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Oral dysbiosis has long been associated with pancreatic ductal adenocarcinoma (PDAC). In this work, we explore the relationship between the oral and tumor microbiomes of patients diagnosed with PDAC. Salivary and tumor microbiomes were analyzed using a variety of sequencing methods, resulting in a high prevalence and relative abundance of oral bacteria, particularly Veillonella and Streptococcus, within tumor tissue. The most prevalent and abundant taxon found within both saliva and tumor tissue samples, Veillonella atypica, was cultured from patient saliva, sequenced and annotated, identifying genes that potentially contribute to tumorigenesis. High sequence similarity was observed between sequences recovered from patient matched saliva and tumor tissue, indicating that the taxa found in PDAC tumors may derive from the mouth. These findings may have clinical implications in the care and treatment of patients diagnosed with PDAC.

Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesized that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF.The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach.A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P.001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone.In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes.

IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence. Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.

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.

Nicotine treatment does not lead to c-Met activation in PC cells.

Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: Taken together, these data demonstrate a novel, microenvironment-dependent paracrine signaling mechanism by which nicotine exposure promotes the growth and metastasis of pancreatic cancer. Clin Cancer Res; 22(7); 1787–99. ©2015 AACR.

Background: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored. Methods: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with a = 0.05 and b = 0.2. Results: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.4 4; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P 1/4 .156). Conclusion: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal. (c) 2021 Elsevier Inc. All rights reserved.

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

Cancer-associated fibroblast (CAF) is abundant in the tumor microenvironment (TME) and broadly accepted as an oncogenic component for pancreatic ductal adenocarcinoma (PDAC). We previously reported a tumor-suppressive role of CAFs via a CAF-specific miRNA that can be efficiently transferred via exosomes within the TME and inhibit PDAC cell growth. In this study, we expanded our search and found several differentially expressed miRNAs within CAFs (CAF-DE-miRNAs) including the most elevated miR-145-5p and miR-199a-5p. These miRNAs exhibit tumor-suppressive roles likely via complex regulation of several signaling proteins within the TGF-β and EGFR (ErbB) signaling pathways. Our study indicates a more complex role of CAFs within the TME and provides a distinct mechanism of CAF-mediated tumor suppression.

BACKGROUND: Evidence suggests that increased early postoperative pain (POP) intensities are associated with increased pain in the weeks following surgery. However, it remains unclear which temporal aspects of this early POP relate to later pain experience. In this prospective cohort study, we used wavelet analysis of clinically captured POP intensity data on postoperative days 1 and 2 to characterize slow/fast dynamics of POP intensities and predict pain outcomes on postoperative day 30. METHODS: The study used clinical POP time series from the first 48 hours following surgery from 218 patients to predict their mean POP on postoperative day 30. We first used wavelet analysis to approximate the POP series and to represent the series at different time scales to characterize the early temporal profile of acute POP in the first two postoperative days. We then used the wavelet coefficients alongside demographic parameters as inputs to a neural network to predict the risk of severe pain 30 days after surgery. RESULTS: Slow dynamic approximation components, but not fast dynamic detailed components, were linked to pain intensity on postoperative day 30. Despite imbalanced outcome rates, using wavelet decomposition along with a neural network for classification, the model achieved an F-score of 0.79 and area under the receiver operating characteristic curve of 0.74 on test-set data for classifying pain intensities on postoperative day 30. The wavelet-based approach outperformed logistic regression (F-score of 0.31) and neural network (F-score of 0.22) classifiers that were restricted to sociodemographic variables and linear trajectories of pain intensities. CONCLUSIONS: These findings identify latent mechanistic information within the temporal domain of clinically documented acute POP intensity ratings, which are accessible via wavelet analyses, and demonstrate that such temporal patterns inform pain outcomes at postoperative day 30. CLINICAL TRIAL NUMBER AND REGISTRY URL: Clinicaltrials.gov, NCT02407743

