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Background: Pancreatic ductal adenocarcinomas (PDAC) have heterogeneous tumor microenvironments relatively devoid of infiltrating immune cells. We aimed to quantitatively assess infiltrating CD3+ and CD8+ lymphocytes in a treatment-naïve patient cohort and assess associations with overall survival and microenvironment inflammatory proteins., Methods: Tissue microarrays were immunohistochemically stained for CD3+ and CD8+ lymphocytes and quantitatively assessed using QuPath. Levels of inflammation-associated proteins were quantified by multiplexed, enzyme-linked immunosorbent assay panels on matching tumor and tissue samples., Results: Our findings revealed a significant increase in both CD3+ and CD8+ lymphocytes populations in PDAC compared with non-PDAC tissue, except when comparing CD8+ percentages in PDAC versus intraductal papillary mucinous neoplasms (IPMN) (p = 0.5012). Patients with quantitatively assessed CD3+ low tumors (lower 50%) had shorter survival (median 273 days) compared to CD3+ high tumors (upper 50%) with a median overall survival of 642.5 days (p = 0.2184). Patients with quantitatively assessed CD8+ low tumors had significantly shorter survival (median 240 days) compared to CD8+ high tumors with a median overall survival of 1059 days (p = 0.0003). Of 41 proteins assessed in the inflammation assay, higher levels of IL-1B and IL-2 were significantly associated with decreased CD3+ infiltration (r = -0.3704, p = 0.0187, and r = -0.4275, p = 0.0074, respectively). Higher levels of IL-1B were also significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045), but not IL-2 (r = -0.0078, p = 0.9616). Principal component analysis of the inflammatory analytes showed diverse inflammatory responses in PDAC., Conclusion: In this work, we found a marked heterogeneity in infiltrating CD3+ and CD8+ lymphocytes and individual inflammatory responses in PDAC. Future mechanistic studies should explore personalized therapeutic strategies to target the immune and inflammatory components of the tumor microenvironment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tushoski-Alemán et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss., Methods: Treatment naïve patients with PDAC who underwent pancreatectomy at a single institution between 2012 and 2020 were identified retrospectively. Patients with pancreatic head or distal tumours were matched by sex, age, N and T stage. Serologic and anthropometric variables were obtained at the time of diagnosis. Skeletal muscle index (SMI), muscle radiation attenuation (MRA) and adiposity were measured. The primary outcome was presence of significant weight loss [>5% body weight (BW) loss in past 6 months]. Signed rank tests, Cochran Mantel Haenszel tests and Kaplan-Meier survival analysis are presented. RNA-seq of tumours was performed to explore enriched pathways related to cachexia and weight loss., Results: Pancreatic head tumours (n = 24) were associated with higher prevalence (70.8% vs. 41.7%, P = 0.081) and degree of weight loss (7.9% vs. 2.5%, P = 0.014) compared to distal tumours (n = 24). BMI (P = 0.642), SMI (P = 0.738) and MRA (P = 0.478) were similar between groups. Combining BW loss, SMI and MRA into a composite score, patients with pancreatic head cancers met more criteria associated with poor prognosis (P = 0.142). Serum albumin (3.9 vs. 4.4 g/dL, P = 0.002) was lower and bilirubin (4.5 vs. 0.4 mg/dL, P < 0.001) were higher with pancreatic head tumours. Survival differed by tumour location (P = 0.014) with numerically higher median overall survival with distal tumours (11.1 vs. 21.8 months; P = 0.066). Transcriptomic analysis revealed inactivation of appetite stimulation, weight regulation and nutrient digestion/metabolism pathways in pancreatic head tumours., Conclusions: Resectable pancreatic head PDAC is associated with higher prevalence of significant weight loss and more poor prognosis features. Pancreaticobiliary obstruction and hypoalbuminemia in patients with head tumours suggests compounding effects of nutrient malabsorption and systemic inflammation on molecular drivers of cachexia, possibly contributing to shorter survival. Therefore, PDAC-associated cachexia is a heterogenous syndrome, which may be influenced by the primary tumour location. Select patients with resectable pancreatic head tumours may benefit from nutritional rehabilitation to improve outcomes., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Biopsy of suspected pancreatic cancer (PDAC) in surgical candidates is informative however not always necessary. Biopsies impact treatment options as histological