krudy, A. G., MILLER, D. L., Marx, S. J., Spiegel, A. M., NORTON, J. A., Brennan, M. F., Schaaf, M., AURBACH, G. D. 1985; 157 (2): 419-423

  Abstract

  Six patients with primary hyperparathyroidism caused by an undescended parathymic adenoma are described. All glands were anterior to the common carotid artery at the level of the hyoid bone. Blood supply was from the superior thyroid artery, and venous drainage was into the superior thyroid vein. Ultrasound (one of five) and computed tomography (two of six) were rarely positive, but glands can be detected with both modalities if the examination is carried high enough. Glands within the carotid sheath are generally lower in the neck and have a blood supply from the inferior thyroid artery with drainage into the vertebral veins.

  View details for Web of Science ID A1985ASU8200027

  View details for PubMedID 3901107

• ULTRASONIC PARATHYROID LOCALIZATION IN PREVIOUSLY OPERATED PATIENTS CLINICAL RADIOLOGY Krudy, A. G., Shawker, T. H., DOPPMAN, J. L., Horvath, K., Schneider, P. D., NORTON, J. A., Marx, S. J., Spiegel, A. M. 1984; 35 (2): 113-118

  Abstract

  Sixty-two patients with hyperparathyroidism and failed prior neck surgery were examined by ultrasound before reoperation to localise abnormally enlarged glands. If mediastinal lesions are excluded, a total of 57 glands greater than 5 mm in size were removed from 48 patients. Ultrasound demonstrated only 18 of these for a true positive rate of 32%. There were 39/57 (68%) false negatives. In addition, there were 16 false positives. In our experience, the detection rate of ultrasound for enlarged parathyroid glands in patients with failed surgery is significantly less than that reported in previously unoperated patients (73%), or in the limited number of reported cases of patients with previous operations (75%). Our high false negative rate is probably partially due to the large number of posteriorly located small glands which cannot be adequately visualised by ultrasound. Nevertheless, because of its non-invasive nature, low cost and ready availability, ultrasound should be utilised as an initial screening procedure in patients with failed previous surgery.

  View details for Web of Science ID A1984SL87900005

  View details for PubMedID 6697653

• VOCAL CORD PARALYSIS AND REOPERATIVE PARATHYROIDECTOMY - A PROSPECTIVE-STUDY SURGICAL FORUM Patow, C. A., NORTON, J. A., Brennan, M. F. 1984; 35: 553-554

  View details for Web of Science ID A1984TW53800231

• GLUCOSE-INTOLERANCE IN SARCOMA PATIENTS CANCER NORTON, J. A., Maher, M., Wesley, R., White, D., Brennan, M. F. 1984; 54 (12): 3022-3027

  Abstract

  Twenty-seven otherwise healthy patients with localized sarcoma were examined to determine if glucose intolerance can be detected before the appearance of clinical signs of cachexia. No patient had lost weight or demonstrated severe malnutrition. Fasting plasma samples for glucose, insulin, glucagon, and free fatty acids (FFA) were obtained, and a standard intravenous glucose tolerance test performed. Glucose disappearance rate (K) was calculated between 5 and 60 minutes. K levels were compared to those of normal controls and to those of patients with more extensive cancer (statistics obtained from the literature). Levels for K were compared to tumor volume measurements following surgery. Fasting glucose, insulin, and glucagon levels were normal. Fasting FFA levels were slightly elevated. K levels for sarcoma patients were significantly lower than in control patients (P = 0.04), and higher than in patients with advanced cancer (P less than 0.0001). The subset of patients who weighed less than the ideal had a significantly lower K level than did the rest of the sarcoma population. K levels correlated inversely with tumor volume (r = -0.34; P = 0.04). These data indicate that mild glucose intolerance (reduction in clearance of a glucose load) occurs early in untreated sarcoma patients, is most prevalent in patients who maintain less than the ideal weight, correlates with tumor burden, and occurs before other signs of cachexia appear.

