- Cancer > GI Oncology
- Adrenal Cancer
- Carcinoid Tumors
- Carcinoid Tumors - Endocrinology
- Carcinoid Tumors - Surgery
- Endocrine - Surgery
- Endocrinology Surgery
- Esophageal Cancer
- Esophageal Cancer - Thoracic Surgery
- Gastrointestinal Cancers
- Gastrointestinal Cancers - Surgical Oncology
- Gastrointestinal Oncology Surgery
- General Surgery
- Liver Cancer
- Liver Cancer - Surgery
- Multiple Endocrine Neoplasias
- Multiple Endocrine Neoplasias - Surgery
- Osteosarcoma - Surgery
- Pancreas Surgery
- Pancreatic Cancer
- Pancreatic Cancer - Surgery
- Parathyroid Disease
- Parathyroid Disease - Surgery
- Sarcomas - Soft Tissue
- Sarcomas - Soft Tissue - Surgery
- Sarcomas - Surgical Oncology
- Stomach Cancer
- Stomach Cancer - Surgery
- Thyroid Cancers
- Thyroid Cancers - Surgery
Internship:Duke University Medical Center (1974) NC
Residency:Duke University Medical Center (1982) NC
Board Certification: General Surgery, American Board of Surgery (1983)
Fellowship:National Cancer Institute (1979) MD
Medical Education:SUNY Upstate Medical University (1973) NY
Current Research and Scholarly Interests
Interleukin-12 is a Th1 cytokine. It is important in the cell mediated immune response. We are investigating its role as an anti-tumor cytokine to augment the immune response against cancer. We are planning a human trial.
Evaluation of Preexisting Immunity Markers in Human Tumor Tissue Sample
The purpose of this study is to evaluate markers of immune response in human tumor samples.
Stanford is currently not accepting patients for this trial. For more information, please contact Robin Malone Cisco, (650) 724 - 5570.
Phase II Gemcitabine + Fractionated Stereotactic Radiotherapy for Unresectable Pancreatic Adenocarcinoma
This multi-institutional trial aims to evaluate the potential benefit and side effects of adding fractionated stereotactic body radiotherapy/surgery (SBRT) before and after chemotherapy with gemcitabine for locally advanced pancreatic cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, 650-736-0792.
Permission to Collect Blood Over Time for Research
To determine whether biomarkers assessed in blood samples can be used to detect individuals at risk for developing blood clots or worsening of their underlying disease. The ultimate goal of the study is to identify key biomarkers derived from blood that are most characteristic and informative of individuals who will go on to develop a clotting complication.
Identification of Key Blood Molecular Markers for Immunotherapy
To identify unique blood markers in cancer patients so that we can identify patients with evidence of pre-existing immunity who may be a responder to immunotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Kangla Tsung, 650-725-8198.
68Ga DOTA-TATE PET/CT in Somatostatin Receptor Positive Tumors
The primary objective of the study is to evaluate 68Ga-DOTA TATE PET/CT for staging and monitoring response to chemotherapy in patients with carcinoid, neuroendocrine tumors, medullary thyroid cancer and other cancers expressing somatostatin receptors.
Prognostic Value of Baseline Computed Tomography (CT) Perfusion Parameters of Pancreatic Cancer for Patients Undergoing Stereotactic Body Radiotherapy or Surgical Resection
The purpose of this study is first, to determine whether baseline perfusion characteristics of pancreatic cancer, as characterized by CT perfusion studies, can predict tumor response to treatment by stereotactic body radiotherapy (SBRT). The second goal of this study is to determine whether baseline perfusion characteristics in those patients with resectable pancreatic cancer correlate with immunohistologic markers of angiogenesis such as microvessel density and vascular endothelial growth factor (VEGF) expression.
Stanford is currently not accepting patients for this trial. For more information, please contact Lindee Burton, (650) 725 - 4712.
Phase I Dose Escalation of Stereotactic Radiosurgical Boost for Locally Advanced Esophageal Cancer
To study the safety and feasibility of stereotactic radiation dose escalation following neoadjuvant chemotherapy with concurrent conventionally fractionated radiation, by evaluating the acute and late toxicity of treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Ann Columbo, (650) 736 - 0792.