diagnosis are presently required for neo-adjuvant therapy, but not surgical resection. We explored the impact of pursuing tissue diagnosis by endoscopic ultrasound (EUS) biopsy on time to treatment in patients with resectable and borderline resectable PDAC., Methods: A retrospective review of surgical patients with ultimately proven PDAC was performed (2011-2021). Milestone dates (cancer suspected, biopsy(ies), surgical or neo-adjuvant treatment) were collected. Mann-Whitney-Wilcoxon tests, Pearson's chi-squared tests, Fisher's exact tests, linear regressions, and Cox proportional hazard models were used for data analysis., Results: Among 131 resectable and 58 borderline resectable patients, the borderline resectable group underwent more biopsies (1.2 vs 0.7, p < 0.0001), were more likely to undergo biopsy at tertiary care centers (67.2% vs 30.5%, p < 0.0001), and trended toward longer time to treatment (49 vs 44 days, p = 0.070). Significant increases in days to treatment were seen in patients with Black race (29 days, p = 0.0002) and Medicare insurance (22 days, p = 0.038) and no biopsies at a tertiary care center (10 days, p = 0.039). After adjusting for covariates, additional biopsies significantly delayed treatment (1 biopsy: 21 days, p = 0.0001; 2 biopsies: 44 days, p < 0.0001; 3 biopsies: 68 days, p < 0.0001)., Conclusions: EUS biopsy significantly impacts time between suspicion and treatment of PDAC. This may be exacerbated by clinical practices increasingly favoring neo-adjuvant therapy that necessitates biopsy-proven disease. Time to treatment may also be impacted by access to tertiary centers and racial disparities., (© 2022. The Society for Surgery of the Alimentary Tract.)

Purpose: The standard of care in resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC) has evolved to include neoadjuvant treatment before surgical resection. Current guidelines call for obtaining histologic tissue diagnosis via endoscopic ultrasound fine-needle aspiration before administration of neoadjuvant therapy, which differ from guidelines discouraging delay in surgical resection for a biopsy., Materials and Methods: Whether to proceed with treatment before a biopsy confirms that malignancy is a nuanced decision and includes considerations of physical and psychological risks entailed in both pursuing and forgoing a biopsy., Results: Accuracy of imaging and biopsy results, the presence of contributing clinical signs/symptoms, and the existing precedents of considering biopsies as waivable such as in scenarios with high clinical suspicion and primary surgical resection., Conclusion: When considering the aspects of ethical medical practice including beneficence (doing good), nonmaleficence (avoiding harm), autonomy (allowing patients to make decisions about their care), and utilitarianism (doing the most good for the most people), analysis of whether guidelines guiding biopsies should continue to differ between resection and neoadjuvant treatments in PDAC is prudent.

Background/objectives: The inherently immunosuppressive tumor microenvironment along with the heterogeneity of pancreatic ductal adenocarcinoma (PDAC) limits the effectiveness of available treatment options and contributes to the disease lethality. Using a machine learning algorithm, we hypothesized that PDAC may be categorized based on its microenvironment inflammatory milieu., Methods: Fifty-nine tumor samples from patients naïve to treatment were homogenized and probed for 41 unique inflammatory proteins using a multiplex assay. Subtype clustering was determined using t-distributed stochastic neighbor embedding (t-SNE) machine learning analysis of cytokine/chemokine levels. Statistics were performed using Wilcoxon rank sum test and Kaplan-Meier survival analysis., Results: t-SNE analysis of tumor cytokines/chemokines revealed two distinct clusters, immunomodulating and immunostimulating. In pancreatic head tumors, patients in the immunostimulating group (N = 26) were more likely to be diabetic (p = 0.027), but experienced less intraoperative blood loss (p = 0.0008). Though there were no significant differences in survival (p = 0.161), the immunostimulating group trended toward longer median survival by 9.205 months (11.28 vs. 20.48 months)., Conclusion: A machine learning algorithm identified two distinct subtypes within the PDAC inflammatory milieu, which may influence diabetes status as well as intraoperative blood loss. Opportunity exists to further explore how these inflammatory subtypes may influence treatment response, potentially elucidating targetable mechanisms of PDAC's immunosuppressive tumor