Daniel James Delitto, MD, PhD, FACS

All Publications

• Postoperative hepatic insufficiency despite preoperative portal vein embolization: Not just about the volumetrics. Surgery Li, A. Y., Ahmad, M. U., Sofilos, M. C., Lee, R. M., Maithel, S. K., Lee, T. C., Chadalavada, S., Shah, S. A., Acher, A. W., Abbott, D. E., Wong, P., Kessler, J., Melstrom, L. G., Kirks, R., Rocha, F. G., Delitto, D. J., Lee, B., Visser, B. C., Poultsides, G. A. 2025; 182: 109345

  Abstract

  Future liver remnant hypertrophy is the primary endpoint of portal vein embolization before major hepatectomy. However, even when adequate future liver remnant is achieved, postoperative hepatic insufficiency is not universally averted. We aimed to identify preoperative risk factors of postoperative hepatic insufficiency despite the use of portal vein embolization.Patients who underwent portal vein embolization followed by major hepatectomy at 6 academic medical centers were retrospectively reviewed. Postoperative hepatic insufficiency was defined as postoperative peak bilirubin >7 mg/dL. Preoperative variables associated with postoperative hepatic insufficiency were analyzed.From 2008 to 2019, 164 patients underwent portal vein embolization followed by major hepatectomy. Twenty (12%) patients developed postoperative hepatic insufficiency. On univariate analysis, postoperative hepatic insufficiency was associated with older age, performance status, preoperative biliary drainage, smaller pre- and post-portal vein embolization future liver remnant volumes, diagnosis of cholangiocarcinoma/gallbladder cancer, and preoperative cholangitis. There was significant future liver remnant hypertrophy noted even in the setting of postoperative hepatic insufficiency (from 27% to 39%); however, degree of hypertrophy >5% (100% vs 93%, P = .6) and kinetic growth rate >2%/week (95% vs 82%, P = .3) did not differ between the postoperative hepatic insufficiency and non-postoperative hepatic insufficiency groups. On multivariate analysis, the diagnosis of cholangiocarcinoma/gallbladder cancer and preoperative cholangitis (postoperative hepatic insufficiency incidence 34% and 62%, respectively), but not future liver remnant volumetrics, were independently associated with postoperative hepatic insufficiency. Postoperative hepatic insufficiency raised post-hepatectomy 90-day mortality from 3.5% to 45% and hospitalization from 7 days to 16 days (both P < .001).Postoperative hepatic insufficiency still occurs in 12% of patients after major hepatectomy despite preoperative portal vein embolization. In addition to traditional volumetric information, surgeons should be aware of preoperative cholangitis and cholangiocarcinoma/gallbladder cancer as powerful predictors of this fatal complication.

  View details for DOI 10.1016/j.surg.2025.109345

  View details for PubMedID 40157125

• Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models. Science translational medicine Foster, D. S., Guo, J. L., Meany, E., Berry, C. E., Fallah, M., Korah, M., Januszyk, M., Bauer-Rowe, K. E., Lopez, D. M., Williams, C. M., Song, R., Griffin, M., Kim, A., Chinta, M. S., Marshall, C. D., Wan, D. C., Hyun, J. S., Wernig, G., Norton, J. A., Appel, E. A., Delitto, D., Longaker, M. T. 2025; 17 (789): eadp9957

  Abstract

  Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224-hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224-hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224-hydrogel. The JUN-inhibiting T-5224-hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.

  View details for DOI 10.1126/scitranslmed.adp9957

  View details for PubMedID 40073155

• Biochemical, Radiographic, or Pathologic Response to Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: Which is Best? Annals of surgery Ahmad, M. U., Javadi, C. S., Chang, J. D., Forgó, E., Delitto, D. J., Dua, M. M., Fisher, G. A., Heestand, G. M., Chang, D. T., Pollom, E., Vitzthum, L. K., Kirane, A., Lee, B., Visser, B. C., Norton, J. A., Poultsides, G. A. 2024

