Daniel James Delitto, MD, PhD, FACS

All Publications

• Predicting Targeted and Immunotherapeutic Response Outcomes in Melanoma With Single-Cell Raman Spectroscopy and Artificial Intelligence. JCO precision oncology Chang, K., Serasanambati, M., Ogunlade, B., Hsu, H. J., Agolia, J., Stiber, A., Gu, J., Chadokiya, J., Rodriguez, G. E., Singh, P., Sharma, S., Gonçalves, A., Verma, O., Safir, F., Vu, N., Garcia, K. C., Delitto, D., Kirane, A., Dionne, J. A. 2026; 10 (9): e2500591

  Abstract

  Identifying reliable predictors of immunotherapeutic response in melanoma remains an outstanding challenge. Existing transcriptomic and proteomic profiling methods for the tumor-immune microenvironment are costly and may not faithfully capture modifications actively affecting tumor behavior. Here, we present a nondestructive, single-cell approach combining Raman spectroscopy and machine learning (ML) that enables rapid cell profiling and therapeutic response prediction.We analyzed single-cell Raman spectra of mouse and human melanoma cell lines alongside nine samples derived from patients with melanoma with known resistance profiles to targeted and immunotherapeutic inhibitors bemcentinib, cabozantinib, dabrafenib, and nivolumab and a combination of nivolumab and relatlimab. We assessed cell phenotyping classification and treatment resistance using random forests and feature importance analysis. For patient samples, we constructed a two-stage evaluation workflow to determine clinical drug resistance through aggregated single-cell predictions and identified corresponding highly variant spectral signatures using computational methods adapted from single-cell RNA sequencing methods.In cell lines, our approach achieved >96% differentiation accuracy across tumor microenvironment cell types and induced functional phenotypes. Persistent (drug-resistant) cells formed subclusters based on genetic mutations rather than sample origin, with Raman signatures reflecting biochemical changes relevant to therapeutic pathways. For patient samples, our workflow correctly inferred resistance likelihoods for 30 of 33 clinically relevant patient-drug combinations (91% accuracy).Single-cell Raman spectroscopy combined with ML offers a scalable, prognostic platform to predict therapeutic resistance likelihood, with further potential to advance clinical, multiomic biomarker efforts for melanoma. Our approach may improve first- and second-line therapy selection assessments for precision medicine by providing rapid, nondestructive prediction of therapeutic response based on cellular spectral profiles.

  View details for DOI 10.1200/PO-25-00591

  View details for PubMedID 42715507

• AXL tyrosine kinase inhibition restores anti-PD-1 efficacy in melanoma through tumor-associated macrophage-dependent mechanisms Kirane, A., Lee, D., Sharma, S., Safrygina, E., Applebee, C., Serasanambati, M., Wagner, E., Delitto, D., Padget, J., Maverakis, E., Larijani, B. OXFORD UNIV PRESS. 2026

  View details for DOI 10.1093/jimmun/vkag141.277

  View details for Web of Science ID 001834280300001

• Protocol to interrogate the role of creeping fat and mechanical tension in Crohn's disease using a surgical mouse model of intestinal fibrosis. STAR protocols Suh, E. J., Pham, B., Bauer-Rowe, K. E., Kim, A., Liang, N. E., Park, J. Y., Foster, D. S., Norton, J. A., Delitto, D., Longaker, M. T., Hyun, J. S. 2026; 7 (2): 104613

  Abstract

  Here, we present a protocol to interrogate the role of creeping fat (CF) and mechanical tension in Crohn's disease (CD) using a surgical mouse model of intestinal fibrosis. We describe steps for preoperative preparation, microsurgical techniques for stricture formation and mechanical stretching, and model variations such as mesenteric grafts. We then detail procedures for postoperative harvest, tissue embedding, and sectioning procedures. This model induces localized CF formation and transmural fibrosis, features distinct from those observed in chemical colitis models. For complete details on the use and execution of this protocol, please refer to Bauer-Rowe et al.1.

  View details for DOI 10.1016/j.xpro.2026.104613

  View details for PubMedID 42241292

• Engineering a hydrogel-based vaccine to prevent recurrence in pancreatic ductal adenocarcinoma Xie, P., Agolia, J. P., Reveron-Thornton, R. F., Guo, C., Korah, M., Delitto, A., Foster, D., Chaudhuri, O., Delitto, D. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-6713

  View details for Web of Science ID 001734377300048

• Integrated multiomic atlas of pancreatic solid pseudopapillary neoplasms suggests acinar cells as a potential cell-of-origin Reddy, B., Korah, M., Agolia, J. P., Reveron-Thornton, R., Lam, M., Foster, D., Longaker, M. T., Delitto, D. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-6202

  View details for Web of Science ID 001734397100026

• Mapping lymphoid responses to tumor growth and lymph node metastasis: multiomic spatial analysis of pancreatic ductal adenocarcinoma reveals tertiary lymph node structures. Agolia, J. P., Guo, C., Reveron-Thornton, R. F., Li, X., Korah, M., Tabora, A., Lee, B., Kirane, A. R., Poultsides, G., Visser, B., Charville, G. W., Longaker, M. T., Foster, D. S., Delitto, D. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-2222

  View details for Web of Science ID 001734600600019

• Multidimensional transcriptomic alas of recurrent uterine leiomyosarcomas uncovers stem-like hormonal cells with high drug sensitivity and improved patient outcomes. Korah, M., Agolia, J. P., Reddy, B., Flojo, R. A., Goncalves, A., Wang, L., Reveron-Thornton, R. F., Guo, C., Sun, B., Kirane, A. R., Poultsides, G., Foster, D., Huang, R., Charville, G. W., Longaker, M. T., Delitto, D. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-2201

  View details for Web of Science ID 001734408500015

• A MUC1-overexpressing epithelial population is associated with CDH1 loss-of-function gastric adenocarcinoma. Guo, C., Reveron-Thornton, R. F., Li, X., Agolia, J. P., Korah, M., Xie, P., Goncalves, A., Tabora, A., Xia, L., Barakat, N., Poultsides, G., Lee, B., Kirane, A. R., Foster, D., Longaker, M. T., Charville, G. W., Delitto, D. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-2270

  View details for Web of Science ID 001734175500036

• A single-cell tumor atlas defines robust pathway and gene signatures enabling cancer cell-line fidelity assessment. Reveron-Thornton, R. F., Guo, C., Agolia, J. P., Korah, M., Xie, P., Delitto, A., Goncalves, A., Tabora, A., Reddy, B., Bobst, W., Kirane, A. R., Dua, M., Visser, B., Lee, B., Poultsides, G., Norton, J. A., Wan, D. C., Longaker, M. T., Foster, D., Delitto, D. AMER ASSOC CANCER RESEARCH. 2026

  View details for DOI 10.1158/1538-7445.AM2026-1426

  View details for Web of Science ID 001734520900046

• A Translational Surgical Porcine Model for Postoperative Intra-Abdominal Adhesion Formation. Journal of visualized experiments : JoVE Reveron-Thornton, R. F., Hsu, C. H., Bobst, W., Guo, J. L., Meany, E. L., M Williams, C., Berry, C., Fallah, M., Korah, M., P Agolia, J., Guo, C., Fell, G. L., Hyun, J., Wan, D. C., Norton, J. A., Appel, E., Longaker, M. T., Delitto, D., Foster, D. S. 2026

  Abstract

  A porcine model of postoperative intra-abdominal adhesion formation was established using Yucatan mini pigs. The protocol combines midline laparotomy, small bowel resection with two-layer primary anastomosis, and a unilateral, parietal peritoneal abrasion in the format of an open abdominal surgical procedure. Adhesion formation was assessed four weeks postoperatively using established gross and histologic scoring criteria, with evaluations performed by blinded observers. Adhesions developed in all animals using this model and were multifocal, involving bowel loops, between the bowel and abdominal wall, involving the peritoneum overlying other organs in the abdomen (e.g. the liver), and operative sites, with variable severity. Histological analysis at four weeks demonstrated adhesions composed predominantly of extracellular matrix, fibroblasts, and blood vessels, consistent with a remodeling-phase wound healing tissue phenotype. This model is relevant for the study of abdominal adhesion fibrosis biology and/or the translational evaluation of candidate anti-adhesion therapeutics. By integrating a clinically relevant intestinal surgical procedure with a defined peritoneal injury and a standardized assessment strategy, this protocol provides a reproducible approach for inducing and evaluating postoperative intra-abdominal adhesions in a large animal model.