Trilogy Stereotactic Body Radiotherapy for Pancreatic Cancer
This study will assess the efficacy of treating locally advanced pancreatic cancer using Stereotactic Body Radiotherapy (using Trilogy) and Gemcitabine
Stanford is currently not accepting patients for this trial. For more information, please contact Jeff Kim, (650) 498 - 7703.
Cyberknife Radiosurgery for Locally Advanced Pancreatic Cancer
The purpose of the trial is to test the efficacy of combining conventional chemoradiotherapy with radiosurgery for locally advanced pancreas cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Stanford Cancer Clinical Trials Office, (650) 498 - 7061.
Phase 1-2 Vatalanib and Gemcitabine in Advanced Pancreatic Cancer
The purpose of the study is to determine the optimal safe and tolerable dose of gemcitabine in combination with once daily or twice daily dose of PTK/ZK in patients with unresectable pancreatic cancer. The Phase II part of this study planned to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Kaiser, (650) 724 - 0079.
- Independent Studies (5)
IL-12 Augments Antitumor Responses to Cycled Chemotherapy.
Journal of immunotherapy
2015; 38 (4): 137-144
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
2015; 13 (3): 319-325
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.
2015; 6 (4): 2549-2561
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
2015; 22 (2): 573-580
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
- Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast BREAST CANCER RESEARCH AND TREATMENT 2014; 148 (3): 637-644
- Single-versus Multifraction Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma: Outcomes and Toxicity INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 2014; 90 (4): 918-925
- Laparoscopic Transgastric Necrosectomy for the Management of Pancreatic Necrosis JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2014; 219 (4): 735-743
Laparoscopic spleen-preserving distal pancreatectomy: the technique must suit the lesion.
Journal of gastrointestinal surgery
2014; 18 (8): 1445-1451
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 2014; 120 (13): 1920-1931
Pancreatic neuroendocrine tumours: hypoenhancement on arterial phase computed tomography predicts biological aggressiveness
2014; 16 (4): 304-311
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 Web of Science ID 000332989700002
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
2014; 111 (7): 2436-2441
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 Web of Science ID 000331396500018
Reassessment of the Current American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Tumors
JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
2014; 218 (2): 188-195
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 Web of Science ID 000329763900008
Postoperative Serum Amylase Predicts Pancreatic Fistula Formation Following Pancreaticoduodenectomy
JOURNAL OF GASTROINTESTINAL SURGERY
2014; 18 (2): 348-353
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 Web of Science ID 000331379100038
View details for PubMedID 23903930
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
2013; 258 (3): 422-429
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 Web of Science ID 000330463900006
View details for PubMedID 23860199
Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine.
2013; 78 (2): 295-302 e2
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
- Metabolomic-derived novel cyst fluid biomarkers for pancreatic cysts: glucose and kynurenine GASTROINTESTINAL ENDOSCOPY 2013; 78 (2): 295-?
Preexisting antitumor immunity augments the antitumor effects of chemotherapy.
Cancer immunology, immunotherapy : CII
2013; 62 (6): 1061-1071
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
2013; 20 (5): 1631-1638
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 Web of Science ID 000317308200032
View details for PubMedID 23149854
Hospital readmission after a pancreaticoduodenectomy: an emerging quality metric?