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play essential roles in gene expression regulation. While miRNAs offer a promising source for developing potent cancer biomarkers, the progress towards clinical utilities remains largely limited, due in part to the long-standing challenge in sensitive, specific, and robust detection of miRNAs in human biofluids. Emerging next-generation molecular technologies, such as the CRISPR-based methods, promise to transform nucleic acid testing. The prevailing strategy used in existing CRISPR-based methods is to hyphenate two separate reactions for pre-amplification, e.g., rolling circle amplification (RCA), and amplicon detection by Cas12a/13a trans-cleavage in tandem. Thus, existing CRISPR-based miRNA assays require multiple manual steps and lack the analytical performance of the gold standard, RT-qPCR. Radically deviating from the existing strategies, we developed a one-step, one-pot isothermal miRNA assay termed “Endonucleolytically eXponenTiated Rolling circle Amplification with the dual-functional CRISPR-Cas12a” (EXTRA-CRISPR) to afford RT-PCR-like performance for miRNA detection. We demonstrated the superior analytical performance of our EXTRA-CRISPR assay to detect miRNAs (miR-21, miR-196a, miR-451a, and miR-1246) in plasma extracellular vesicles, which allowed us to define a potent EV miRNA signature for detection of pancreatic cancer. The analytical and diagnostic performance of our one-pot assay were shown to be comparable with that of the commercial RT-qPCR assays, while greatly simplifying and expediting the analysis workflow. Therefore, we envision that our technology provides a promising tool to advance miRNA analysis and clinical marker development for liquid biopsy-based cancer diagnosis and prognosis.

To investigate the role of intraoperative estimated blood loss (EBL) on development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD).Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development.This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150mL; 151-400mL; 401-1,000 mL;1,000 mL). Impact of additive EBL was assessed using 20 3- factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk.CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P0.001). EBL400mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P0.001).EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.

Background Patients with chronic pancreatitis or pancreatic cancer commonly develop exocrine pancreatic insufficiency, and may not be adequately treated with pancreatic enzyme replacement therapy (PERT). Aims To estimate the frequency of diagnostic testing for exocrine insufficiency, and appropriate use of PERT, in a commercially insured population in the US. Methods We utilised a nationally representative administrative database representing 48.67 million individuals in over 80 US healthcare plans to assess testing for and treatment of exocrine insufficiency in patients who received a diagnosis of chronic pancreatitis (n = 37 061) or pancreatic cancer (n = 32 461) from 2001 to 2013. We identified the details of any testing for exocrine insufficiency and PERT use. We defined appropriate PERT use as a dosage of ≥120 000 USP units of lipase daily. Multiple logistic regression was used to identify predictors of appropriate use of PERT. Results In patients with chronic pancreatitis, 6.5% had any testing for exocrine insufficiency, 30.4% filled a prescription for PERT, and 8.5% were prescribed an adequate dose. In those with pancreatic cancer, 1.9% had testing for exocrine insufficiency, 21.9% filled a prescription for PERT, and 5.5% were prescribed an adequate dose. Number of comorbidities, testing for exocrine insufficiency, pancreatic surgery and duration of enrolment were independent predictors for use and appropriate dosing. Conclusions Testing for exocrine insufficiency, and appropriate dosing of PERT in patients with chronic pancreatitis or pancreatic cancer, is infrequent and inconsistent in an insured US population. Efforts are needed to educate medical providers on the best practices for managing exocrine pancreatic insufficiency in these patients.

Virtually all cells release various types of vesicles into the extracellular environment. These extracellular vesicles (EVs) transport molecular cargoes, performing as communicants for information exchange both within the tumor microenvironment (TME) and to distant organs. Thus, understanding the selective packaging of EV cargoes and the mechanistic impact of those cargoes - including metabolites, lipids, proteins, and/or nucleic acids - offers an opportunity to increase our knowledge of cancer biology and identify EV cargoes that might serve as cancer biomarkers in blood, saliva, or urine samples. In this review, we collect and organize recent advances in this field with an emphasis on pancreatic cancer (pancreatic adenocarcinoma, PDAC) and the concept that cells selectively package cargo into EVs. These studies demonstrate PDAC EV cargoe signals to reprogram and remodel the TME and impact distant organs. EV cargoes identified as potential PDAC diagnostic and prognostic biomarkers are summarized.