  View details for DOI 10.3791/70377

  View details for PubMedID 41911229

• Predicting targeted- and immunotherapeutic response outcomes in melanoma with single-cell Raman spectroscopy and AI. bioRxiv : the preprint server for biology Chang, K., Serasanambati, M., Ogunlade, B., Hsu, H. J., Agolia, J., Stiber, A., Gu, J., Chadokiya, J., Rodriguez, G. E., Singh, P., Sharma, S., Gonçalves, A., Verma, O., Safir, F., Vu, N., Garcia, K. C., Delitto, D., Kirane, A., Dionne, J. A. 2026

  Abstract

  Identifying reliable predictors of immunotherapeutic response in melanoma remains an outstanding challenge. Existing transcriptomic and proteomic profiling methods for the tumor-immune microenvironment (TIME) are costly and may not faithfully capture modifications actively impacting tumor behavior. Here, we present a non-destructive, single-cell approach combining Raman spectroscopy and machine learning (ML) that enables rapid cell profiling and therapeutic response prediction.We analyzed single-cell Raman spectra of mouse and human melanoma cell lines alongside nine melanoma patient-derived samples with known resistance profiles to targeted and immunotherapeutic inhibitors bemcentinib, cabozantinib, dabrafenib, nivolumab, and a combination of nivolumab and relatlimab. We assessed cell phenotyping classification and treatment resistance using random forests and feature importance analysis. For patient samples, we constructed a two-stage evaluation workflow to determine clinical drug resistance through aggregated single-cell predictions and identified corresponding highly variant spectral signatures using computational methods adapted from single-cell RNA sequencing methods.In cell lines, our approach achieved >96% differentiation accuracy across tumor microenvironment cell types and induced functional phenotypes. Persistent (drug-resistant) cells formed subclusters based on genetic mutations rather than sample origin, with Raman signatures reflecting biochemical changes relevant to therapeutic pathways. For patient samples, our workflow correctly inferred resistance likelihoods for 30 of 33 clinically-relevant patient-drug combinations (91% accuracy).Single-cell Raman spectroscopy combined with machine learning offers a scalable, prognostic platform to predict therapeutic resistance likelihood, with further potential to advance clinical, multi-omic biomarker efforts for melanoma. Our approach may improve first- and second-line therapy selection assessments for precision medicine by providing rapid, non-destructive prediction of therapeutic response based on cellular spectral profiles.

  View details for DOI 10.1101/2025.05.16.654612

  View details for PubMedID 41889902

  View details for PubMedCentralID PMC13014145

• A Pan-Cancer Single-Cell Atlas to Evaluate Tumor Identity, Cell Line Concordance, and Dependency Mapping. bioRxiv : the preprint server for biology Reveron-Thornton, R. F., Agolia, J. P., Guo, C., Korah, M., Hsu, C. H., Xie, P. Y., Flojo, R. A., Delitto, A. E., Gonçalves, A., Tabora, A. D., Januszyk, M., Sanchez, V. E., Nee, K., Reddy, B., Bobst, W., Lee, B., Poultsides, G. A., Kirane, A. R., Wan, D. C., Norton, J. A., Engleman, E. G., Newman, A. M., Longaker, M. T., Foster, D. S., Delitto, D. 2026

  Abstract

  Bulk RNA sequencing enables pan-cancer transcriptional analyses, but obscures cancer cell-specific programs due to admixture with nonmalignant cells, thereby limiting direct comparison between experimental models and primary tumors. Single-cell RNA sequencing (scRNA-seq) overcomes these limitations; however, the biological interpretability of public datasets is often compromised by variable data quality, inconsistent annotation, and atlas-scale aggregation strategies that prioritize data volume over biological coherence. We therefore developed a stringent integration framework that prioritizes representative malignant transcriptional states. Using Mahalanobis distance-based selection within batch-corrected latent space, we constructed a pan-cancer atlas comprising 135,424 high-quality malignant cells from 499 samples across 36 adult and pediatric cancers. Atlas-derived cancer signatures were used to determine tumor-cell line concordance and project ElasticNet models trained on DepMap CRISPR screens to infer cancer-specific gene dependencies. The scTumor Atlas establishes a scalable framework for tumor identity inference, cancer cell line benchmarking, and systematic identification of genetic vulnerabilities.

  View details for DOI 10.64898/2026.02.14.705396

  View details for PubMedID 42124572

  View details for PubMedCentralID PMC13160036

• NFAT mediates pro-tumorigenic inflammation in cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cell reports Guo, C., Griffin, M. F., Morgan, A. G., Foster, D. S., Parker, J. B., Januszyk, M., Lindsay, H. G., Guardino, N. J., Reveron-Thornton, R., Xie, P. Y., Valencia, C., Kuhnert, M. M., Korah, M., Gonçalves, A., Guo, J. L., Delitto, A. E., Agolia, J. P., Tabora, A. D., Dua, M. M., Visser, B. C., Poultsides, G. A., Delitto, D., Longaker, M. T., Norton, J. A. 2026; 45 (1): 116849

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma, low immunogenicity, and resistance to therapy. Cancer-associated fibroblasts (CAFs) are key stromal cells within the tumor microenvironment (TME) that drive tumor progression. Interleukin-1 (IL-1) promotes fibrosis, pathogenic inflammation, and poor prognosis in PDAC. Using a single-cell multi-omic approach, we investigate the IL-1 signaling axis in human and mouse models of PDAC, identifying nuclear factor of activated T cells (NFAT) transcription factors as key mediators. IL1R1+ CAFs activate an inflammatory phenotype associated with elevated NFAT motif activity and gene expression. In vivo, NFAT inhibition in a mouse model of PDAC significantly reduces tumor weight and fibrosis, supporting its pro-tumorigenic role. Our findings suggest that NFAT mediates IL-1-induced inflammation in PDAC, highlighting its potential as a therapeutic target. This study demonstrates the power of multi-omic analyses to uncover therapeutic targets within the complex TME.

  View details for DOI 10.1016/j.celrep.2025.116849

  View details for PubMedID 41533513

• Protocol for orthotopic implantation of a collagen hydrogel to model pancreatic ductal adenocarcinoma in mice. STAR protocols Agolia, J. P., Xie, P. Y., Korah, M., Fallah, M., Reveron-Thornton, R. F., Guo, C., Reddy, B., Sivasubramanian, R., Longaker, M. T., Chaudhuri, O., Foster, D. S., Delitto, D. 2026; 7 (1): 104337

  Abstract

  Available mouse models for pancreatic ductal adenocarcinoma (PDAC) are limited by slow tumor development and failure to recapitulate key stromal and immune characteristics. Here, we present a protocol for generating a collagen hydrogel mouse model for orthotopic PDAC. We describe steps for embedding mouse pancreatic cancer cells in a dense collagen hydrogel and surgically implanting it into the mouse pancreas. Mouse PDAC tumors typically reach 1 cm in diameter by 10 days after implantation and show immune and stromal cell recruitment. For complete details on the use and execution of this protocol, please refer to Korah et al.1.

  View details for DOI 10.1016/j.xpro.2025.104337

  View details for PubMedID 41533505

• A Developmental Roadmap Toward Abdominal Adhesions Prevention Technologies. Annals of surgery open : perspectives of surgical history, education, and clinical approaches Christensen, R. R., Wright, K. E., Ives, J. K., Minnick, C. E., Chen, Q., Girgis, M. D., Ko, C., Gibbons, M. M., Russell, T. A., Huy, T. C., Bercz, A., Smith, J. J., Bailey, A., Ten Broek, R. P., de Wilde, R. L., Zindel, J., Cardenas, J. C., Mutsaers, S., Wiseman, D., Meany, E. A., Appel, E. A., Foster, D. S., Delitto, D. J., Longaker, M. T., Rinkevich, Y., Bauer, S. R., Carmichael, S. P. 2025; 6 (4): e637

  Abstract

  Abdominal adhesions are a globally disruptive problem to patients and healthcare systems, with limited preventative strategies. Multiple discovery prophylactics have been evaluated previously for adhesions prevention with inadequate transfer to patient care. Clinical translation is fundamentally restricted by the ability of a discovery prophylactic to simultaneously navigate 3 key components of adhesions formation throughout the entire abdomen: the innate immune system, the coagulation system, and the local peritoneal cell populations. Furthermore, challenging handling characteristics and product restrictions have decreased the utilization of clinically available prophylactics by surgeons. The success of future adhesions prevention strategies must also be anchored in clinically valid animal modeling with attention towards future regulatory approval. The purpose of the present roadmap article is to provide a state-of-the-art review of adhesions pathophysiology, hydrogel development, animal modeling, and regulatory science, from which a framework for future developmental strategies may be outlined.