2013; 15 (2): 142-148
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 Web of Science ID 000313548400009
View details for PubMedID 23297725
Diagnostic Utility of Metabolomic-Derived Biomarkers for Pancreatic Cysts
LIPPINCOTT WILLIAMS & WILKINS. 2012: 1394-1394
View details for Web of Science ID 000310360500241
- Recurrent Duodenal Stricture Secondary to Untreated Crohn's Disease DIGESTIVE DISEASES AND SCIENCES 2012; 57 (10): 2516-2518
Lymph Nodes and Survival in Pancreatic Neuroendocrine Tumors
ARCHIVES OF SURGERY
2012; 147 (9): 820-827
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 Web of Science ID 000308883700011
View details for PubMedID 22987171
Value of Surgery in Patients With Negative Imaging and Sporadic Zollinger-Ellison Syndrome
ANNALS OF SURGERY
2012; 256 (3): 509-517
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 Web of Science ID 000308670900023
View details for PubMedID 22868363
Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes
2012; 14 (8): 539-547
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 Web of Science ID 000305993800007
View details for PubMedID 22762402
Pancreatic Neuroendocrine Tumors: Radiographic Calcifications Correlate with Grade and Metastasis
ANNALS OF SURGICAL ONCOLOGY
2012; 19 (7): 2295-2303
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 Web of Science ID 000305558000030
View details for PubMedID 22396008
Intensity-Modulated Radiotherapy for Pancreatic Adenocarcinoma
ELSEVIER SCIENCE INC. 2012: E595-E601
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 Web of Science ID 000300980300003
View details for PubMedID 22197234
Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts
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 Web of Science ID 000301923400002
View details for PubMedID 22333441
A Prospective Study of Total Gastrectomy for CDH1-Positive Hereditary Diffuse Gastric Cancer
ANNALS OF SURGICAL ONCOLOGY
2011; 18 (9): 2594-2598
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 Web of Science ID 000294346700027
View details for PubMedID 21424370
Surgical Management of Neuroendocrine Tumors of the Gastrointestinal Tract
2011; 25 (9): 794-803
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 Web of Science ID 000293651000002
View details for PubMedID 21936439
- Ruptured Biliary Cystadenoma Managed by Angiographic Embolization and Interval Partial Hepatectomy DIGESTIVE DISEASES AND SCIENCES 2011; 56 (7): 1949-1953
Pancreatic Endocrine Tumors With Major Vascular Abutment, Involvement, or Encasement and Indication for Resection
ARCHIVES OF SURGERY
2011; 146 (6): 724-732
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 Web of Science ID 000291851500018
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
2011; 35 (2): 228-234
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
2011; 127 (1): 173-180
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 Web of Science ID 000285992100023
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
WILEY-BLACKWELL. 2010: 5179-5187
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 Web of Science ID 000284047400009
View details for PubMedID 20665497
Comparison of Intensity-Modulated Radiotherapy and 3-Dimensional Conformal Radiotherapy as Adjuvant Therapy for Gastric Cancer
JOHN WILEY & SONS INC. 2010: 3943-3952
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 Web of Science ID 000280677100025
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
2010; 14 (8): 1311-1318
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 Web of Science ID 000280260700017
View details for PubMedID 20517651
A NOVEL PRKAR1A MUTATION ASSOCIATED WITH PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE AND THE CARNEY COMPLEX
2010; 16 (2): 198-204
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 Web of Science ID 000277497400011
View details for PubMedID 19833579
INTERFRACTIONAL UNCERTAINTY IN THE TREATMENT OF PANCREATIC CANCER WITH RADIATION
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
2010; 76 (2): 603-607
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 Web of Science ID 000274121500040
View details for PubMedID 19879062
- Solid Pseudopapillary Tumor of the Pancreas: An Unexpected Finding After Minor Abdominal Trauma DIGESTIVE DISEASES AND SCIENCES 2010; 55 (2): 240-241
Appendiceal Mucinous Neoplasms Clinicopathologic Study of 116 Cases With Analysis of Factors Predicting Recurrence
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2009; 33 (10): 1425-1439
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 Web of Science ID 000270399700001
View details for PubMedID 19641451
Surgical Management of Zollinger-Ellison Syndrome; State of the Art
SURGICAL CLINICS OF NORTH AMERICA
2009; 89 (5): 1091-?
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 Web of Science ID 000271782300005
View details for PubMedID 19836486
Major Blood Vessel Reconstruction During Sarcoma Surgery
ARCHIVES OF SURGERY
2009; 144 (9): 817-822
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 Web of Science ID 000269833500004
View details for PubMedID 19797105
The value of surgery for retroperitoneal sarcoma.
2009; 2009: 605840-?