Objective This exploratory study seeks to identify distinct circulating immune signatures among patients having recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic adenocarcinoma (PDAC). Methods A retrospective analysis of human serum samples from collaborating institutions of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was performed. Samples came from the North American Pancreatitis Studies 2 (NAPS2) cohort and the Pancreatic Adenocarcinoma Gene Environment Risk Study (PAGER) and were analyzed using a 62-plex Luminex assay in a blinded fashion. Group and pairwise comparisons were performed to identify unique immune signature panels and to calculate diagnostic utility using area under the curve analysis. Results A total of 179 patients’ samples were included: 41 controls, 40 CP, 78 PDAC and 20 RAP patients, of which 20 controls, 20 CP, and 58 PDAC patients had diabetes mellitus (DM). A unique immune signature panel could discriminate RAP, CP, and PDAC from controls with an AUC range from 0.77 to 0.86 (95% CI range: 0.64–0.94), RAP from CP, and CP from PDAC with an AUC of 0.77 (95% CI 0.64–0.90) and 0.76 (95% CI 0.67–0.86), respectively. Furthermore, an immune signature panel could also discriminate PDAC-DM from DM controls with an AUC of 0.96 (95% CI: 0.93–1.00) Conclusion This study identifies unique immune analytes that may serve as novel diagnostic and predictive non-invasive biomarkers of RAP, CP, and PDAC. Further validation is warranted in prospective cohorts as developed by the CPDPC.

In the United States, 37% of all opioids are prescribed in the surgical setting. Among those addicted to narcotics, many report initial exposure in the postoperative period.We aimed to assess the impact of a narcotic-sparing enhanced recovery after surgery protocol on postoperative narcotic use by patients and to assess its impact on the narcotic prescribing practices of physicians.Data regarding consecutive narcotic-naïve patients who underwent an elective inpatient abdominal colorectal surgical procedure from January 2013 to August 2017 were retrospectively reviewed.Patients were divided into 2 cohorts: pre-implementation (2013-2015) and post-implementation (2015-2017) of the enhanced recovery after surgery protocol.Elective inpatient abdominal colorectal surgery patients at University of Florida Health.Primary outcome measure was 30-day postoperative narcotic use (inpatient and outpatient). Other outcomes measured included pain scores, time to diet institution, length of hospital stay, cost of hospitalization, and postoperative complications.Baseline characteristics were similar between the pre- (n = 537) and post-protocol (n = 790) groups. Protocol implementation was associated with a decrease in total 30-day postoperative narcotic amount used by patients (2481 mg vs 31 mg morphine equivalents, p = 0.05), inpatient patient-controlled analgesia use (63% vs 0.5%, p0.00001; dosage 1254 mg vs 5 mg), inpatient on-demand oral narcotic use (90% vs 32%, p = 0.001; dosage 47 mg vs 5 mg), and outpatient narcotic amount used (46 mg vs 6 mg, p = 0.001). Average pain scores were similar.Retrospective nature of the study and possible underestimation of pre- and postoperative narcotic use were limitations to the study findings.Implementation of a narcotic-sparing enhanced recovery after surgery protocol was associated with a decrease in both inpatient and 30-day outpatient postoperative narcotic use. Variation in resident physician prescribing practices suggests the need for ongoing education to accompany these protocols. See Video Abstract at http://links.lww.com/DCR/B936.