  View details for DOI 10.1097/AS9.0000000000000637

  View details for PubMedID 41451177

• LI-RADS CT/MRI Nonradiation Treatment Response Assessment Version 2024 for Detecting Local Recurrence of Surgically Resected Hepatocellular Carcinoma. AJR. American journal of roentgenology Chiu, S. H., Yoon, L., Altmayer, S., Delitto, D. J., Kamaya, A., Tse, J. R. 2025

  Abstract

  Background: LI-RADS CT/MRI Nonradiation Treatment Response Assessment (TRA) version 2024 (v2024) specifies that the updated algorithm may be applied for evaluating the surgical margin after hepatocellular carcinoma (HCC) resection. Objective: To compare detection of local recurrences after surgical resection of HCC between LI-RADS CT/MRI Nonradiation TRA v2024 and the LI-RADS CT/MRI Core version 2018 (v2018) diagnostic algorithm. Methods: This retrospective study included patients with surgically resected HCC who underwent at least one liver CT or MRI performed ≥6 months postoperatively. Two radiologists independently reviewed all postoperative CT and MRI examinations in included patients in separate sessions, assessing the surgical margin using LI-RADS CT/MRI Nonradiation TRA v2024 and LI-RADS CT/MRI Core v2018, respectively; a third radiologist resolved discrepancies. Local recurrence was defined by v2024 as LR-TR Viable (i.e., masslike enhancement at the margin, in any phase and of any size) and by v2018 as LR-5, LR-M, or LR-TIV. Results: The study included 200 patients (142 men, 58 women; median age 67 years) with median follow-up of 30.5 months. Interreader agreement for v2024 categorization was substantial (κ=0.71). By v2024, LR-TR Viable at the surgical margin was assigned in 56 (28.0%) patients (on the initial postoperative examination in 21 patients, directly after an LR-Nonviable assignment without intervening LR-TR Equivocal assignment in 31 patients, and after an LR-TR Equivocal assignment in remaining patients), after a median of 5.1 months and at a median size of 1.5 cm. By v2018, LR-5, LR-M, or LR-TIV was assigned at the surgical margin in 53 (26.5%) patients after a median of 12.0 months (p<.001) and at a median size of 2.1 cm (p<.001). At the time of the 56 initial LR-TR Viable assignments, categories assigned for v2018 were LR-3, LR-4, LR-5, LR-M, and LR-TIV in 21, 10, 18, 3, and 4 patients, respectively. Upgrade of LR-3 and LR-4 observations to LR-5, LR-M, or LR-TIV occurred after a median of 5.1 and 3.0 months, respectively. Conclusion: v2024 detects local recurrence in 28% of patients, at an earlier time and smaller size than v2018. Clinical Impact: The findings support application of v2024 for surgical margin evaluation after HCC resection.

  View details for DOI 10.2214/AJR.25.33787

  View details for PubMedID 41190834

• T Cells Tear Apart Confining Extracellular Matrix Via a Breaststroke-like Motion to Generate Migration Paths. bioRxiv : the preprint server for biology Ha, B., Xie, P., Johns, B., Allan, C., Korah, M., Delitto, D., Bollyky, P., Torok, N., Chaudhuri, O. 2025

  Abstract

  T cells migrate through soft tissues to target infected and abnormal cells and regulate immunity. T cell migration is typically studied in microfluidic devices or other contexts where there is a pre-existing migration path; how they create paths in confining nanoporous extracellular matrices (ECM), such as can occur during fibrosis and around tumors, remains unclear. Here, we studied T cell migration in confining collagen-rich matrices with a range of stiffness, viscoelasticity, mechanical plasticity, and shear strength, or the stress at which the material fails. Strikingly, only shear strength, the stress at which a material fails, not stiffness or viscoelasticity, correlates with migration. During migration, T-cells extend thin actin-rich, finger-like protrusions into the ECM, which then undergo a divergent breaststroke-like motion. Thus, T cells tear apart confining matrices using a breaststroke-like motion to generate migration paths.

  View details for DOI 10.1101/2025.10.03.680352

  View details for PubMedID 41256507

  View details for PubMedCentralID PMC12622025

• Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma. Cell reports Korah, M., Reveron-Thornton, R. F., Fallah, M., Xie, P. Y., Gonçalves, A., Guo, C., Agolia, J. P., Delitto, A. E., Flojo, R. A., Reddy, B., Yip, K. A., Lu, J. M., Tomasso, A., Tabora, A. D., Guo, J. L., Bauer-Rowe, K. E., Pham, B., Goyal, L., Kirane, A. R., Charville, G. W., Chaudhuri, O., Dua, M. M., Visser, B. C., Lee, B., Poultsides, G. A., Wan, D. C., Norton, J. A., Foster, D. S., Longaker, M. T., Delitto, D. 2025; 44 (10): 116347

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) continues to carry a dismal prognosis. The disease is characterized by a uniquely dense fibrotic matrix generated by cancer-associated fibroblasts (CAFs). We have previously demonstrated that fibroblast-driven chronic inflammation suppresses T cell function through a myeloid differentiation primary response protein 88 (MYD88)-dependent mechanism. While extensively studied in myeloid cells, the role of MYD88 signaling in CAFs and its effects on PDAC remain poorly understood. In this study, we identify a MYD88-driven inflammatory CAF population in PDAC using a combination of bulk, single-cell, and spatial transcriptomic studies. Using an innovative collagen gel implantation model, we demonstrate that loss of MYD88 in CAFs enhances T cell infiltration and suppresses tumor growth. Combining MYD88 inhibition with immune checkpoint blockade significantly reduces tumor size and enhances antitumor immune responses, underscoring its potential as a therapeutic target in PDAC.

  View details for DOI 10.1016/j.celrep.2025.116347

  View details for PubMedID 41004339

• Surgical Strategies for Tumors of the Pancreas and Duodenum. Cancers Reveron-Thornton, R. F., Huang, K. X., Delitto, D., Longaker, M. T., Norton, J. A. 2025; 17 (18)

  Abstract

  The recommended surgery for pancreatic tumors is dependent on the diagnosis. For pancreatic adenocarcinoma, duodenal, and ampullary adenocarcinoma, a Whipple pancreaticoduodenectomy with lymph node dissection is recommended. For small < 2 cm or non-imageable gastrinomas, duodenal transillumination, duodenotomy, duodenal tumor excision and adjacent lymphadenectomy is recommended. For large > 3 cm gastrinomas, a Whipple pancreaticoduodenectomy with adjacent lymph node dissection is recommended. For small 1-2 cm insulinomas, intraoperative ultrasound with enucleation is recommended. If the patient with gastrinoma, insulinoma, or multiple nonfunctional NETs occurs in the setting of MEN-1, a subtotal pancreatectomy with or without splenectomy with enucleation of pancreatic head tumors is recommended, with adjacent lymph node dissection. The detail of each procedure is described with illustrations.

  View details for DOI 10.3390/cancers17183091

  View details for PubMedID 41008933

  View details for PubMedCentralID PMC12468946

• Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn's disease strictures. Cell Bauer-Rowe, K. E., Pham, B., Griffin, M., Liang, N. E., Kim, A., Lu, J. M., Januszyk, M., Guo, J. L., De Santis, S., Xing, Y., Prystupa, A., Sidhu, I., Suh, E. J., Foster, D. S., Korah, M., Goyal, A., Wan, D. C., Norton, J. A., Delitto, D., Pizarro, T. T., Naik, S. L., Hyun, J. S., Longaker, M. T. 2025

  Abstract

  A significant complication of Crohn's disease (CD) is intestinal fibrosis, which narrows the bowel lumen to form a stricture. Creeping fat (CF) is the wrapping of mesenteric adipose tissue around diseased bowel, of which the role in CD stricture progression is unclear. By constructing a human single-cell CD fibroblast atlas, we identified CF-derived, CTHRC1+ fibroblasts enriched for Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signatures and localized to a fibrotic CF-bowel wall interface within the stricture. We further showed that analogous Cthrc1+ mouse fibroblasts derive from mesenteric adipose tissue stromal cells, infiltrate fibrotic bowel, and deposit extracellular matrix in a YAP/TAZ-dependent manner in a mouse model of intestinal fibrosis. Our findings identify CF as a key source of pro-fibrotic fibroblasts and raise the possibility of improving future clinical management of stricture progression by targeting not only the bowel but also CF.

