Daniel James Delitto, MD, PhD

All Publications

• 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

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

  Abstract

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

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

  View details for PubMedID 30514931

  View details for PubMedCentralID PMC6279809

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

  Abstract

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

  View details for DOI 10.1093/jnci/djx228

  View details for PubMedID 29165692

  View details for PubMedCentralID PMC6279292

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

  Abstract

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

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

  View details for PubMedID 27864347

  View details for PubMedCentralID PMC5290036

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

  Abstract

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

  View details for DOI 10.1016/j.pharmthera.2016.06.008

  View details for PubMedID 27343757