  View details for Web of Science ID A1984TY03300033

  View details for PubMedID 6498776

• CONTRIBUTION OF INERT MASS TO EXPERIMENTAL CANCER CACHEXIA IN RATS JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Morrison, S. D., Moley, J. F., NORTON, J. A. 1984; 73 (4): 991-998

  Abstract

  An inert artificial tumor (AFT) was inflated in male F344 rats to simulate, experimentally, the growth in mass of large transplantable tumors that produce cachexia. The AFT depressed host weight gain and skeletal muscle mass up to 30% and food intake up to 20% of the depression induced by tumors of comparable size. When the growth rate of the AFT was low, there was no depression of food intake. Work-induced hypertrophy of skeletal muscles, as assessed by a gastrocnemius tenotomy model, was approximately equal to that of normal, tumor-bearing, and AFT-bearing animals. The AFT elevated host total energy expenditure by 12.5% and compartment-of-energy expenditure attributable to motor activity by 10.5%. The elevation of energy expenditure accounted for most of the depression of weight gain of AFT-bearing animals below that of intact animals. The large mass of most transplantable tumors leads to an overestimate of the malignant tissue-depletive effects of tumor and an under-estimate of the asthenic effects.

  View details for Web of Science ID A1984TN61800027

  View details for PubMedID 6592392

• INTRAOPERATIVE URINARY CYCLIC ADENOSINE-MONOPHOSPHATE AS A GUIDE TO SUCCESSFUL REOPERATIVE PARATHYROIDECTOMY ANNALS OF SURGERY NORTON, J. A., Brennan, M. F., Saxe, A. W., Wesley, R. A., DOPPMAN, J. L., Krudy, A. G., Marx, S. J., Santora, A. C., Hicks, M., AURBACH, G. D., Spiegel, A. M. 1984; 200 (4): 389-395

  Abstract

  Sixty patients with persistent or recurrent primary hyperparathyroidism underwent reexploration during which urinary cyclic adenosine monophosphate (UcAMP) levels were determined at half-hour intervals by radioimmunoassay. Retrospective analysis of the data allowed us to develop UcAMP criteria for surgical success. Following removal of parathyroid tissue, if an individual UcAMP level dropped 50% from the median baseline level, or if elevated levels dropped to less than 4.0 nmol/dl glomerular filtrate, surgery was predicted to be successful. Eight unsuccessful procedures in seven patients produced no decline in UcAMP, and the intraoperative results accurately predicted surgical failure. Fifty-three patients underwent successful procedures and in every case UcAMP fell. Ninety-eight per cent of these successful procedures were predicted by our criteria. Levels of UcAMP fell 1.5 +/- 0.5 hours (means +/- SD) following abnormal parathyroidectomy. In 19 of 36 successful cases diagnosed before surgery as adenoma, the operative procedure was terminated before a significant drop in UcAMP. In 16 of 17 successful cases diagnosed before surgery as hyperplasia or uncertain histology, UcAMP fell during the operation. Intraoperative determination of UcAMP is helpful in reoperative parathyroid surgery. The criteria established allow intraoperative prediction of success with remarkable accuracy. Urinary cyclic AMP is especially helpful in reoperation for multigland disease; when enough pathologic tissue has been removed, the criteria will be met and the procedure may be terminated with confidence.

  View details for Web of Science ID A1984TM59200001

  View details for PubMedID 6091573

• HYPERFUNCTIONING CYSTIC PARATHYROID-GLANDS - CT AND SONOGRAPHIC FINDINGS AMERICAN JOURNAL OF ROENTGENOLOGY Krudy, A. G., DOPPMAN, J. L., Shawker, T. H., Spiegel, A. M., Marx, S. J., Norton, J., Schaaf, M., Moss, M. L., Weiss, M. A., SCHACHNER, S. H. 1984; 142 (1): 175-178

  Abstract

  Four functioning cystic parathyroid glands were evaluated with computed tomography (CT) and sonography in four patients, only one of whom had prior surgery. Sonography demonstrated solid lesions of decreased echogenicity with fluid-filled cavities near the lower thyroid poles or in the posterosuperior mediastinum. On CT the cystic parts of the lesions were of low attenuation (1-44 H), often with a well defined wall that was better demonstrated after intravenous contrast administration. Fine-needle aspiration biopsy of two of the cystic parathyroids revealed elevated parathyroid hormone levels. These lesions probably represent degenerating adenomas rather than true parathyroid cysts. While the CT and sonographic findings are nonspecific, the diagnosis of a cystic parathyroid should be entertained when a fluid-filled lesion is encountered in the neck of a patient with or without hypercalcemia. The diagnosis may be confirmed by assay of parathyroid hormone from the fluid aspirate.