  View details for DOI 10.1016/j.cell.2025.08.029

  View details for PubMedID 40967215

• Cancer-derived mitochondria fuel fibroblasts to become pro-tumorigenic. Nature cancer Delitto, D., Longaker, M. T. 2025

  View details for DOI 10.1038/s43018-025-01005-1

  View details for PubMedID 40877412

  View details for PubMedCentralID 8076293

• Hepatocellular Carcinoma: A Practical Anatomy-Based Guide for Staging and Treatment Planning, From the AJR Special Series on Critical Anatomy. AJR. American journal of roentgenology Chiu, S. H., Kesselman, A., Delitto, D. J., Dhanasekaran, R., Chang, W. C., Kamaya, A., Tse, J. R. 2025

  Abstract

  Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and is rising in incidence. Treatment is complex and rapidly evolving but is also highly algorithmic. Radiologic imaging (primarily CT and MRI) guides treatment at each management step, and radiologists command a central role across the continuum of HCC care, from early detection during surveillance to diagnosis, staging, treatment, and response assessment. Recent updates to major guidelines, including the 2022 Barcelona Clinic Liver Cancer staging system and the 2023 American Association for the Study of Liver Diseases guidelines, reflect significant advances in surgical approaches, interventional techniques, and systemic therapies. Radiologists must accurately assess tumor burden, background liver, and vascular anatomy to determine eligibility for each treatment pathway. This review provides an overview of clinically relevant anatomic considerations for HCC staging and treatment planning, informed by recent major treatment advances. We present a practical anatomy-based approach to radiology reporting that aligns with clinical decision-making pathways. By incorporating these elements, radiologists can effectively communicate relevant findings, facilitate appropriate therapy selection, and guide multidisciplinary discussions.

  View details for DOI 10.2214/AJR.25.33389

  View details for PubMedID 40833222

• The Two-Decade Experience of Onco-vascular Reconstruction in Patients with Retroperitoneal Sarcoma. Annals of vascular surgery Zahiri, A., Fereydooni, A., Eshraghian, E., Ho, M., Delitto, D., Lee, B., Poultsides, G. A., Norton, J. A., Harris, E. J., George, E. L. 2025

  Abstract

  Surgical resection remains the cornerstone of sarcoma treatment; however, tumor involvement of major vasculature presents challenges. Multidisciplinary approaches incorporating vascular surgery have expanded feasibility of resection, yet long-term outcome data remain limited.We performed a retrospective review of patients with retroperitoneal sarcomas who underwent resection with vascular reconstruction at a tertiary referral center from 2001-2024. Data included demographics, tumor characteristics, operative details, and outcomes including mortality, graft patency, and reinterventions.A total of 263 vascular procedures were performed in 101 patients (median age 59; 52% female). Prior sarcoma resection occurred in 36.3%, 53.5% received chemoradiation, and 41.7% had stage IV disease. The most common histology was leiomyosarcoma (34.7%). Concurrent procedures included nephrectomy (53.5%) and colectomy (36.3%). Thirty-day mortality was 5%, with a 64.4% Clavien-Dindo grade II+ complication rate. Median overall survival was 5.9 years. Vascular reintervention occurred in 11.9%. One-year vascular reintervention-free survival was 90.5%, with no 1-year survival difference between patients with (93.3%, n=84) and without reconstruction thrombosis (81.7%, n=16; P=0.454). Univariate analysis associated thrombosis with diabetes, dual antiplatelet therapy, anticoagulation with antiplatelet therapy, iliac vein reconstruction using cryopreserved grafts, and 90-day readmission. On multivariate analysis, only use of cryopreserved grafts for iliac vein reconstruction remained significantly associated with thrombosis (OR 12.75, 95% CI 1.68-18.93; P = 0.019).Over two decades, vascular reconstructions facilitated complex sarcoma resections with favorable long-term outcomes. Iliac vein reconstructions using cryopreserved grafts carry higher thrombosis risk. Despite the complexity of these cases, the outcomes reflect the effectiveness of multidisciplinary management.

  View details for DOI 10.1016/j.avsg.2025.08.014

  View details for PubMedID 40840720

• Spleen Preservation in Solid Pseudopapillary Neoplasms of the Distal Pancreas: A Single-Center Experience. The Journal of surgical research Yue, T. M., Sun, B. J., Delitto, D. J., Dua, M. M., Norton, J. A., Poultsides, G. A., Visser, B. C., Lee, B. 2025; 310: 17-21

  Abstract

  Solid pseudopapillary neoplasms (SPNs) are rare tumors of the pancreas that are typically low-grade but may carry malignant potential. While concurrent splenectomy is recommended for oncologic resection of malignant distal pancreas tumors, this is not well-described for SPN. This study evaluates the outcomes of spleen preservation for distal pancreas SPN.A retrospective review was conducted for adult patients with SPN who underwent surgical resection at a single tertiary center (2010-2023). Distal tumors were located within the pancreatic body or tail. Patient factors and outcomes were compared between those who underwent spleen-preserving (SP) versus nonspleen-preserving (NSP) distal pancreatectomy.In total, 52 patients underwent surgery for SPN. Thirty six had localized distal pancreatic tumors and underwent distal/subtotal pancreatectomy: 25 (69%) were SP and 11 (31%) were NSP. Overall, median age was 31 y, 86% were female, and 61% were symptomatic at diagnosis. Median tumor size (4.9 cm SP versus 6.0 cm NSP, P = 0.469) and number of lymph nodes examined (6 SP versus 11 NSP, P = 0.241) were similar. The majority of SP operations were completed minimally invasively via laparoscopic or robotic approaches (84% SP versus 36% NSP, P = 0.008). There was no difference in operative time, complications, length of stay, or readmission between groups. Neither cohort had recurrence of SPN at median follow-up of 3 y.SP pancreatectomy can be performed safely for distal SPN with excellent long-term oncologic outcomes. This technique may be achieved minimally invasively and should be considered for localized SPN in the body or tail of the pancreas.

  View details for DOI 10.1016/j.jss.2025.03.062

  View details for PubMedID 40273731

• 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

• Outcomes of minimally invasive and open prophylactic gastrectomy for hereditary diffuse gastric cancer SURGICAL ONCOLOGY INSIGHT Daniel, S. K., Foster, D. S., Ahmad, M., Forrester, J. D., Lee, B., Delitto, D., Kirane, A. R., Visser, B. C., Dua, M. M., Norton, J. A., Poultsides, G. A. 2025; 2 (1)

  View details for DOI 10.1016/j.soi.2024.100112

  View details for Web of Science ID 001578898700002

• Using Circulating Tumor DNA to Monitor Sarcoma Treatment and Recurrence Sun, B. J., Yue, T. M., Hur, D., Allen, J., Delitto, D., Poultsides, G., Lee, B. SPRINGER. 2025: S32-S33

  View details for Web of Science ID 001610671600060

• Defining Gene Signature of Tumor-Associated Macrophages in Intrahepatic Cholangiocarcinoma as Target for Immunotherapy Using Single Cell and Bulk RNA Sequencing Livers Badshah, J. S., Lee, R., Reitsma, A., Melcher, M. L., Martinez, O. M., Krams, S. M., Delitto, D. J., Kirchner, V. A. 2025; 5 (4): 1-17

  View details for DOI 10.3390/livers5040053

• 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. B. 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. B. 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; 30 (19-20): 605-613

  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 Web of Science ID 001258923800001

  View details for PubMedID 38874979

• 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

• Machine Learning Applications in Solid Organ Transplantation and Related Complications FRONTIERS IN IMMUNOLOGY Balch, J. A. A., Delitto, D., Tighe, P. J. J., Zarrinpar, A., Efron, P. A. A., Rashidi, P., Upchurch Jr, G. R. R., Bihorac, A., Loftus, T. J. J. 2021; 12: 739728

  Abstract

  The complexity of transplant medicine pushes the boundaries of innate, human reasoning. From networks of immune modulators to dynamic pharmacokinetics to variable postoperative graft survival to equitable allocation of scarce organs, machine learning promises to inform clinical decision making by deciphering prodigious amounts of available data. This paper reviews current research describing how algorithms have the potential to augment clinical practice in solid organ transplantation. We provide a general introduction to different machine learning techniques, describing their strengths, limitations, and barriers to clinical implementation. We summarize emerging evidence that recent advances that allow machine learning algorithms to predict acute post-surgical and long-term outcomes, classify biopsy and radiographic data, augment pharmacologic decision making, and accurately represent the complexity of host immune response. Yet, many of these applications exist in pre-clinical form only, supported primarily by evidence of single-center, retrospective studies. Prospective investigation of these technologies has the potential to unlock the potential of machine learning to augment solid organ transplantation clinical care and health care delivery systems.