This study aims to present a full spectrum of individual patient presentations of pancreatic fistula risk, and to define the utility of mitigation strategies amongst some of the most prevalent, and vulnerable scenarios surgeons encounter.The FRS has been utilized to identify technical strategies associated with reduced CR-POPF incidence across various risk strata. However, risk-stratification using the FRS has never been investigated with greater granularity. By deriving all possible combinations of FRS elements, individualized risk assessment could be utilized for precision medicine purposes.FRS profiles and outcomes of 5533 PDs were accrued from 17 international institutions (2003-2019). The FRS was used to derive 80 unique combinations of patient "scenarios." Risk-matched analyses were conducted using a Bonferroni adjustment to identify scenarios with increased vulnerability for CR-POPF occurrence. Subsequently, these scenarios were analyzed using multivariable regression to explore optimal mitigation approaches.The overall CR-POPF rate was 13.6%. All 80 possible scenarios were encountered, with the most frequent being scenario #1 (8.1%) - the only negligible-risk scenario (CR-POPF rate = 0.7%). The moderate-risk zone had the most scenarios (50), patients (N = 3246), CR-POPFs (65.2%), and greatest non-zero discrepancy in CR-POPF rates between scenarios (18-fold). In the risk-matched analysis, 2 scenarios (#59 and 60) displayed increased vulnerability for CR-POPF relative to the moderate-risk zone (both P0.001). Multivariable analysis revealed factors associated with CR-POPF in these scenarios: pancreaticogastrostomy reconstruction [odds ratio (OR) 4.67], omission of drain placement (OR 5.51), and prophylactic octreotide (OR 3.09). When comparing the utilization of best practice strategies to patients who did not have these conjointly utilized, there was a significant decrease in CR-POPF (10.7% vs 35.5%, P0.001; OR 0.20, 95% confidence interval 0.12-0.33).Through this data, a comprehensive fistula risk catalog has been created and the most clinically-impactful scenarios have been discerned. Focusing on individual scenarios provides a practical way to approach precision medicine, allowing for more directed and efficient management of CR-POPF.

Drain management algorithms are based on studies that predict clinically relevant postoperative pancreatic fistula (CR-POPF) using drain fluid amylase level on POD1 (DFA1). These studies are focused on pancreaticoduodenectomy which is inherently different than distal pancreatectomy. Moreover, the change of DFA between POD1 and POD3 (ΔDFA) is underutilized despite its importance in predicting CR-POPF. We sought to generate a calculator that estimates the risk of CR-POPF following distal pancreatectomy.The 2014-2018 pancreas-targeted ACS-NSQIP database was used to identify patients who underwent elective distal pancreatectomy. Models to predict CR-POPF were constructed using DFA1 with/without ΔDFA. The fittest model was used to construct a calculator.Out of 12,042 distal pancreatectomies, 692 patients met the study's inclusion criteria. The risk of CR-POPF was 15.9% in the included cohort versus 14.8% in the excluded one (P = 0.421). The predictors of the CR-POPF were age, operative time, DFA1, and ΔDFA. Adding ΔDFA decreased the Akaike's information criterion of the model (507.7 vs 544.7)-indicating a significantly better model fit-and improved the cross-validated area under the curve from 0.731 to 0.791. An easy-to-use calculator was created for surgeons to estimate the risk of CR-POPF based on the abovementioned variables. A sensitivity/specificity table was created at various cutoffs to direct clinical decision-making with respect to early drain removal.This study highlights the importance of ΔDFA, in addition to DFA1, in predicting CR-POPF. The provided calculator will facilitate predicting CR-POPF and postoperative drain management following distal pancreatectomy.