  Abstract

  To examine the optimal method of assessing response to neoadjuvant therapy (NAT) in operable pancreatic ductal adenocarcinoma (PDAC) patients.PDAC response to NAT is measured with biochemical, radiographic and pathologic parameters, which can often be discordant with each other.PDAC patients undergoing resection after NAT at a single institution were retrospectively analyzed. Tumor response was assessed using pre-/post-NAT Carbohydrate Antigen 19-9 (CA 19-9) levels, radiographic decrease in tumor diameter, and pathologic Tumor Regression Grade (TRG). The association of these factors with overall survival (OS) was compared using Kaplan-Meier, Cox regression, and recursive partitioning analysis (RPA), a machine learning technique that can validate prediction models for complex hierarchical relationships.From 2011 to 2022, 225 patients underwent pancreatectomy after NAT (Folfirinox, 70%; Gem+nab-paclitaxel, 19%; radiation, 18%). Almost half required vascular resection (portal vein, 39%; celiac axis 8%). Improved OS was observed after CA 19-9 decrease >50% (32 vs. 24 mo, P=0.0028), but not after major pathologic (TRG 0-1, P=0.067) or radiographic response (tumor diameter decrease >30%, P=0.89). However, RPA identified that the co-existence of biochemical and major pathologic response (achieved in 9% of patients) was associated with the longest OS (40 mo, P=0.0086). This optimal dual response combination was more commonly observed after neoadjuvant radiotherapy was used after systemic chemotherapy (45% vs. 11%, P<0.001).CA19-9 response to NAT alone is not enough to identify long-term post-resection PDAC survivors. The co-existence of CA19-9 and major pathologic response was predictive of the most optimal survival outcome.

  View details for DOI 10.1097/SLA.0000000000006609

  View details for PubMedID 39676639

• Defining the Tumor Microenvironment Across Thousands of Tumors Lu, J., Korah, M., Jing, S. L., Guo, J. L., Berry, C., Wan, D. C., Norton, J. A., Delitto, D., Januszyk, M., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2024: S440-S441

  View details for Web of Science ID 001348680703081

• Creeping Fat-Derived Fibroblasts Promote Intestinal Fibrosis in Crohn's Disease Bauer-Rowe, K. E., Pham, B., Korah, M., Guo, J. L., Liang, N., Griffin, M., Delitto, D., Longaker, M. T., Hyun, J. S. LIPPINCOTT WILLIAMS & WILKINS. 2024: S346

  View details for Web of Science ID 001348680702165

• Utilizing Single Cell Transcriptomics to Delineate Cancer Associated Fibroblasts in Sarcomas Korah, M., Lu, J., Jing, S. L., Berry, C., Wan, D. C., Norton, J. A., Delitto, D., Januszyk, M., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2024: S460-S461

  View details for Web of Science ID 001348680703121

• Organoid Assessment of IL-1 Inhibition in Human Pancreatic Ductal Adenocarcinoma Morgan, A., Griffin, M., Guo, C., Parker, J. L., Januszyk, M., Foster, D. S., Poultsides, G. A., Delitto, D., Longaker, M. T., Norton, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2024: S451-S452

  View details for Web of Science ID 001348680703104

• Simultaneous Multiomic Single-Cell Analysis Reveals Gene Regulatory Mechanism of Interleukin-Based Immunotherapy in Pancreatic Ductal Adenocarcinoma Guo, C., Morgan, A., Griffin, M., Parker, J. L., Januszyk, M., Foster, D., Delitto, D., Longaker, M. T., Norton, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2024: S456

  View details for Web of Science ID 001348680703113

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

  Abstract

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

  View details for DOI 10.3390/cancers16203467

  View details for PubMedID 39456561

• Circulating Tumor DNA in the Monitoring of Soft Tissue Sarcoma Treatment and Recurrence. Annals of surgical oncology Sun, B. J., Li, A. Y., Hur, D. G., Zhou, M., Poultsides, G. A., Delitto, D. J., Lee, B. 2024

  View details for DOI 10.1245/s10434-024-15902-9

  View details for PubMedID 39060690

  View details for PubMedCentralID 10119774

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

  Abstract

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

  View details for DOI 10.1089/ten.TEA.2024.0039

  View details for PubMedID 38874979

• Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative JOURNAL OF SURGICAL ONCOLOGY Makris, E. A., Tran, T. B., Delitto, D. J., Lee, B., Ethun, C. G., Grignol, V., Howard, J., Bedi, M., Gamblin, T., Tseng, J., Roggin, K. K., Chouliaras, K., Votanopoulos, K., Cullinan, D., Fields, R. C., Cardona, K., Poultsides, G., Kirane, A. 2024

  Abstract

  Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS.From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed.Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation.For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