microenvironment., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Clinical trials determine safety and efficacy of cancer therapeutics and establish standards of care. Minority patient participation in cancer clinical trials is dismal. We aimed to determine the impact of eligibility criteria on disparities in pancreatic ductal adenocarcinoma (PDAC) clinical trial candidacy., Methods: Traditional PDAC trial eligibility criteria were obtained from ClinicalTrials.gov. Patients with PDAC who sought care at Virginia Commonwealth University Health from 2010 to 2019 were included. Clinical data were obtained from billing codes and discrete values in the electronic medical record. Eligibility criteria differences between racial groups were determined using chi-squared tests and unconditional maximum likelihood-based odds ratios., Results: Among 676 patients, most identified as Black or White race (42.5% and 51.6%, respectively). Using traditional criteria, Black patients were more likely to be ineligible for participation compared with White patients (42.4% v 33.2%, P = .023) secondary to hypoalbuminemia (14.1% v 7.9%, P = .023), HIV (3.1% v 0.3%, P = .010), hepatitis B (1.7% v 0%, P = .043), and hepatitis C (9.1% v 3.4%, P = .005). Black patients were also numerically more likely to be ineligible because of renal dysfunction, recent coronary stenting, and uncontrolled diabetes mellitus. Prior cancer treatment excluded fewer Black than White patients (9.1% v 14.0%, P = .072), most attributable to lower rates of neoadjuvant chemotherapy received. Strategic eligibility criteria revisions could equalize ineligibility rates between Black and White patients (26.8% v 24.8%, P = .581)., Conclusion: Traditional eligibility criteria differentially exclude Black patients from participating in PDAC clinical trials. These criteria perpetuate disparities, limit generalizability, and are often not medically justifiable. Revised criteria may improve participant diversity, without compromising safety or study results., Competing Interests: Thomas J. GeorgeConsulting or Advisory Role: Tempus, PfizerResearch Funding: Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca/MedImmune (Inst), Lilly (Inst), Bayer (Inst), Incyte (Inst), Ipsen (Inst), Seattle Genetics (Inst), Genentech (Inst), Astellas Pharma (Inst), BioMed Valley Discoveries (Inst), GlaxoSmithKline (Inst)Open Payments Link: https://https://openpaymentsdata.cms.gov/physician/321938No other potential conflicts of interest were reported.

Rationale: The biology of the pancreatic ductal adenocarcinoma (PDAC) is heterogenous, but how heterogenity of the tumor microenvironment contributes to disparate patient outcomes remains essentially unstudied. Methods: A strategy employing multiplex digital spatial profiling (mplxDSP) technology was employed to evaluate the nature and dynamics of microenvironment components including cancer associated fibroblasts (CAFs) and infiltrating immune cells at the single-cell level based upon their spatial relationship within the tumor. Results: We report that myofibroblasts directly adjacent to PDAC tumors comparatively overexpress genes (BATF3, IL12B, ITGB8, CD4 and IFNAR1), constructing pathways prone to stimulating an adaptive immune response. Markers of innate immune cells (Natural Killer cells, Dendritic Cells and macrophages) are predominant in CD45+ cells immediately adjacent to PDAC tumor, however, the checkpoint protein CTLA4 is also overwhelmingly expressed, fostering tolerance. Finaly, mRNA profiling of adjacent CAFs identified clusters of genes that correlate with survival. Conclusion: CAFs and leukocytes in close proximity to PDAC significantly differ from those remote from the tumor, providing insight into microenvironment influence on immune tolerance mediated through relative populations of leukocytes and subsets of CAFs and monocytes. mRNA expression profiling of CAFs adjacent to PDAC cells may hold promise for prognostication., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Interleukin-1 (IL-1) plays a key role in carcinogenesis and several IL-1-targeted therapeutics are under investigation for the treatment of pancreatic ductal adenocarcinoma (PDAC). We sought to broaden our understanding of how the family of IL-1 ligands and receptors impact the tumor immune landscape and patient survival in PDAC. Gene expression data and DNA methylation data for IL1A, IL1B, IL1RN, IL1R1, IL1R2, and IL1RAP was attained from The Cancer Genome Atlas (TCGA) database and cross validated using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Immune cell-type abundance was estimated using CIBERSORTx. Further confirmatory soluble protein analysis and peripheral blood immunophenotyping were performed on available tissue samples from our institution. 