  View details for DOI 10.3389/fimmu.2021.739728

  View details for Web of Science ID 000701566800001

  View details for PubMedID 34603324

  View details for PubMedCentralID PMC8481939

• Impact of Margin Status on Survival in Patients with Pancreatic Ductal Adenocarcinoma Receiving Neoadjuvant Chemotherapy JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Schmocker, R. K., Delitto, D., Wright, M. J., Ding, D., Cameron, J. L., Lafaro, K. J., Burns, W. R., Wolfgang, C. L., Burkhart, R. A., He, J. 2021; 232 (4): 405-413

  Abstract

  Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear.Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011 to 2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or fewer than 90 days of follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin.Four hundred and sixty-eight patients met inclusion criteria. Median age was 65 years and 53% were female. Preoperative clinical staging demonstrated that most had locally advanced (n = 222 [47%]) or borderline resectable (n = 172 [37%]) disease. Median follow-up was 18.5 months (interquartile range 10.6 to 30.0 months). Median duration of NAC was 119 days (interquartile range 87 to 168 days). FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). Forty percent were node-positive and 80% had an R0 resection. Fifty-six percent received at least 1 cycle of adjuvant therapy. Median overall survival and recurrence-free survival were 22.0 months (95% CI, 19.4 to 25.1 months) and 11.0 months (95% CI, 10.0 to 12.1 months). On multivariate analysis, margin status was not a significant predictor of overall survival or recurrence-free survival. Factors associated with overall survival included clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy.Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high-volume centers should be considered in selected patients after extensive NAC.

  View details for DOI 10.1016/j.jamcollsurg.2020.11.018

  View details for Web of Science ID 000632610800016

  View details for PubMedID 33338577

• E-cigarette promotes breast carcinoma progression and lung metastasis: Macrophage-tumor cells crosstalk and the role of CCL5 and VCAM-1 CANCER LETTERS Kien Pham, Do Huynh, Le, L., Delitto, D., Yang, L., Huang, J., Kang, Y., Steinberg, M. B., Li, J., Zhang, L., Liu, D., Tang, M., Liu, C., Wang, H. 2020; 491: 132-145

  Abstract

  Young women represent a target of E-cigarette (E-cig) companies, raising concern for potential connections with breast cancer (BC) that have not yet been elucidated. We hypothesized that E-cig promotes BC development and lung metastasis possibly through BC-monocyte/tumor-associated macrophage (TAM) crosstalk via CCL5 and V-CAM-1 axes. We demonstrated that E-cig promoted the infiltration of circulating monocytes in mammary fat pad (MFP) model. Furthermore, E-cig exposure significantly enhanced BC cell growth in MFP tumor and metastatic lung colonization; immunohistochemical stains illustrated the increase of TAMs infiltration, reduced BC cell apoptosis and increased proliferation index after E-cig exposure. In vitro studies show E-cig vapor condensate (EVC) treatment upregulated protein expressions of CCL5, V-CAM-1, and other pro-tumorigenic factors in BC cells. Mechanistically, co-culture system demonstrated both EVC and macrophages independently stimulated BC cell growth and the migration via CCL5/CCR1/CCR5 axis. During metastasis, E-Cig exposure stimulated BC cell survival via direct interaction with infiltrated macrophages, regulated by VCAM-1 and integrin α4β1. Our findings, for the first time, showed that E-cig promotes BC growth and metastasis. This study highlights the critical role of TAMs via CCL5 and VCAM-1 pathways in E-cig promoted BC tumor development.

  View details for DOI 10.1016/j.canlet.2020.08.010

  View details for Web of Science ID 000581513900013

  View details for PubMedID 32829009

  View details for PubMedCentralID PMC9703643

• Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE Nosacka, R. L., Delitto, A. E., Delitto, D., Patel, R., Judge, S. M., Trevino, J. G., Judge, A. R. 2020; 11 (3): 820-837

  Abstract

  Cancer cachexia is a life-threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre-clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre-clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient-derived xenograft (PDX) mice.To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice.Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up-regulated in the DIA were enriched for extracellular matrix protein-encoding genes and genes related to the inflammatory response, while down-regulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed up-regulation of canonical atrophy-associated pathways such as ubiquitin-mediated protein degradation and apoptosis, and down-regulation of genes encoding extracellular matrix proteins.These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.

  View details for DOI 10.1002/jcsm.12550

  View details for Web of Science ID 000512164900001

  View details for PubMedID 32039571

  View details for PubMedCentralID PMC7296265

• Nicotine Induces IL-8 Secretion from Pancreatic Cancer Stroma and Worsens Cancer-Induced Cachexia CANCERS Underwood, P. W., Zhang, D., Cameron, M. E., Gerber, M. H., Delitto, D., Maduka, M. U., Cooper, K. J., Han, S., Hughes, S. J., Judge, S. M., Judge, A. R., Trevino, J. G. 2020; 12 (2)

  Abstract

  Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

  View details for DOI 10.3390/cancers12020329

  View details for Web of Science ID 000522477300075

  View details for PubMedID 32024069

  View details for PubMedCentralID PMC7072641

• Mysteries, Epistemological Modesty, and Artificial Intelligence in Surgery FRONTIERS IN ARTIFICIAL INTELLIGENCE Loftus, T. J., Upchurch, G. R., Delitto, D., Rashidi, P., Bihorac, A. 2020; 2

  Abstract

  Life is filled with puzzles and mysteries, and we often fail to recognize the difference. As described by Gregory Treverton and Malcolm Gladwell, puzzles are solved by gathering and assimilating all relevant data in a logical, linear fashion, as in deciding which antibiotic to prescribe for an infection. In contrast, mysteries remain unsolved until all relevant data are analyzed and interpreted in a way that appreciates their depth and complexity, as in determining how to best modulate the host immune response to infection. When investigating mysteries, we often fail to appreciate their depth and complexity. Instead, we gather and assimilate more data, treating the mystery like a puzzle. This strategy is often unsuccessful. Traditional approaches to predictive analytics and phenotyping in surgery use this strategy.

  View details for DOI 10.3389/frai.2019.00032

  View details for Web of Science ID 000751673700001

  View details for PubMedID 33117989

  View details for PubMedCentralID PMC7591149

• The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC PLOS ONE Brown, M., Zhang, W., Yan, D., Kenath, R., Le, L., Wang, H., Delitto, D., Ostrov, D., Robertson, K., Liu, C., Pham, K. 2020; 15 (1): e0226917

  Abstract

  Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin's action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.