  View details for Web of Science ID A1984RW79400043

  View details for PubMedID 6606954

• PARATHYROID ASPIRATION DIRECTED BY ANGIOGRAPHY - AN ALTERNATIVE TO VENOUS SAMPLING RADIOLOGY Krudy, A. G., DOPPMAN, J. L., Marx, S. J., NORTON, J. A., Spiegel, A. M., Santora, A. C., AURBACH, G. D. 1984; 152 (1): 207-208

  Abstract

  Not all parathyroid glands can be visualized by CT or ultrasound and, therefore, cannot be aspirated using these techniques. We report the localization of a parathyroid gland by arteriography and needle aspiration under fluoroscopic guidance. This technique can be used to confirm a diagnosis of hypervascular parathyroid tissue that cannot otherwise be confirmed.

  View details for Web of Science ID A1984SW88400041

  View details for PubMedID 6729114

• REMOVAL OF GASTRINOMAS FOR CONTROL OF ZOLLINGER-ELLISON SYNDROME ANNALS OF SURGERY Harmon, J. W., NORTON, J. A., Collin, M. J., Krudy, A. G., Shawker, T. H., DOPPMAN, J. L., Davis, J., Jensen, R. T. 1984; 200 (4): 396-404

  Abstract

  There are two distinct problems in patients with Zollinger-Ellison Syndrome (ZES): peptic ulcer diathesis and malignant tumors. Antisecretory drugs have allowed us to control the ulcer symptoms and acid output in 45 patients with ZES. We report here the initial seven patients selected for surgical exploration with the goal of removing their gastrinomas. Prior to surgery, an extensive and rigorous protocol to localize the gastrinoma was carried out, including hypotonic duodenography, abdominal ultrasonography, selective arteriography, portal vein sampling for gastrin, and computerized tomography. With this protocol of radiographic localization, gastrinomas were found in two of the seven cases and the syndrome was "cured" in three of the seven patients. The results also demonstrate that preoperative localization is not a substitute for careful surgical exploration as tumors were found in two patients in whom localization failed.

  View details for Web of Science ID A1984TM59200002

  View details for PubMedID 6148919

• DETECTION OF MEDIASTINAL PARATHYROID-GLANDS BY NONSELECTIVE DIGITAL ARTERIOGRAPHY AMERICAN JOURNAL OF ROENTGENOLOGY Krudy, A. G., DOPPMAN, J. L., MILLER, D. L., NORTON, J. A., Marx, S. J., Spiegel, A. M., Santora, A. C., AURBACH, G. D., Schaaf, M. 1984; 142 (4): 693-695

  Abstract

  Six patients with failed previous operations and anterior mediastinal parathyroid glands were evaluated with selective angiography and nonselective arterial digital arteriography. Selective angiography depicted two of nine mediastinal glands; nonselective arterial digital arteriography depicted only one of nine mediastinal glands and missed a sizable (4.5 cm) gland demonstrated by routine arteriography. Nonselective arterial digital arteriography did not demonstrate any additional mediastinal glands. From this preliminary experience, it was concluded that nonselective arterial digital arteriography is not a sensitive method for detecting mediastinal glands.

  View details for Web of Science ID A1984SH78400007

  View details for PubMedID 6608224

• LOCALIZATION OF ISLET CELL TUMORS BY DYNAMIC CT - COMPARISON WITH PLAIN CT, ARTERIOGRAPHY, SONOGRAPHY, AND VENOUS SAMPLING AMERICAN JOURNAL OF ROENTGENOLOGY Krudy, A. G., DOPPMAN, J. L., Jensen, R. T., NORTON, J. A., COLLEN, M. J., Shawker, T. H., Gardner, J. D., McArthur, K., GORDEN, P. 1984; 143 (3): 585-589