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
2008; 72 (4): 1146-1153
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
2008; 72 (3): 678-686
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 Web of Science ID 000259894300008
View details for PubMedID 18395362
Hereditary diffuse gastric cancer - Implications of genetic testing for screening and prophylactic surgery
2008; 113 (7): 1850-1856
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 Web of Science ID 000259661800013
View details for PubMedID 18798546
Hereditary diffuse gastric cancer: surgery, surveillance and unanswered questions
2008; 4 (4): 553-559
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 10.2217/14796622.214.171.1243
View details for Web of Science ID 000261774900013
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
2008; 32 (6): 799-809
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
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
2008; 247 (3): 501-510
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 Web of Science ID 000253436200016
View details for PubMedID 18376196
Tissue effects after stereotactic body radiotherapy using cyberknife for patients with abdominal malignancies
2008; 20 (1): 69-75
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
SPRINGER. 2008: 88-88
View details for Web of Science ID 000252887900277
- Role of surgery in Zollinger-Ellison syndrome JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2007; 205 (4): S34-S37
CDH1 truncating mutations in the E-cadherin gene - An indication for total gastrectomy to treat hereditary diffuse gastric cancer
ANNALS OF SURGERY
2007; 245 (6): 873-879
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 Web of Science ID 000246873000007
View details for PubMedID 17522512
Surgery for gastrinoma.
Advances in surgery
2007; 41: 165-176
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
Surgery increases survival in patients with gastrinoma
ANNALS OF SURGERY
2006; 244 (3): 410-419
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 Web of Science ID 000240261500009
View details for PubMedID 16926567
Lessons from Coley's Toxin
2006; 15 (1): 25-28
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 Web of Science ID 000240759000003
View details for PubMedID 16814541
- Surgery for primary pancreatic neuroendocrine tumors JOURNAL OF GASTROINTESTINAL SURGERY 2006; 10 (3): 327-331
Surgery for gastrinoma and insulinoma in multiple endocrine neoplasia type 1.
Journal of the National Comprehensive Cancer Network
2006; 4 (2): 148-153
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
2006; 13 (1): 118-124
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 Web of Science ID 000234752000018
View details for PubMedID 16372153
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
2005; 63 (2): 320-323
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 Web of Science ID 000232083700002
View details for PubMedID 16168826
Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor
BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY
2005; 19 (5): 699-704
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 Web of Science ID 000233664500003
View details for PubMedID 16253894
Surgical treatment and prognosis of gastrinoma
BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY
2005; 19 (5): 799-805
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 Web of Science ID 000233664500010
View details for PubMedID 16253901
Computed tomography, endoscopic, laparoscopic, and intra-operative sonography for assessing resectability of pancreatic cancer
2005; 14 (2): 105-113
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 Web of Science ID 000231899500005
View details for PubMedID 16125619
Endocrine tumours of the gastrointestinal tract. Surgical treatment of neuroendocrine metastases.
Best practice & research. Clinical gastroenterology
2005; 19 (4): 577-583
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
JOURNAL OF GASTROINTESTINAL SURGERY
2005; 9 (1): 15-20
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
2004; 136 (6): 1267-1273
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 Web of Science ID 000225874800046
View details for PubMedID 15657586
Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome
ANNALS OF SURGERY
2004; 240 (5): 757-773
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 Web of Science ID 000224739200005
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?
ANNALS OF SURGERY
2004; 239 (5): 617-625
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 Web of Science ID 000221023600008
View details for PubMedID 15082965
Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1
2003; 134 (6): 858-864
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
Management and outcome of patients with sporadic gastrinoma arising in the duodenum
ANNALS OF SURGERY
2003; 238 (1): 42-48
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
Possible primary lymph node gastrinoma: Occurrence, natural history, and predictive factors a prospective study
ANNALS OF SURGERY
2003; 237 (5): 650-657
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
Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome
ANNALS OF SURGERY
2001; 234 (4): 495-505
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
Prognostic value of initial pasting serum gastrin levels in patients with Zollinger-Ellison syndrome
JOURNAL OF CLINICAL ONCOLOGY
2001; 19 (12): 3051-3057
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
2001; 291 (5507): 1298-?