  View details for DOI 10.1002/jso.27620

  View details for Web of Science ID 001194891800001

  View details for PubMedID 38562002

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

  View details for Web of Science ID 001185577500451

• Single cell pharmacogenic pipeline identifies novel opportunities in uterine leiomyosarcoma Daniel, S. K., Foster, D., Nosrati, F., Korah, M., Fallah, M., Sun, B. J., Loftus, T., Hu, D., Dua, M., Visser, B., Poultsides, G., Kirane, A., Longaker, M., Ganjoo, K., Lee, B., Delitto, D. SPRINGER. 2024: S42

  View details for Web of Science ID 001185577500085

• Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer research Zabransky, D. J., Chhabra, Y., Fane, M. E., Kartalia, E., Leatherman, J. M., Hüser, L., Zimmerman, J. W., Delitto, D., Han, S., Armstrong, T. D., Guinn, S., Pramod, S., Thompson, E. D., Hughes, S. J., O'Connell, J., Egan, J. M., Jaffee, E. M., Weeraratna, A. T. 2024

  Abstract

  Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in non-malignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Since fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, while aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging.

  View details for DOI 10.1158/0008-5472.CAN-24-0086

  View details for PubMedID 38330147

• Overexpression of Senescence-Associated Genes, SFN and CDC6, Correlates with Poor Survival in Patients with Stage II Hepatocellular Carcinoma (HCC) Badshah, J., Subramanian, S., Melcher, M., Sasaki, K., Visser, B., Delitto, D., Pruett, T., Niedernhofer, L., Kirchner, V. ELSEVIER SCIENCE INC. 2024: S64

  View details for Web of Science ID 001162078700140

• ASO Visual Abstract: Patterns of Recurrence after Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation. Annals of surgical oncology Hui, C., Ewongwo, A., Lau, B., Fisher, G., Delitto, D., Poultsides, G., Ho, Q. A., Rahimy, E., Pollom, E., Chang, D. T., Vitzthum, L. K. 2023

  View details for DOI 10.1245/s10434-023-14475-3

  View details for PubMedID 37875741

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

  Abstract

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

  View details for DOI 10.3791/65831

  View details for PubMedID 37902368

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

  Abstract

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

  View details for DOI 10.1016/j.xcrm.2023.101248

  View details for PubMedID 37865092

• Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation. Annals of surgical oncology Hui, C., Ewongwo, A., Lau, B., Fisher, G., Delitto, D., Poultsides, G., Ho, Q., Rahimy, E., Pollom, E., Chang, D. T., Vitzthum, L. K. 2023

  Abstract

  BACKGROUND: Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy.PATIENTS AND METHODS: We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence.RESULTS: A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR.CONCLUSIONS: Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.

  View details for DOI 10.1245/s10434-023-14350-1

  View details for PubMedID 37755563

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

  View details for Web of Science ID 001046841200059

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

  Abstract

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

  View details for DOI 10.1016/j.ccell.2022.09.015

  View details for PubMedID 36270275

• Postoperative Chemotherapy is Associated with Improved Survival in Patients with Node-Positive Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy. World journal of surgery Ivey, G. D., Shoucair, S., Delitto, D. J., Habib, J. R., Kinny-Koster, B., Shubert, C. R., Lafaro, K. J., Cameron, J. L., Burns, W. R., Burkhart, R. A., Thompson, E. L., Narang, A., Zheng, L., Wolfgang, C. L., He, J. 2022

  Abstract

  BACKGROUND: Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is unclear.METHODS: Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015-2019) were identified. Patients who received less than 2months of neoadjuvant chemotherapy or died within 90days from surgery were excluded.RESULTS: A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4months, P=0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 & 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5months, P<0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9months; P=0.406).CONCLUSION: Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.

  View details for DOI 10.1007/s00268-022-06667-x

  View details for PubMedID 35861852

• First Recurrence of Synovial Sarcoma Presenting With Solitary Pancreatic Mass CUREUS JOURNAL OF MEDICAL SCIENCE Narayan, R. R., Charville, G. W., Delitto, D., Ganjoo, K. N. 2022; 14 (6)

  View details for DOI 10.7759/cureus.26356

  View details for Web of Science ID 000818961000017

• Age-related changes in pancreatic fibroblasts promote growth and progression of pancreatic cancer Zabransky, D. J., Chhabra, Y., Fane, M. E., Delitto, D., Zimmermann, J. W., Jaffee, E. M., Weeraratna, A. T. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509508158

• First Recurrence of Synovial Sarcoma Presenting With Solitary Pancreatic Mass. Cureus Narayan, R. R., Charville, G. W., Delitto, D., Ganjoo, K. N. 2022; 14 (6): e26356