Importance Diversity in academic surgery is lacking, particularly among positions of leadership. Objective To evaluate trends among racial/ethnical minority groups stratified by gender along the surgical pipeline, as well as in surgical leadership. Design, setting, and participants This cross-sectional and longitudinal analysis assessed US surgical faculty census data obtained from the Association of American Medical Colleges faculty roster in the Faculty Administrative Management Online User System database. Surgical faculty members captured in census data from December 31, 2013, to December 31, 2019, were included in the analysis. Faculty were identified from the surgery category of the faculty roster, which includes general surgeons and subspecialists, neurosurgeons, and urologists. Main outcomes and measures Gender and race/ethnicity were obtained for surgical faculty stratified by rank. Descriptive statistics with annual percentage of change in representation are reported based on faculty rank. Results A total of 15 653 US surgical faculty, including 3876 women (24.8%), were included in the data set for 2019. Female faculty from racial/ethnic minority groups experienced an increase in representation at instructor and assistant and associate professorship appointments, with a more favorable trajectory than male faculty from racial/ethnic minority groups across nearly all ranks. White faculty maintain most leadership positions as full professors (3105 of 3997 [77.7%]) and chairs (294 of 380 [77.4%]). The greatest magnitude of underrepresentation along the surgical pipeline has been among Black (106 of 3997 [2.7%]) and Hispanic/Latinx (176 of 3997 [4.4%]) full professors. Among full professors, although Black and Hispanic/Latinx male representation increased modestly (annual change, 0.07% and 0.10%, respectively), Black female representation remained constant (annual change, 0.00004%) and Hispanic/Latinx female representation decreased (annual change, -0.16%). Overall Hispanic/Latinx (20 of 380 [5.3%]) and Black (13 of 380 [3.4%]) representation as chairs has not changed, with only 1 Black and 1 Hispanic/Latinx woman ascending to chair from 2013 to 2019. Conclusions and relevance A disproportionately small number of faculty from minority groups obtain leadership positions in academic surgery. Intersectionality may leave female members of racial/ethnic minority groups more disadvantaged than their male colleagues in achieving leadership positions. These findings highlight the urgency to diversify surgical leadership.

Lessons Learned Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders. Background Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D). Methods In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1–14, oxaliplatin 85 mg/m2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls. Results Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3–8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9–12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%). Conclusion The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC.

Background: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood.Methods: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models.Results: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (>400 pancreatoduodenectomies performed or >21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruc-tion and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experi-ence. Moreover, minimizing blood loss (

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death in the United States. Recently, intensive research has revealed the remarkable heterogeneity and complexity of the different components in the pancreatic cancer tumor microenvironment. However, our knowledge regarding active stroma (dominated with activated cancer-associated fibroblasts), infiltrated immune cells and actual tumor cells interactions in the tumor microenvironment, and how these interactions impact patient outcomes, remains limited. Digital spatial profiling (DSP) technology now allows us to quantitatively analyze transcript and protein expression on intact tissue, offering an opportunity to study the intra-tumor cell-to-cell communication. Formalin-fixed paraffin-embedded (FFPE) pancreatic tumors from patients with shorter survival (DFS < 12 months, n=2), and longer survival (DFS > 36 months, n=2) were recruited in this study. Immunofluorescent histochemistry staining of tissue morphology identification uses antibodies to pan-cytokeratin (panCK+) for PDAC cells, alpha-smooth muscle actin (aSMA+) for cancer-associated fibroblasts (CAFs). Six replicated regions of interest (ROI) of tumor, CAFs adjacent and distal to tumor area were annotated from each tissue sample and a panel of 78 transcripts (73 target genes and 5 reference genes) were profiled using GeoMx DSP (Nanostring). Person’s correlation (R2) was computed for regression of GeoMx DSP data. All statistical analyses were performed using the GraphPad Prism software. p-values were calculated on two-sided t-tests and p < 0.05 was considered statistically significant. As expected, the morphologic selection successfully separates panCK+ PDAC cells from CAFs demonstrated by the correspondent expression of epithelial genes of EpCam and KRT, allowing single cell profiling. Within the panel of 78 genes, 9 genes (approximal 12%) were detected with significantly higher expression levels in PDAC cells than CAFs. Five genes (BATF3, IL12b, ITGB8, CD4 and IFNAR1) were found increased expression levels in CAFs-adj comparing to CAFs-dis, regulating molecular functions of Organismal Death (p value = 3.88E-03), Maturation of Cells (p value = 2.94E-06), and Migration of Cells (p value = 2.37E-03). When comparing the differential transcriptomes in PDAC cells between the longer and shorter survival groups, higher expression of antigen presentation gene HLA-E and integrin alpha- and beta- family genes (ITGAV, ITGAX, ITGB2, and ITGB8) was seen in longer-lived patients. Proliferation genes (CCND1 and MKI67) were also found to be increased in CAFs in patients with longer survival. Our results suggest that further exploration of gene and protein expression and interactions within the pancreatic tumor microenvironment may improve our understanding of tumor and stromal communication and how it impacts on patient outcomes. Citation Format: Gerik W Tushoski, Dongtao Ann Fu, Lingsong Meng, Kelly Herremans, Andrea N Riner, Christopher E Forsmark, Zhiguang Huo, Steven J Hughes, Song Han. Digital spatial profiling for determination of pancreatic stromal components and correlation with survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5676.