  Abstract

  Ten patients with suspected islet cell tumors (seven with possible gastrinomas, three with insulinomas) underwent diagnostic evaluation with dynamic CT scanning, routine CT scanning, angiography, and sonography. Venous sampling was also performed in selected instances. Nine sites of gastrinoma and three insulinomas were confirmed surgically in eight patients. Two patients had negative surgical explorations. Routine CT demonstrated five of the nine gastrinomas and one of two insulinomas. Angiography was positive in six of nine gastrinomas and all three insulinomas. Sonography showed only two of the nine gastrinomas and two of the three insulinomas. Dynamic CT scanning demonstrated three additional lesions (two gastrinomas, one insulinoma) not visible on routine CT scanning. Although most of these lesions were visible arteriographically, dynamic CT scans at the appropriate level localized the pathology in the transverse plane and greatly aided in surgical resection of these lesions. Dynamic CT scanning is a useful adjunct to routine angiographic and CT workup of patients with islet cell tumors.

  View details for Web of Science ID A1984TE56200026

  View details for PubMedID 6087646

• WORK IN PROGRESS - ABNORMAL PARATHYROID-GLANDS - COMPARISON OF NON-SELECTIVE ARTERIAL DIGITAL ARTERIOGRAPHY, SELECTIVE PARATHYROID ARTERIOGRAPHY, AND VENOUS DIGITAL ARTERIOGRAPHY AS METHODS OF DETECTION RADIOLOGY Krudy, A. G., DOPPMAN, J. L., MILLER, D. L., Marx, S. J., NORTON, J. A., Santora, A. C., Lasker, R. D., Downs, R. W., Spiegel, A. M., AURBACH, G. D. 1983; 148 (1): 23-29

  Abstract

  Nonselective arterial digital arteriography (NSADA), selective parathyroid arteriography (SPA), and venous digital arteriography (VDA) were compared as methods of detecting parathyroid enlargement in 14 patients with primary hyperparathyroidism undergoing preoperative localization following unsuccessful neck surgery. All 14 had SPA and NSADA, consisting of contrast injections into the ascending aorta, innominate artery, and left subclavian artery; 7 also had VDA. Surgery was performed in 9 patients, and 2 additional glands were confirmed by fine-needle aspiration and venous sampling. Parathyroid glands could not be located in 3 patients, who were not re-explored. SPA demonstrated 11/13 abnormal glands (85%). NSADA detected 7/13 (54%), and there were 2 false positives. VDA showed 5/6 glands detected by NSADA (83%); the seventh patient did not have VDA. The overall quality of VDA was inferior to NSADA. Although NSADA and VDA are less sensitive than SPA, they are safer and easier to perform and should be the initial vascular screening procedures following unsuccessful parathyroid surgery.

  View details for Web of Science ID A1983QV03900005

  View details for PubMedID 6134300

• IRON SUPPLEMENTATION OF TOTAL PARENTERAL-NUTRITION - A PROSPECTIVE-STUDY JOURNAL OF PARENTERAL AND ENTERAL NUTRITION NORTON, J. A., Peters, M. L., Wesley, R., Maher, M. M., Brennan, M. F. 1983; 7 (5): 457-461

  Abstract

  A prospective study to evaluate the iron dosage needed to restore serum iron levels was performed on patients receiving prolonged total parenteral nutrition (TPN). Intravenous iron intakes of 0, 25, 87.5, and 175 mg/wk were sequentially studied. No untoward responses were seen in 42 patients studied for 2758 patient days. When compared to pre-TPN levels, serum iron levels increased significantly with increasing iron dosage (p less than 0.002). In every single patient at the two highest dosage levels, serum iron levels at 3 wk rose from the pre-TPN level. Hemoglobin, reticulocyte count, transfusion requirement, total iron binding capacity, and red cell indices were not affected by iron dosage. There was no increased incidence of sepsis in patients who received increasing iron dosage. Both the 87.5 and 175 mg/wk iron doses increased serum iron levels from pre-TPN values, but the highest dose increased serum iron levels above the normal range in 80% of patients after 3 wk of administration allowing us to recommend the 87.5 mg/wk dose.