  Abstract

  Synovial sarcoma usually presents in the lower extremities and metastasizes to the lungs; however, unusual patterns of recurrence can occur. For patients with recurrent synovial sarcoma to a proximal peripancreatic lymph node, a pancreaticoduodenectomy or Whipple procedure is the best option for a cure. Lymph node metastasis from synovial sarcoma is exceptionally rare, and data guiding the use of the Whipple procedure for curative resection of metastatic synovial sarcoma are even more sparse. In this report, we describe the management of a patient with metastatic synovial sarcoma to a proximal peripancreatic lymph node with a pancreaticoduodenectomy.

  View details for DOI 10.7759/cureus.26356

  View details for PubMedID 35903565

  View details for PubMedCentralID PMC9326242

• Surgical solution for a paraneoplastic neurodegenerative disorder. Trauma surgery & acute care open Muhammad, H., Strayve, D. G., Narayan, R. R., Blayney, D. W., Delitto, D. 2022; 7 (1): e000928

  View details for DOI 10.1136/tsaco-2022-000928

  View details for PubMedID 35574257

  View details for PubMedCentralID PMC9062873

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

  View details for Web of Science ID 000789811800041

• Surgical solution for a paraneoplastic neurodegenerative disorder TRAUMA SURGERY & ACUTE CARE OPEN Muhammad, H., Strayve, D. G., Narayan, R. R., Blayney, D. W., Delitto, D. 2022; 7 (1)

  View details for DOI 10.1136/tsaco-2022-000928

  View details for Web of Science ID 000790371200001

• Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection. Oncoimmunology Delitto, D., Zabransky, D. J., Chen, F., Thompson, E. D., Zimmerman, J. W., Armstrong, T. D., Leatherman, J. M., Suri, R., Lopez-Vidal, T. Y., Huff, A. L., Lyman, M. R., Guinn, S. R., Baretti, M., Kagohara, L. T., Ho, W. J., Azad, N. S., Burns, W. R., He, J., Wolfgang, C. L., Burkhart, R. A., Zheng, L., Yarchoan, M., Zaidi, N., Jaffee, E. M. 2021; 10 (1): 2001159

  Abstract

  Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.

  View details for DOI 10.1080/2162402X.2021.2001159

  View details for PubMedID 34777919

  View details for PubMedCentralID PMC8583296

• IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy CANCERS Callaway, C. S., Delitto, A. E., D'Lugos, A. C., Patel, R., Nosacka, R. L., Delitto, D., Deyhle, M. R., Trevino, J. G., Judge, S. M., Judge, A. R. 2019; 11 (12)

  Abstract

  Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2.​.

  View details for DOI 10.3390/cancers11121863

  View details for Web of Science ID 000507382100042

  View details for PubMedID 31769424

  View details for PubMedCentralID PMC6966692

• GSK3 suppression upregulates β-catenin and c-Myc to abrogate KRas-dependent tumors. Nature communications Kazi, A., Xiang, S., Yang, H., Delitto, D., Trevino, J., Jiang, R. H., Ayaz, M., Lawrence, H. R., Kennedy, P., Sebti, S. M. 2018; 9 (1): 5154

  Abstract

  Mutant KRas is a significant driver of human oncogenesis and confers resistance to therapy, underscoring the need to develop approaches that disable mutant KRas-driven tumors. Because targeting KRas directly has proven difficult, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. Here we show that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but is dispensable for mutant KRas-independent tumors. Further, inhibiting phosphorylation of GSK3 substrates c-Myc on T58 and β-catenin on S33/S37/T41 and their subsequent upregulation contribute to the antitumor activity of GSK3 inhibition. Importantly, GSK3 blockade inhibits the in vivo growth of G12D, G12V, and G12C mutant KRas primary and metastatic patient-derived xenografts from pancreatic cancer patients who progressed on chemo- and radiation therapies. This discovery opens new avenues to target mutant KRas-dependent cancers.