e16306 Background: Duodenal adenocarcinoma (DA) is a rare malignancy with poor outcomes. Tumor markers are used to assess disease response and to monitor for recurrence. Specifically, CA-19-9 and CEA have been validated for use in pancreatic cancer and colorectal cancer, respectively. However, these tumor markers have never been validated in patients with DA. We aim to assess the association of these biomarkers with clinical outcomes in patients with DA. Methods: This is a retrospective cohort study. After obtaining IRB approval (IRB202102705), we accessed the University of Florida medical records of patient treated for DA from January 1, 2006, until December 31, 2021. CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal CA 19-9 < = 35 U/ml; CEA < = 3 ng/ml). Analysis was conducted using Kaplan Meyer curves, log-rank test and Cox proportional hazards model. Results: A total of 68 patients were included in the final analysis. Median age was 67 years and median follow-up was 22.2 months. CA 19-9 and CEA were elevated in 36.8% and 48.5% of patients, respectively. Patients with an elevated CA 19-9 had a median overall survival (OS) of 8.5 months vs. 27.4 months in patients with normal levels (HR 1.67; 95%CI 0.94–2.99; p = 0.081). Patients with an elevated CEA had a median OS of 13.4 months vs. 16.8 months in patients with normal level normal levels (HR 1.43; 95%CI 0.81–2.52; p value = 0.221). In a sensitivity analysis, a concomitant elevation of both tumoral markers was significantly associated with worsened OS (HR 1.9; 95%CI 1.05–3.06; p = 0.035). Conclusions: In patients with duodenal adenocarcinoma, elevation of both CA 19-9 and CEA was associated with a statistically significant worse overall survival. CA 19-9 level had a higher prognostic impact on OS than CEA levels. To our knowledge, this is the first study to evaluate the role of CA 19-9 and CEA in patients with DA. Further research is required for validation.[Table: see text]

e15548 Background: Stage IV colon cancer has a dismal prognosis with a 5-yr survival rate of only 14%. The role of liver metastasectomy is well established. However, it is not clear if there is a survival benefit for metastasectomy in cases of extrahepatic disease. Methods: We conducted a retrospective cohort study, US hospital-based. The NCDB version 2017 was accessed. Exposure variable: metastasectomy for extrahepatic distant disease, analyzed as binary. Outcome: overall survival. Kaplan Meier curves and log rank test were used for survival analysis. The primary endpoint was to estimate the association between metastasectomy and survival. Covariates demographic factors, age, sex, race, insurance status, site of metastatic disease – lung, liver, bone, brain. A Cox proportional hazards model was used to evaluate the impact of metastasectomy of extrahepatic disease in patients with stage IV colon cancer. 95% confidence intervals and p values of less than 0.05 were used for statistical significance. Missing data as handled with complete and available case analysis. Statistical analysis was done using Stata 16. Results: A total of 68,334 adult patients with stage IV colon cancer diagnosed in from 2010 -2016 were included in the final analysis. Median age was 64 years (SD 14.1). Prevalence of metastases in this stage IV population was as follows: Liver 72.12%, Lung 20.12%, Bone 5.06%, Brain: 1.6%. A total of 10,595 patients (15.5%) had metastasectomy. Median overall survival were as follows: Lung, 21.59 months with surgery vs 8.41 months no surgery. Bone, 7.03 mo vs 4.53 mo respectively; Brain 9.3 mo vs 3.15 mo; Liver 33.28 mo vs 10.97 mo. In univariate analysis, patients with lung metastases had an improved survival if they had metastasectomy (vs no surgery, HR 0.58, p < 0.0001, 95% CI 0.52 – 0.60). The same benefit was observed in patients with bone (HR 0.80, p 0.001, 95% CI 0.69 – 0.91) and brain metastases (HR 0.56, p < 0.001, 95%CI 0.49 – 0.65). In multivariable analysis the survival advantage was still significant. In a sensitivity analysis, excluding patients with liver metastases, the improvement in survival persisted. Conclusions: Metastasectomy for extrahepatic disease improved overall survival in patients with colon cancer in this retrospective analysis. Further research is needed before routinely incorporating it in clinical practice.[Table: see text]