  View details for Web of Science ID A1983RJ19600004

  View details for PubMedID 6417364

• MUSCLE MASS AND ITS RELATIONSHIP TO TUMOR MASS AND ACTIVITY SURGICAL FORUM NORTON, J. A., Moley, J. F., Morrison, S. 1983; 34: 425-427

  View details for Web of Science ID A1983RX76000170

• EFFECTS OF EXOGENOUS INSULIN ADMINISTRATION ON FOOD-INTAKE, BODY-WEIGHT CHANGE, AND TUMOR DOUBLING TIME SURGICAL FORUM Moley, J. F., Morrison, S., NORTON, J. A. 1983; 34: 91-93

  View details for Web of Science ID A1983RX76000036

• ASPIRATION OF ENLARGED PARATHYROID-GLANDS FOR PARATHYROID-HORMONE ASSAY RADIOLOGY DOPPMAN, J. L., Krudy, A. G., Marx, S. J., Saxe, A., Schneider, P., NORTON, J. A., Spiegel, A. M., Downs, R. W., Schaaf, M., Brennan, M. E., Schneider, A. B., AURBACH, G. D. 1983; 148 (1): 31-35

  Abstract

  Enlarged parathyroid glands were percutaneously aspirated under computed tomographic (CT) control in 7 patients, and levels of parathyroid hormone (PTH) and human thyroglobulin (HTg) were measured. All 7 patients had high levels of PTH in at least 1 specimen. It is concluded that the measurement of high concentrations of PTH in the aspirate from a cervical or mediastinal mass, with CT documentation of needle position, provides absolute localization of parathyroid masses.

  View details for Web of Science ID A1983QV03900006

  View details for PubMedID 6856859

• CAPACITANCE PLETHYSMOGRAPHY - VALIDATION IN AN EXVIVO HUMAN LIMB MODEL JOURNAL OF SURGICAL RESEARCH NORTON, J. A., Burt, M. E., Brennan, M. F. 1982; 32 (2): 127-129

  View details for Web of Science ID A1982NE33500005

  View details for PubMedID 7057629

• THE INFLUENCE OF TUMOR-BEARING ON PROTEIN-METABOLISM IN THE RAT JOURNAL OF SURGICAL RESEARCH NORTON, J. A., Shamberger, R., Stein, T. P., Milne, G. W., Brennan, M. F. 1981; 30 (5): 456-462

  View details for Web of Science ID A1981LW89400006

  View details for PubMedID 7242064

• GLUCOSE DISPOSAL AND GLUCONEOGENESIS FROM ALANINE IN TUMOR-BEARING FISCHER-344 RATS JOURNAL OF THE NATIONAL CANCER INSTITUTE Lowry, S. F., Foster, D. M., NORTON, J. A., Berman, M., Brennan, M. F. 1981; 66 (4): 653-658

  Abstract

  For the study of glucose carbon recycling and incorporation of carbon atoms from plasma glucose, [3-3H]glucose and [U-14C]alanine were injected into inbred non-tumor-bearing (NTB) and tumor-bearing (TB) male F344 rats. The glucose and alanine kinetics were determined in relation to antecedent food intake and carcass weight loss. Whereas fed NTB and TB rats appropriately experienced reduced glucose disposal with decreased food intake (0.99 vs. 0.29 mg/min -100 g(-1) compared wtih observations in starved NTB rats), starved TB rats exhibited increased glucose utilization. Both fully fed and cachectic TB groups exhibited increased isotopic carbon recycling compared to the carbon recycling of NTB control groups, whereas starved TB rats did not demonstrate increased recycling compared to the carbon recycling (27% of C-atoms recycled). These findings suggest that alterations of glucose turnover, carbon recycling, and gluconeogenesis in the fed host parallel hypophagia and weight loss, regardless of TB status.

  View details for Web of Science ID A1981LL70100010

  View details for PubMedID 6939912

• LOCALIZATION AND RESECTION OF CLINICALLY INAPPARENT MEDULLARY CARCINOMA OF THE THYROID SURGERY NORTON, J. A., DOPPMAN, J. L., Brennan, M. F. 1980; 87 (6): 616-622

  Abstract

  Seven patients who, following thyroidectomy for medullary carcinoma of the thyroid (MCT) had elevated peripheral basal or stimulated plasma calcitonin (CT) levels but no other evidence of disease, were prospectively studied to determine if disease could be localized by selective venous catheterization with pentagastrin stimulation. Disease was correctly localized to a surgically resectable area of the neck in every case and removed with low morbidity rates. Postoperative CT levels decreased in six of seven patients studied, suggesting reduction in tumor burden. One patient had no detectable CT following repeat selective venous catheterization with pentagastrin stimulation. Preoperative and postoperative carcinoembryonic antigen levels changed in a similar manner to CT levels in four of five patients studied. All patients remain alive 6 months to 3 years following the initial operation.