  View details for DOI 10.1038/s41467-018-07644-6

  View details for PubMedID 30514931

  View details for PubMedCentralID PMC6279809

• Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant Therapy. Journal of the National Cancer Institute Delitto, D., George, T. J., Loftus, T. J., Qiu, P., Chang, G. J., Allegra, C. J., Hall, W. A., Hughes, S. J., Tan, S. A., Shaw, C. M., Iqbal, A. 2018; 110 (5): 460-466

  Abstract

  Neoadjuvant chemoradiation is currently standard of care in stage II-III rectal cancer, resulting in tumor downstaging for patients with treatment-responsive disease. However, the prognosis of the downstaged patient remains controversial. This work critically analyzes the relative contribution of pre- and post-therapy staging to the anticipated survival of downstaged patients.The National Cancer Database (NCDB) was queried for patients with rectal cancer treated with transabdominal resection between 2004 and 2014. Stage II-III patients downstaged with neoadjuvant radiation were compared with stage I patients treated with definitive resection alone. Patients with positive surgical margins were excluded. Overall survival was evaluated using both Kaplan-Meier analyses and Cox proportional hazards models. All statistical tests were two-sided.A total of 44 320 patients were eligible for analysis. Survival was equivalent for patients presenting with cT1N0 disease undergoing resection (mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with those downstaged to pT1N0 from both cT3N0 (mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12) and cT3N1 disease (mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22). Survival statistically significantly improved in patients downstaged to pT2N0 from cT3N0 disease (mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001) and cT3N1 (mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001), compared with cT2N0 patients undergoing resection alone (mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months). Multiple survival analysis confirmed that final pathologic stage dictated long-term outcomes in patients undergoing neoadjuvant radiation (hazard ratio [HR] of pT2 = 1.24, 95% CI = 1.10 to 1.41; HR of pT3 = 1.81, 95% CI = 1.61 to 2.05; HR of pT4 = 2.72, 95% CI = 2.28 to 3.25, all P ≤ .001 vs pT1; HR of pN1 = 1.50, 95% CI = 1.41 to 1.59; HR of pN2 = 2.17, 95% CI = 2.00 to 2.35, both P < .001 vs pN0); while clinical stage at presentation had little to no predictive value (HR of cT2 = 0.81, 95% CI = 0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI = 0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI = 0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI = 0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI = 0.86 to 1.08, P = .48 vs cN0).Survival in patients with rectal cancer undergoing neoadjuvant radiation is driven by post-therapy pathologic stage, regardless of pretherapy clinical stage. These data will further inform prognostic discussions with patients.

  View details for DOI 10.1093/jnci/djx228

  View details for PubMedID 29165692

  View details for PubMedCentralID PMC6279292

• Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment. Cancer research Delitto, D., Delitto, A. E., DiVita, B. B., Pham, K., Han, S., Hartlage, E. R., Newby, B. N., Gerber, M. H., Behrns, K. E., Moldawer, L. L., Thomas, R. M., George, T. J., Brusko, T. M., Mathews, C. E., Liu, C., Trevino, J. G., Hughes, S. J., Wallet, S. M. 2017; 77 (3): 672-683

  Abstract

  Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the cross-talk between pancreatic cancer and its TAS in primary human cell culture models. Upon exposure of TAS to pancreatic cancer cell-conditioned media, we documented robust secretion of IL6 and IL8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T-cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared with healthy controls. The TAS response also directly suppressed CD8+ T-cell-mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Res; 77(3); 672-83. ©2016 AACR.

  View details for DOI 10.1158/0008-5472.CAN-16-1765

  View details for PubMedID 27864347

  View details for PubMedCentralID PMC5290036

• Targeting tumor tolerance: A new hope for pancreatic cancer therapy? Pharmacology & therapeutics Delitto, D., Wallet, S. M., Hughes, S. J. 2016; 166: 9-29

  Abstract

  With a 5-year survival rate of just 8%, pancreatic cancer (PC) is projected to be the second leading cause of cancer deaths by 2030. Most PC patients are not eligible for surgery with curative intent upon diagnosis, emphasizing a need for more effective therapies. However, PC is notoriously resistant to chemoradiation regimens. As an alternative, immune modulating strategies have recently achieved success in melanoma, prompting their application to other solid tumors. For such therapeutic approaches to succeed, a state of immunologic tolerance must be reversed in the tumor microenvironment and that has been especially challenging in PC. Nonetheless, knowledge of the PC immune microenvironment has advanced considerably over the past decade, yielding new insights and perspectives to guide multimodal therapies. In this review, we catalog the historical groundwork and discuss the evolution of the cancer immunology field to its present state with a specific focus on PC. Strategies currently employing immune modulation in PC are reviewed, specifically highlighting 66 clinical trials across the United States and Europe.

  View details for DOI 10.1016/j.pharmthera.2016.06.008

  View details for PubMedID 27343757