  View details for DOI 10.1371/journal.pone.0226917

  View details for Web of Science ID 000534352500022

  View details for PubMedID 31929540

  View details for PubMedCentralID PMC6957139

• Protein Signatures and Tissue Diagnosis of Pancreatic Cancer Underwood, P. W., Gerber, M. H., Nguyen, K., Delitto, D., Han, S., Thomas, R. M., Forsmark, C. E., Trevino, J. G., Gooding, W. E., Hughes, S. J. LIPPINCOTT WILLIAMS & WILKINS. 2020: 26-+

  Abstract

  Endoscopic ultrasound-guided fine-needle aspiration fails to diagnose up to 25% of patients with pancreatic ductal adenocarcinoma (PDAC). Proteomics can help to overcome this clinical dilemma. We hypothesized that soluble protein signatures can differentiate PDAC from benign tissues.Tissues were obtained from resected surgical specimens, lysed, and homogenates collected for analysis with a 41-protein multiplex assay. Analyte concentrations were normalized to total protein. Statistical analysis was performed to evaluate for differences in PDAC vs benign tissue.Tissues were obtained from 159 patients, 82 patients with PDAC naïve to therapy and 77 with benign pancreatic pathology. Fourteen analytes had a receiver operating characteristic curve area of >0.75 for predicting PDAC vs benign tissue. A recursive partitioning model using only 2 analytes, interleukin 1 receptor antagonist and transforming growth factor-α, provided an accuracy, sensitivity, and specificity of 91.2%, 90.2%, and 92.2%, respectively. A penalized logistic regression model found 12 analytes that provide diagnostic value to a protein signature. The mean area under the receiver operating characteristic after 50 tenfold cross-validations was 0.951. Accuracy, sensitivity, and specificity of this model were 91.2%, 87.8%, and 94.8%, respectively. Applying the scenario of 80% disease prevalence in patients undergoing endoscopic ultrasound with fine-needle aspiration for a pancreatic head mass, positive predictive value is 98.5% (95% CI 93.0% to 99.7%) and negative predictive value is 66.0% (95% CI 54.9% to 75.6%).Protein signatures from pancreatic specimens can differentiate PDAC from benign tissue. Additional work to validate these findings in a unique sample set is warranted.

  View details for DOI 10.1016/j.jamcollsurg.2019.10.002

  View details for Web of Science ID 000504019700004

  View details for PubMedID 31672677

  View details for PubMedCentralID PMC6986686

• 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

• Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Gerber, M. H., Underwood, P. W., Judge, S. M., Delitto, D., Delitto, A. E., Nosacka, R. L., DiVita, B. B., Thomas, R. M., Permuth, J. B., Hughes, S. J., Wallet, S. M., Judge, A. R., Trevino, J. G. 2018; 19 (12)

  Abstract

  Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

  View details for DOI 10.3390/ijms19123836

  View details for Web of Science ID 000455323500138

  View details for PubMedID 30513792

  View details for PubMedCentralID PMC6321633

• Rectal Cancer Patients Younger Than 50 Years Lack a Survival Benefit From NCCN Guideline-Directed Treatment for Stage II and III Disease CANCER Kolarich, A., George, T. J., Hughes, S. J., Delitto, D., Allegra, C. J., Hall, W. A., Chang, G. J., Tan, S. A., Shaw, C. M., Iqbal, A. 2018; 124 (17): 3510-3519

  Abstract

  The incidence of rectal cancer in patients younger than 50 years is increasing. To test the hypothesis that the biology in this younger cohort may differ, this study compared survival patterns, stratifying patients according to National Comprehensive Cancer Network (NCCN) guideline-driven care and age.The National Cancer Data Base was queried for patients treated with curative-intent transabdominal resections with negative surgical margins for stage I to III rectal cancer between 2004 and 2014. Outcomes and overall survival for patients younger than 50 years and patients 50 years old or older were compared by subgroups based on NCCN guideline-driven care.A total of 43,106 patients were analyzed. Younger patients were more likely to be female and minorities, to be diagnosed at a higher stage, and to have travelled further to be treated at academic/integrated centers. Short- and long-term outcomes were significantly better for patients younger than 50 years, with age-specific survival rates calculated. Younger patients were more likely to receive radiation treatment outside NCCN guidelines for stage I disease. In younger patients, the administration of neoadjuvant chemoradiation for stage II and III disease was not associated with an overall survival benefit.Age-specific survival data for patients with rectal cancer treated with curative intent do not support an overall survival benefit from NCCN guideline-driven therapy for stage II and III patients younger than 50 years. These data suggest that early-onset disease may differ biologically and in its response to multimodality therapy.

  View details for DOI 10.1002/cncr.31527

  View details for Web of Science ID 000447376600007

  View details for PubMedID 29984547

• The Postinjury Inflammatory State and the Bone Marrow Response to Anemia AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Loftus, T. J., Mira, J. C., Miller, E. S., Kannan, K. B., Plazas, J. M., Delitto, D., Stortz, J. A., Hagen, J. E., Parvataneni, H. K., Sadasivan, K. K., Brakenridge, S. C., Moore, F. A., Moldawer, L. L., Efron, P. A., Mohr, A. M. 2018; 198 (5): 629-638

  Abstract

  The pathophysiology of persistent injury-associated anemia is incompletely understood, and human data are sparse.To characterize persistent injury-associated anemia among critically ill trauma patients with the hypothesis that severe trauma would be associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, and decreased erythropoiesis.A translational prospective observational cohort study comparing severely injured, blunt trauma patients who had operative fixation of a hip or femur fracture (n = 17) with elective hip repair patients (n = 22). Bone marrow and plasma obtained at the index operation were assessed for circulating catecholamines, systemic inflammation, erythropoietin, iron trafficking pathways, and erythroid progenitor growth. Bone marrow was also obtained from healthy donors from a commercial source (n = 8).During admission, trauma patients had a median of 625 ml operative blood loss and 5 units of red blood cell transfusions, and Hb decreased from 10.5 to 9.3 g/dl. Compared with hip repair, trauma patients had higher median plasma norepinephrine (21.9 vs. 8.9 ng/ml) and hepcidin (56.3 vs. 12.2 ng/ml) concentrations (both P < 0.05). Bone marrow erythropoietin and erythropoietin receptor expression were significantly increased among patients undergoing hip repair (23% and 14% increases, respectively; both P < 0.05), but not in trauma patients (3% and 5% increases, respectively), compared with healthy control subjects. Trauma patients had lower bone marrow transferrin receptor expression than did hip repair patients (57% decrease; P < 0.05). Erythroid progenitor growth was decreased in trauma patients (39.0 colonies per plate; P < 0.05) compared with those with hip repair (57.0 colonies per plate; P < 0.05 compared with healthy control subjects) and healthy control subjects (66.5 colonies per plate).Severe blunt trauma was associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, erythroid progenitor growth suppression, and persistent injury-associated anemia. Clinical trial registered with www.clinicaltrials.gov (NCT 02577731).

  View details for DOI 10.1164/rccm.201712-2536OC

  View details for Web of Science ID 000443435800017

  View details for PubMedID 29768025

  View details for PubMedCentralID PMC6118010

• 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

• Viscoelastic properties of human pancreatic tumors and <i>in vitro</i> constructs to mimic mechanical properties ACTA BIOMATERIALIA Rubiano, A., Delitto, D., Han, S., Gerber, M., Galitz, C., Trevino, J., Thomas, R. M., Hughes, S. J., Simmons, C. S. 2018; 67: 331-340

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal, in large part due to a protective fibrotic barrier generated by tumor-associated stromal (TAS) cells. This barrier is thought to promote cancer cell survival and confounds attempts to develop effective therapies. We present a 3D in vitro system that replicates the mechanical properties of the PDAC microenvironment, representing an invaluable tool for understanding the biology of the disease. Mesoscale indentation quantified viscoelastic metrics of resected malignant tumors, inflamed chronic pancreatitis regions, and histologically normal tissue. Both pancreatitis (2.15 ± 0.41 kPa, Mean ± SD) and tumors (5.46 ± 3.18 kPa) exhibit higher Steady-State Modulus (SSM) than normal tissue (1.06 ± 0.25 kPa; p < .005). The average viscosity of pancreatitis samples (63.2 ± 26.7 kPa·s) is significantly lower than that of both normal tissue (252 ± 134 kPa·s) and tumors (349 ± 222 kPa·s; p < .005). To mimic this remodeling behavior, PDAC and TAS cells were isolated from human PDAC tumors. Conditioned medium from PDAC cells was used to culture TAS-embedded collagen hydrogels. After 7 days, TAS-embedded gels in control medium reached SSM (1.45 ± 0.12 kPa) near normal pancreas, while gels maintained with conditioned medium achieved higher SSM (3.38 ± 0.146 kPa) consistent with tumors. Taken together, we have demonstrated an in vitro system that recapitulates in vivo stiffening of PDAC tumors. In addition, our quantification of viscoelastic properties suggests that elastography algorithms incorporating viscosity may be able to more accurately distinguish between pancreatic cancer and pancreatitis.Understanding tumor-stroma crosstalk in pancreatic ductal adenocarcinoma (PDAC) is challenged by a lack of stroma-mimicking model systems. To design appropriate models, pancreatic tissue must be characterized with a method capable of evaluating in vitro models as well. Our indentation-based characterization tool quantified the distinct viscoelastic signatures of inflamed resections from pancreatitis, tumors from PDAC, and otherwise normal tissue to inform development of mechanically appropriate engineered tissues and scaffolds. We also made progress toward a 3D in vitro system that recapitulates mechanical properties of tumors. Our in vitro model of stromal cells in collagen and complementary characterization system can be used to investigate mechanisms of cancer-stroma crosstalk in PDAC and to propose and test innovative therapies.