  View details for Web of Science ID A1980JV08900003

  View details for PubMedID 7376073

• GLUCOSE-TURNOVER AND GLUCONEOGENESIS DURING HYPOCALORIC GLUCOSE-INFUSION IN TUMOR-BEARING F344 MALE-RATS JOURNAL OF THE NATIONAL CANCER INSTITUTE Lowry, S. F., NORTON, J. A., GORSCHBOTH, C. M., Brennan, M. F. 1980; 64 (2): 291-296

  Abstract

  Glucose turnover ([3(3)H]glucose) and gluconeogenesis from alanine ([U-14C]alanine) were measured in non-tumor bearing (NTB) and tumor-bearing (TB) inbred F344 male rats during starvation and in response to graded levels of glucose infusion. All groups demonstrated a glucose turnover appropriate to the prevailing steady-state plasma glucose level. Whereas NTB animals exhibited maximal suppression of gluconeogenesis from alanine at infusion rates of 0.39 mg/100 g total body weight/minute, TB animals suppressed alanine-to-glucose conversion only at a glucose infusion rate of 0.71 mg/100 g total body weight/minute. Glucose clearance was consistently higher in TB groups but did not change in either NTB or TB groups during infusion. Blood lactate levels increased in response to glucose infusion only in TB animals. These results suggested that starved TB animals obligately utilized more glucose than did NTB controls but were able to adjust turnover appropriately to plasma glucose levels. However, gluconeogenesis was suppressed only at higher glucose infusion rates in TB rats compared to NTB animals.

  View details for Web of Science ID A1980JF50000012

  View details for PubMedID 6928221

• HUMAN TUMOR-BEARING LIMB - EX-VIVO MODEL SURGERY Burt, M. E., NORTON, J. A., Brennan, M. F. 1980; 87 (2): 128-132

  Abstract

  The present report describes a viable, isolated, perfused, human, tumor-bearing limb model suitable for the study of human host-tumor metabolism. The model is hemodynamically stable with high flow rates (50 cc/kg/min) and low perfusion pressures (mean, 77.2 mm Hg) which are stable over time. Metabolically, the preparation is viable with initial oxygen and glucose uptake 0.88 cc/kg/min and 0.029 mmole/kg/min, respectively. These parameters and lactate concentrations do not change significantly with time.

  View details for Web of Science ID A1980JE84800002

  View details for PubMedID 6928328

• WHOLE-BODY PROTEIN-TURNOVER STUDIES IN NORMAL HUMANS AND MALNOURISHED PATIENTS WITH AND WITHOUT CANCER SURGICAL FORUM NORTON, J. A., Stein, T. P., Brennan, M. F. 1980; 31: 94-96

  View details for Web of Science ID A1980KU26000042

• INVIVO UTILIZATION OF SUBSTRATE BY HUMAN SARCOMA-BEARING LIMBS CANCER NORTON, J. A., Burt, M. E., Brennan, M. F. 1980; 45 (12): 2934-2939

  Abstract

  Human sarcoma-bearing limb substrate utilization was characterized by studying 10 otherwise healthy patients with extremity sarcomas (five osteosarcomas, five soft tissue sarcomas). All patients were studied in the postabsorptive state. Extremity blood flow was measured using a non-invasive capacitance plethysmograph. Percutaneous arterial and venous effluent blood samples from the tumor-bearing (TB) and control extremity were obtained and flux was calculated for free fatty acids (FFA), glucose, and amino acids. The control limb showed a release of amino acids similar to that reported previously. There was a dramatic difference in the TB extremity, which consistently released fewer amino acids. Both the TB and control limbs released FFA at the same rate. A significant difference in glucose uptake between TB and control limbs was noted for soft tissue sarcoma patients but not osteogenic sarcoma patients. The amount extracted correlated with excised tumor size and gluconeogenic amino acid release from the contralateral normal limb. This study suggests that the tumor-bearing limb ignores the inherent conservation mechanisms in the postabsorptive state and continues to utilize substrate, apparently at the expense of host tissues.