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
Results of heterotopic parathyroid autotransplantation: A 13-year experience
1999; 126 (6): 1042-1048
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
1999; 341 (9): 635-644
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
Analysis of factors associated with longterm (five or more years) cure in patients undergoing operation for Zollinger-Ellison syndrome
1998; 124 (6): 1160-1166
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
Operative management of islet-cell tumors arising in the head of the pancreas
1998; 124 (6): 1056-1061
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
1998; 124 (6): 1145-1152
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
Prospective study of somatostatin receptor scintigraphy and its effect on operative outcome in patients with Zolinger-Ellison syndrome
ANNALS OF SURGERY
1998; 228 (2): 228-238
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
A prospective analysis of the frequency, location, and curability of ectopic (nonpancreaticoduodenal, nonnodal) gastrinoma
1997; 122 (6): 1176-1182
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
Is reoperation for gastrinoma excision indicated in Zollinger-Ellison syndrome?
1996; 120 (6): 1055-1062
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
A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma
ANNALS OF SURGERY
1996; 224 (3): 308-320
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
Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy
ANNALS OF SURGICAL ONCOLOGY
1996; 3 (2): 198-203
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
- PLASMA PROINSULIN-LIKE COMPONENT IN INSULINOMA - A 25-YEAR EXPERIENCE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 1995; 80 (10): 2884-2887
LOCALIZATION OF INSULINOMAS TO REGIONS OF THE PANCREAS BY INTRAARTERIAL STIMULATION WITH CALCIUM
ANNALS OF INTERNAL MEDICINE
1995; 123 (4): 269-273
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
PALLIATIVE OPERATIONS FOR PATIENTS WITH UNRESECTABLE ENDOCRINE NEOPLASIA
SURGICAL CLINICS OF NORTH AMERICA
1995; 75 (3): 525-538
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
LOCALIZATION AND OPERATIVE MANAGEMENT OF UNDESCENDED PARATHYROID ADENOMAS IN PATIENTS WITH PERSISTENT PRIMARY HYPERPARATHYROIDISM
1994; 116 (6): 982-990
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
SURGERY IN ZOLLINGER-ELLISON SYNDROME ALTERS THE NATURAL-HISTORY OF GASTRINOMA
ANNALS OF SURGERY
1994; 220 (3): 320-330
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
CONTROVERSIES IN SURGICAL THERAPY FOR APUDOMAS
SEMINARS IN SURGICAL ONCOLOGY
1993; 9 (5): 437-442
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
USE OF INTRAOPERATIVE ULTRASONOGRAPHY TO LOCALIZE ISLET-CELL TUMORS
WORLD JOURNAL OF SURGERY
1993; 17 (4): 448-454
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
INTRAARTERIAL CALCIUM STIMULATION TEST FOR DETECTION OF INSULINOMAS
WORLD JOURNAL OF SURGERY
1993; 17 (4): 439-443
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
THE ROLE OF TUMOR-NECROSIS-FACTOR IN THE TOXICITY AND THE ANTINEOPLASTIC ACTIVITY OF INTERLEUKIN-2 IMMUNOTHERAPY
TUMOR NECROSIS FACTOR : MOLECULAR AND CELLULAR BIOLOGY AND CLINICAL RELEVANCE
View details for Web of Science ID A1993BY26K00031
RECOMBINANT INTERLEUKIN-1 RECEPTOR ANTAGONIST (IL-1RA) - EFFECTIVE THERAPY AGAINST GRAM-NEGATIVE SEPSIS IN RATS
1992; 112 (2): 188-194
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
CURATIVE RESECTION IN ZOLLINGER-ELLISON SYNDROME - RESULTS OF A 10-YEAR PROSPECTIVE-STUDY
ANNALS OF SURGERY
1992; 215 (1): 8-18
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
The use of intraoperative ultrasound during cancer surgery.