  View details for DOI 10.1016/j.actbio.2017.11.037

  View details for Web of Science ID 000424853600029

  View details for PubMedID 29191507

  View details for PubMedCentralID PMC5797706

• Analysis of the Cost Effectiveness of Laparoscopic Pancreatoduodenectomy JOURNAL OF GASTROINTESTINAL SURGERY Gerber, M. H., Delitto, D., Crippen, C. J., George, T. J., Behrns, K. E., Trevino, J. G., Cioffi, J. L., Hughes, S. J. 2017; 21 (9): 1404-1410

  Abstract

  We sought to determine if laparoscopic pancreatoduodenectomy (LPD) is a cost-effective alternative to open pancreatoduodenectomy (OPD).Hospital cost data, discharge disposition, readmission rates, and readmission costs from periampullary cancer patient cohorts of LPD and OPD were compared. The surgical cohorts over a 40-month period were clinically similar, consisting of 52 and 50 patients in the LPD and OPD groups, respectively.The total operating room costs were higher in the LPD group as compared to the OPD group (median US$12,290 vs US$11,299; P = 0.05) due to increased costs for laparoscopic equipment and regional nerve blocks (P ≤ 0.0001). Although hospital length of stay was shorter in the LPD group (median 7 vs 8 days; P = 0.025), the average hospital cost was not significantly decreased compared to the OPD group (median $28,496 vs $28,623). Surgery-related readmission rates and associated costs did not differ between groups. Compared to OPD patients, significantly more LPD patients were discharged directly home rather than to other healthcare facilities (88% vs 72%; P = 0.047).For the index hospitalization, the cost of LPD is equivalent to OPD. Total episode-of-care costs may favor LPD via reduced post-hospital needs for skilled nursing and rehabilitation.

  View details for DOI 10.1007/s11605-017-3466-2

  View details for Web of Science ID 000408474500005

  View details for PubMedID 28567575

  View details for PubMedCentralID PMC6032973

• The pancreatic tumor microenvironment drives changes in miRNA expression that promote cytokine production and inhibit migration by the tumor associated stroma ONCOTARGET Han, S., Gonzalo, D. H., Feely, M., Delitto, D., Behrns, K. E., Beveridge, M., Zhang, D., Thomas, R., Trevino, J. G., Schmittgen, T. D., Hughes, S. J. 2017; 8 (33): 54054-54067

  Abstract

  The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS.

  View details for DOI 10.18632/oncotarget.10722

  View details for Web of Science ID 000407826100014

  View details for PubMedID 28903323

  View details for PubMedCentralID PMC5589562

• Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human Disease PANCREAS Go, K. L., Delitto, D., Judge, S. M., Gerber, M. H., George, T. J., Behrns, K. E., Hughes, S. J., Judge, A. R., Trevino, J. G. 2017; 46 (6): 813-819

  Abstract

  Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model. The purpose of this study was to evaluate the degree to which an orthotopic PDX model of PC recapitulates these aspects of the human disease.Human PDX-derived PC tumors were implanted directly into the pancreas of NOD.Cg-Prkdc Il2rg/SzJ mice. Tumor growth, metastasis, and muscle wasting were then evaluated.Orthotopically implanted PDX-derived tumors consistently incorporated into the murine pancreatic parenchyma, metastasized to both the liver and lungs and induced muscle wasting directly proportional to the size of the tumor, consistent of the cancer cachexia syndrome.Through the orthotopic implantation technique described, we demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human PC.

  View details for DOI 10.1097/MPA.0000000000000843

  View details for Web of Science ID 000403506700020

  View details for PubMedID 28609371

  View details for PubMedCentralID PMC7094873

• A clinically applicable muscular index predicts long-term survival in resectable pancreatic cancer SURGERY Delitto, D., Judge, S. M., George, T. J., Sarosi, G. A., Thomas, R. M., Behrns, K. E., Hughes, S. J., Judge, A. R., Trevino, J. G. 2017; 161 (4): 930-938

  Abstract

  The relationship between myopenia, nutritional status, and long-term oncologic outcomes remains poorly characterized in patients with clinically resectable pancreatic cancer. We sought to reliably quantify prognostic indicators of preoperative cachexia in a manner applicable to any clinical setting.Preoperative computed tomographies were available electronically and suitable for analysis in 73 of 82 consecutive patients with pancreatic cancer undergoing pancreatoduodenectomy between November 2010 and February 2014. The psoas index was computed from the cross-sectional area of the psoas muscles normalized to vertebral body area at the third lumbar vertebra. Correlation and proportional hazards analyses were performed to identify relationships between muscularity, preoperative nutritional markers, clinicopathologic parameters, and long-term survival.The psoas index correlated strongly with preoperative hemoglobin and albumin levels (P = .001 and .014, respectively) identifying a pattern of preoperative frailty. High psoas index and the albumin and hemoglobin levels were associated with improved long-term survival (hazard ratio 0.014, P < .001; hazard ratio 0.43, P < .001; and hazard ratio = 0.80, P = .014); however, on multivariate analysis, the psoas index proved to be the only independent predictor of survival (hazard ratio 0.021; P = .003). Rapid decreases in the psoas index during neoadjuvant chemotherapy were associated with poor postoperative outcomes, as were decreases in the psoas index during the postoperative period.The data indicate that the psoas index, a calculation derived from a clinically mandated, preoperative computed tomography, is a statistically powerful and easily calculated predictor of survival in pancreatic cancer when compared to tumor grade and stage as well as previously validated nutritional parameters.

  View details for DOI 10.1016/j.surg.2016.09.038

  View details for Web of Science ID 000398430400007

  View details for PubMedID 27932030

• 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

• Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia ONCOTARGET Delitto, D., Judge, S. M., Delitto, A. E., Nosacka, R. L., Rocha, F. G., DiVita, B. B., Gerber, M. H., George, T. J., Behrns, K. E., Hughes, S. J., Wallet, S. M., Judge, A. R., Trevino, J. G. 2017; 8 (1): 1177-1189

  Abstract

  Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

  View details for DOI 10.18632/oncotarget.13593

  View details for Web of Science ID 000391503300092

  View details for PubMedID 27901481

  View details for PubMedCentralID PMC5352045

• 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

• Standardization of surgical care in a high-volume center improves survival in resected pancreatic head cancer AMERICAN JOURNAL OF SURGERY Delitto, D., Black, B. S., Cunningham, H. B., Sliesoraitis, S., Lu, X., Liu, C., Sarosi, G. A., Thomas, R. M., Trevino, J. G., Hughes, S. J., George, T. J., Behrns, K. E. 2016; 212 (2): 195-+

  Abstract

  Durable clinical gains in surgical care are frequently reliant on well-developed standardization of practices. We hypothesized that the standardization of surgical management would result in improved long-term survival in pancreatic cancer.Seventy-seven consecutive, eligible patients representing all patients who underwent pancreaticoduodenectomy and received comprehensive, long-term postoperative care at the University of Florida were analyzed. Patients were divided into prestandardization and poststandardization groups based on the implementation of a pancreatic surgery partnership, or standardization program.Standardization resulted in a reduction in median length of stay (10 vs 12 days; P = .032), as well as significant gains in disease-free survival (17 vs 11 months; P = .017) and overall survival (OS; 26 vs 16 months; P = .004). The improvement in overall survival remained significant on multivariate analysis (hazard ratio = .46, P = .005).Standardization of surgical management of pancreatic cancer was associated with significant gains in long-term survival. These results suggest strongly that management of pancreatic head adenocarcinoma be standardized likely by regionalization of care at high performing oncologic surgery programs.