  View details for Web of Science ID A1980JW87700005

  View details for PubMedID 6930315

• INFLUENCE OF DIABETES-MELLITUS AND INSULIN-TREATMENT ON PROTEIN-TURNOVER IN THE RAT JOURNAL OF SURGICAL RESEARCH Sloan, G. M., NORTON, J. A., Brennan, M. F. 1980; 28 (5): 442-448

  View details for Web of Science ID A1980JU77400009

  View details for PubMedID 6993790

• MULTIPLE ENDOCRINE NEOPLASIA TYPE-IIB - MOST AGGRESSIVE FORM OF MEDULLARY-THYROID CARCINOMA SURGICAL CLINICS OF NORTH AMERICA NORTON, J. A., FROOME, L. C., Farrell, R. E., Wells, S. A. 1979; 59 (1): 109-118

  View details for Web of Science ID A1979HA35200011

  View details for PubMedID 441904

• COMPARISON OF N-15 FLUX AND NITROGEN-BALANCE WITH CARCASS ANALYSIS DURING ORAL AND IV NUTRITION SURGICAL FORUM NORTON, J. A., Popp, M. B., Brennan, M. F. 1979; 30: 55-57

  View details for Web of Science ID A1979JB37300026

  View details for PubMedID 120030

• EFFECT OF CHRONIC PROTEIN-MALNUTRITION ON HOST-TUMOR COMPOSITION AND GROWTH JOURNAL OF SURGICAL RESEARCH Lowry, S. F., GOODGAME, J. T., NORTON, J. A., Jones, D. C., Brennan, M. F. 1979; 26 (1): 79-86

  View details for Web of Science ID A1979GE11100011

  View details for PubMedID 759729

• EFFECT OF WORK-INDUCED HYPERTROPHY ON SKELETAL-MUSCLE OF TUMOR-BEARING AND NON-TUMOR-BEARING RATS JOURNAL OF APPLIED PHYSIOLOGY NORTON, J. A., Lowry, S. F., Brennan, M. F. 1979; 46 (4): 654-657

  Abstract

  Synergistic muscles (soleus and plantaris) from a gastrocnemius-tenotomized hindlimb were compared to the same muscles in a sham-operated hindlimb in both tumor-bearing and non tumor-bearing rats. In nontumor-bearing animals muscle from the tenotomized hindlimb had a significant increase in wet weight (26%), percent-water (5%), and total nitrogen/muscle (10%) consistent with muscular hypertrophy. In tumor-bearing animals, muscle from the tenotomized hindlimb had a significant increase in wet weight and percent water, but there was no significant difference in total nitrogen/muscle. As the tumor burden increased, the final muscle weight, in both the tenotomized and sham-operated hindlimb, was found to decrease proportionately. Only in animals with large (23% body wt) tumor burdens did hypertrophied muscle weigh significantly less than sham-operated muscle from nontumor-bearing animals. This indicated that, in rats with large tumor burdens, work-induced hypertrophy was unable to preserve muscle mass despite the fact that hypertrophied muscle was 24% heavier than contralateral sham-operated muscle.

  View details for Web of Science ID A1979GS97500005

  View details for PubMedID 457541

• GLUCOSE TURNOVER AND GLUCONEOGENESIS FROM ALANINE IN TUMOR-BEARING ANIMALS SURGICAL FORUM Lowry, S. F., NORTON, J. A., Brennan, M. F. 1978; 29: 140-142

  View details for Web of Science ID A1978GA40500058

  View details for PubMedID 401117

• SEVERE THROMBOCYTOPENIA FOLLOWING INTRA-LESIONAL BCG THERAPY CANCER NORTON, J. A., Shulman, N. R., Corash, L., Smith, R. L., Au, F., Rosenberg, S. A. 1978; 41 (3): 820-826

  View details for Web of Science ID A1978ES84800006

  View details for PubMedID 638969

• EFFECT OF PROTEIN-MALNUTRITION ON HOST-TUMOR COMPOSITION AND GROWTH SURGICAL FORUM Lowry, S. F., GOODGAME, J. T., NORTON, J. A., Jones, D. C., Brennan, M. F. 1977; 28: 143-145

  View details for Web of Science ID A1977ED91100059

  View details for PubMedID 103213