Important advances in oncology
View details for PubMedID 1582672
RESULTS OF A PROSPECTIVE STRATEGY TO DIAGNOSE, LOCALIZE, AND RESECT INSULINOMAS
1991; 110 (6): 989-997
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
INSULINOMAS - LOCALIZATION WITH SELECTIVE INTRAARTERIAL INJECTION OF CALCIUM
1991; 178 (1): 237-241
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
LOCALIZATION AND SURGICAL-TREATMENT OF OCCULT INSULINOMAS
ANNALS OF SURGERY
1990; 212 (5): 615-620
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
UNDESCENDED PARATHYROID ADENOMA - AN IMPORTANT ETIOLOGY FOR FAILED OPERATIONS FOR PRIMARY HYPERPARATHYROIDISM
WORLD JOURNAL OF SURGERY
1990; 14 (3): 342-348
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
THE ROLE OF SURGERY IN THE MANAGEMENT OF ISLET CELL TUMORS
GASTROENTEROLOGY CLINICS OF NORTH AMERICA
1989; 18 (4): 805-830
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
REVERSAL OF THE TOXIC EFFECTS OF CACHECTIN BY CONCURRENT INSULIN ADMINISTRATION
AMERICAN JOURNAL OF PHYSIOLOGY
1989; 256 (6): E725-E731
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
- TOLERANCE TO TUMOR NECROSIS FACTOR NUTRITION 1989; 5 (2): 131-135
- LOCALIZATION AND RESECTION OF INSULINOMAS AND GASTRINOMAS JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 1988; 259 (24): 3601-3605
INTRAOPERATIVE ULTRASONOGRAPHIC LOCALIZATION OF ISLET CELL TUMORS - A PROSPECTIVE COMPARISON TO PALPATION
ANNALS OF SURGERY
1988; 207 (2): 160-168
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
- THE USE OF HIGH-RESOLUTION ULTRASOUND TO LOCATE PARATHYROID TUMORS DURING REOPERATIONS FOR PRIMARY HYPERPARATHYROIDISM WORLD JOURNAL OF SURGERY 1987; 11 (5): 579-585
- THE USE OF HIGH-RESOLUTION INTRAOPERATIVE ULTRASOUND TO LOCALIZE GASTRINOMAS - AN INITIAL REPORT OF A PROSPECTIVE-STUDY WORLD JOURNAL OF SURGERY 1987; 11 (5): 648-653
INFERIOR THYROID ARTERY ARISING FROM COMMON CAROTID-ARTERY WITH ABERRANT RIGHT SUBCLAVIAN ARTERY
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
1987; 10 (3): 150-152
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
LOCALIZATION OF PARATHYROID ADENOMAS IN PATIENTS WHO HAVE UNDERGONE SURGERY .2. INVASIVE PROCEDURES
1987; 162 (1): 138-141
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
1987; 162 (1): 133-137
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
1986; 105 (6): 841-847
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
PROSPECTIVE-STUDY OF GASTRINOMA LOCALIZATION AND RESECTION IN PATIENTS WITH ZOLLINGER-ELLISON SYNDROME
ANNALS OF SURGERY
1986; 204 (4): 468-479
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 1986; 10 (4): 631-639
- DEMONSTRATION OF AN ANGIOGRAPHICALLY HYPOVASCULAR INSULINOMA WITH INTRAARTERIAL DYNAMIC CT AMERICAN JOURNAL OF ROENTGENOLOGY 1985; 144 (3): 555-556
PARATHYMIC PARATHYROID - CT, US, AND ANGIOGRAPHIC FINDINGS
1985; 157 (2): 419-423
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
1984; 35 (2): 113-118
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
INTRAOPERATIVE URINARY CYCLIC ADENOSINE-MONOPHOSPHATE AS A GUIDE TO SUCCESSFUL REOPERATIVE PARATHYROIDECTOMY
ANNALS OF SURGERY
1984; 200 (4): 389-395
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
1984; 142 (1): 175-178
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
1984; 152 (1): 207-208
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
1984; 200 (4): 396-404
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
1984; 142 (4): 693-695
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
1984; 143 (3): 585-589
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
1983; 148 (1): 23-29
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
ASPIRATION OF ENLARGED PARATHYROID-GLANDS FOR PARATHYROID-HORMONE ASSAY
1983; 148 (1): 31-35
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
LOCALIZATION AND RESECTION OF CLINICALLY INAPPARENT MEDULLARY CARCINOMA OF THE THYROID
1980; 87 (6): 616-622
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