169 PDAC patients and 50 benign pancreatic TCGA-based samples were analyzed. IL1A (p < 0.001), IL1RN (p < 0.001), IL1R2 (p < 0.001), and IL1RAP (p = 0.006) were markedly increased in PDAC tumor tissue compared to benign pancreatic tissue. Furthermore, expression of IL1A, IL1B and IL1R1 were positively correlated with gene expression of immune checkpoints PVR, CD274, CD47, CD80, and HLA-A/B/C (p < 0.001). IL1B and IL1R1 were correlated to expression of PDCD1, CD86, CTLA4 and IDO1 (<0.001). Low expression of IL1RN (p = 0.020), IL1R2 (p = 0.015), and IL1RAP (p = 0.003) and high expression of IL1B (p = 0.031) were correlated with increased patient survival. At the protein level, IL-1β was correlated with increased peripheral central memory CD4+ and CD8+ T-cells as well as decreased Th2 cells. These findings suggest that the IL-1 axis plays a complex and pivotal role in the host immune response to PDAC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background and Objectives: Pancreatic neuroendocrine tumors (PNETs) represent a rare form of pancreatic cancer. Racial/ethnic disparities have been documented in pancreatic ductal adenocarcinoma, but health disparities have not been well described in patients with PNETs., Methods: A retrospective review of patients with PNETs in the National Cancer Database was performed for 2004-2014. Approximately 16 605 patients with PNETs and available vital status were identified. Survival was compared by race/ethnicity and socioeconomic status using Kaplan-Meier methods and Cox regression., Results: There were no significant differences in survival between Non-Hispanic, White; Hispanic, White; or Non-Hispanic, Black patients on univariate analysis. Kaplan-Meier analysis showed that patients from communities with lower median household income and education level had worse survival (p < 0.001). Patients age less than 65 without insurance, similarly, had worse survival (p < 0.001). Multivariable modeling found no association between race/ethnicity and risk of mortality (p = 0.37). Lower median household income and lower education level were associated with increased mortality (p < 0.001)., Conclusions: Unlike most other malignancies, race/ethnicity is not associated with survival differences in patients with PNETs. Patients with lower socioeconomic status had worse survival. The presence of identifiable health disparities in patients with PNETs represents a target for intervention and opportunity to improve survival in patients with this malignancy., (© 2021 Wiley Periodicals LLC.)

Background: Disparities exist among patients with pancreatic ductal adenocarcinoma (PDAC). Non-White race is regarded as a negative predictor of expected treatment and overall survival. Data suggest that Academic Research Programs (ARP) provide better outcomes for minorities, but ethnic/minority outcomes are underreported. We hypothesize that outcomes among racially/ethnically diverse PDAC patients may be influenced by treatment facility., Methods: The National Cancer Database was used to identify 170,327 patients diagnosed with PDAC between 2004 and 2015. Cox proportional-hazard regression was used to compare survival between race/ethnic groups across facilities., Results: In unadjusted models, compared to non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB) had the worst overall survival (HR = 1.05, 95%CI: 1.03-1.06, P < .001) and Hispanics had the best overall survival (HR = 0.92, 95%CI: 0.90-0.94, P < .001). After controlling for socioeconomic and clinical covariates, NHB (HR = 0.95, 95%CI: 0.93-0.96, P < .001) had better overall survival compared to NHW, and Hispanics continued to have the best comparative outcomes (HR = 0.84, 95%CI: 0.82-0.86, P < .001). Among Hispanics, Dominicans and South/Central Americans lived the longest, at 10.25 and 9.82 months, respectively. The improved survival in Hispanics was most pronounced at ARP (HR = 0.80, 95%CI: 0.77-0.84, P < .001) and Integrated Network Cancer Programs (HR = 0.78, 95%CI: 0.73-0.84, P < .001). NHB had improved survival over NHW at Comprehensive Community Care Programs (HR = 0.96, 95%CI: 0.93-0.98, P = .002) and ARP (HR = 0.96, 95%CI: 0.94-0.98, P = .001), which was influenced by income, education, and surgical resection., Conclusion: Survival was improved at ARP for all populations. Hispanics had the best comparative overall survival. NHB had improved overall survival at higher volume centers, but this was dependent upon income, education, and surgical resection., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)