  View details for DOI 10.1016/j.amjsurg.2016.03.001

  View details for Web of Science ID 000382234300001

  View details for PubMedID 27260793

  View details for PubMedCentralID PMC4969126

• Oncologic and Perioperative Outcomes Following Selective Application of Laparoscopic Pancreaticoduodenectomy for Periampullary Malignancies JOURNAL OF GASTROINTESTINAL SURGERY Delitto, D., Luckhurst, C. M., Black, B. S., Beck, J. L., George, T. J., Sarosi, G. A., Thomas, R. M., Trevino, J. G., Behrns, K. E., Hughes, S. J. 2016; 20 (7): 1343-1349

  Abstract

  Data are sparse regarding patient selection criteria or evaluating oncologic outcomes following laparoscopic pancreaticoduodenectomy (LPD). Having prospectively limited LPD to patients with resectable disease defined by National Comprehensive Cancer Network (NCCN) criteria, we evaluated perioperative and long-term oncologic outcomes of LPD compared to a similar cohort of open pancreaticoduodenectomy (OPD).Consecutive patients (November 2010-February 2014) undergoing pancreaticoduodenectomy (PD) for periampullary adenocarcinoma were reviewed. Patients were excluded from further analysis for benign pathology, conversion to OPD for portal vein resection, and contraindications for LPD not related to their malignancy. Outcomes of patients undergoing LPD were analyzed in an intention-to-treat manner against a cohort of patients undergoing OPD.These selection criteria resulted in offering LPD to 77 % of all cancer patients. Compared to the OPD cohort, LPD was associated with significant reductions in wound infections (16 vs. 34 %; P = 0.038), pancreatic fistula (17 vs. 36 %; P = 0.032), and median hospital stay (9 vs. 12 days; P = 0.025). Overall survival (OS) was not statistically different between patients undergoing LPD vs. OPD for periampullary adenocarcinoma (median OS 27.9 vs. 23.5 months; P = 0.955) or pancreatic adenocarcinoma (N = 28 vs. 22 patients; median OS 20.7 vs. 21.1 months; P = 0.703).The selective application of LPD for periampullary malignancies results in a high degree of eligibility as well as significant reductions in length of stay, wound infections, and pancreatic fistula. Overall survival after LPD is similar to OPD.

  View details for DOI 10.1007/s11605-016-3136-9

  View details for Web of Science ID 000378866200008

  View details for PubMedID 27142633

  View details for PubMedCentralID PMC6033586

• Isolation of Pancreatic Cancer Cells from a Patient-Derived Xenograft Model Allows for Practical Expansion and Preserved Heterogeneity in Culture AMERICAN JOURNAL OF PATHOLOGY Pham, K., Delitto, D., Knowlton, A. E., Hartlage, E. R., Madhavan, R., Gonzalo, D. H., Thomas, R. M., Behrns, K. E., George, T. J., Hughes, S. J., Wallet, S. M., Liu, C., Trevino, J. G. 2016; 186 (6): 1537-1546

  Abstract

  Commercially available, highly passaged pancreatic cancer (PC) cell lines are of limited translational value. Attempts to overcome this limitation have primarily consisted of cancer cell isolation and culture directly from human PC specimens. However, these techniques are associated with exceedingly low success rates. Here, we demonstrate a highly reproducible culture of primary PC cell lines (PPCLs) from patient-derived xenografts, which preserve, in part, the intratumoral heterogeneity known to exist in PC. PPCL expansion from patient-derived xenografts was successful in 100% of attempts (5 of 5). Phenotypic analysis was evaluated with flow cytometry, immunofluorescence microscopy, and short tandem repeat profiling. Importantly, tumorigenicity of PPCLs expanded from patient-derived xenografts was assessed by subcutaneous injection into nonobese diabeteic.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice. Morphologically, subcutaneous injection of all PPCLs into mice yielded tumors with similar characteristics to the parent xenograft. PPCLs uniformly expressed class I human leukocyte antigen, epithelial cell adhesion molecule, and cytokeratin-19. Heterogeneity within each PPCL persisted in culture for the frequency of cells expressing the cancer stem cell markers CD44, CD133, and c-Met and the immunologic markers human leukocyte antigen class II and programmed death ligand 1. This work therefore presents a reliable method for the rapid expansion of primary human PC cells and, thereby, provides a platform for translational investigation and, importantly, potential personalized therapeutic approaches.

  View details for DOI 10.1016/j.ajpath.2016.02.009

  View details for Web of Science ID 000377236800012

  View details for PubMedID 27102771

  View details for PubMedCentralID PMC4901138

• Nicotine Reduces Survival via Augmentation of Paracrine HGF-MET Signaling in the Pancreatic Cancer Microenvironment CLINICAL CANCER RESEARCH Delitto, D., Zhang, D., Han, S., Black, B. S., Knowlton, A. E., Vlada, A. C., Sarosi, G. A., Behrns, K. E., Thomas, R. M., Lu, X., Liu, C., George, T. J., Hughes, S. J., Wallet, S. M., Trevino, J. G. 2016; 22 (7): 1787-1799

  Abstract

  The relationship between smoking and pancreatic cancer biology, particularly in the context of the heterogeneous microenvironment, remains incompletely defined. We hypothesized that nicotine exposure would lead to the augmentation of paracrine growth factor signaling between tumor-associated stroma (TAS) and pancreatic cancer cells, ultimately resulting in accelerated tumor growth and metastasis.The effect of tobacco use on overall survival was analyzed using a prospectively maintained database of surgically resected patients with pancreatic cancer. Nicotine exposure was evaluated in vitro using primary patient-derived TAS and pancreatic cancer cells independently and in coculture. Nicotine administration was then assessed in vivo using a patient-derived pancreatic cancer xenograft model.Continued smoking was associated with reduced overall survival after surgical resection. In culture, nicotine-stimulated hepatocyte growth factor (HGF) secretion in primary patient-derived TAS and nicotine stimulation was required for persistent pancreatic cancer cell c-Met activation in a coculture model. c-Met activation in this manner led to the induction of inhibitor of differentiation-1 (Id1) in pancreatic cancer cells, previously established as a mediator of growth, invasion and chemoresistance. HGF-induced Id1 expression was abrogated by both epigenetic and pharmacologic c-Met inhibition. In patient-derived pancreatic cancer xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression by qRT-PCR and phospho-Met levels by ELISA. Similarly, elevated levels of phospho-Met in surgically resected pancreatic cancer specimens correlated with reduced overall survival.Taken together, these data demonstrate a novel, microenvironment-dependent paracrine signaling mechanism by which nicotine exposure promotes the growth and metastasis of pancreatic cancer.

  View details for DOI 10.1158/1078-0432.CCR-15-1256

  View details for Web of Science ID 000373360600026

  View details for PubMedID 26667487

  View details for PubMedCentralID PMC4818664

• Improved Breast Cancer Care Quality Metrics After Implementation of a Standardized Tumor Board Documentation Template JOURNAL OF ONCOLOGY PRACTICE Farrugia, D. J., Fischer, T. D., Delitto, D., Spiguel, L. R. P., Shaw, C. M. 2015; 11 (5): 421-+

  Abstract

  Cancer treatment requires a coordinated multidisciplinary treatment approach, which led to the development of the Rapid Quality Reporting System by the Commission on Cancer. However, the lack of immediate availability of documented treatment plans and the inefficiency of global medical record reviews represent significant barriers to adherence reporting and the timely implementation of quality improvement measures.Adherence to national guidelines in the areas of radiation treatment, chemotherapy, and hormone therapy was assessed after breast conservation surgery (BCS). Adherence rates within 1 year of BCS were analyzed 10 weeks before and after the implementation of a standardized documentation template at weekly multidisciplinary breast cancer conferences.Documented adherence rates increased postimplementation in patients undergoing consideration for both radiation treatment and hormone therapy within 1 year of BCS (89% v 65%; P = .045% and 85% v 62%; P = .002, respectively). No change was observed in patients undergoing evaluation for cytotoxic chemotherapy (80% v 85%; P = 1.00).The addition of a documentation template to multidisciplinary breast cancer conferences resulted in increased recorded adherence rates to national guidelines. This template provided a means of both accurate and efficient documentation of evidence-based practice, which represents a concept with broad application in quality improvement. Although evaluation of the project was not continued beyond the pilot stage, current quality measure scores remain within the same range.

  View details for DOI 10.1200/JOP.2015.003988

  View details for Web of Science ID 000370638800014

  View details for PubMedID 26384016