TPS4196 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) is FDA approved in combination with 5-FU/LV with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]

OBJECTIVE: Acute postoperative pain intensity is associated with persistent postsurgical pain risk. However, it remains unclear whether acute postoperative pain intensity mediates the relationship between clinical factors and persistent pain. METHODS: Subjects from a mixed surgical population completed the Brief Pain Inventory and pain catastrophizing scale before surgery, and the Brief Pain Inventory daily after surgery for 7 days and at 30 and 90 days after surgery. We considered mediation models using the mean of the worst pain intensities collected daily on each of postoperative days (PODs) 1 to 7 against outcomes of worst pain intensity at the surgical site endpoints reflecting persistent postsurgical pain (POD 90) and subacute pain (POD 30). RESULTS: The analyzed cohort included 284 subjects for the POD 90 outcome. For every unit increase of maximum acute postoperative pain intensity through PODs 1 to 7, there was a statistically significant increase of mean POD 90 pain intensity by 0.287 after controlling for confounding effects. The effects of female vs. male sex (m=0.212, P=0.034), pancreatic/biliary vs. colorectal surgery (m=0.459, P=0.012), thoracic cardiovascular vs. colorectal surgery (m=0.31, P=0.038), every minute increase of anesthesia time (m=0.001, P=0.038), every unit increase of preoperative average pain score (m=0.012, P=0.015), and every unit increase of catastrophizing (m=0.044, P=0.042) on POD 90 pain intensity were mediated through acute PODs 1 to 7 postoperative pain intensity. DISCUSSION: Our results suggest the mediating relationship of acute postoperative pain on persistent postsurgical pain may be predicated on select patient and surgical factors.

Background Neoadjuvant therapy prior to resection of adenocarcinoma of the pancreatic head increases time to surgery and thus the possibility of biliary complications. We hypothesized that biliary complications during neoadjuvant therapy negatively impact clinical outcomes. Methods We completed a retrospective study of a cohort of borderline resectable patients consistently treated with neoadjuvant therapy from May 2014 through March 2019. Biliary complications were defined as new-onset biliary obstruction, existing stent failure, cholecystitis, and cholangitis. Results Of 59 patients that met inclusion criteria, 34 (57.6%) went on to resection. Biliary complications affected 16 patients (27%); 8 (50%) of these patients went on to surgical resection. Of those 43 patients who did not have a biliary intervention, 26 went on to surgical resection (60.4%). There was no significant effect of a biliary complication on total number of chemotherapy cycles (p = 0.12), proceeding to surgical resection (p = 0.56) or on median survival (p = 0.23). Among patients who did proceed to surgery, there was a notable difference in median survival for patients who required a biliary intervention (17.9 vs 31.0 months) that did not reach significance (p = 0.35). Conclusion The need for further biliary interventions during neoadjuvant therapy for pancreatic adenocarcinoma is common, but does not appear to have a significant effect on number of cycles of neoadjuvant therapy or proceeding to surgical resection. Larger studies are necessary to determine if these events compromise overall survival.

Minimally invasive approaches to abdominal surgical procedures have provided superior outcomes when compared to the open approach and thus have become the standard of care. However, minimally invasive pancreatoduodenectomy (MIPD) presents unique difficulties for both laparoscopic and robotic platforms and remains controversial. Ongoing concerns continue about the minimally invasive approach creating meaningful benefit when system-wide data may suggest MIPD results in increased morbidity and mortality during the learning curve. This treatise explores the current state of MIPD, reviewing the volume and quality of data that supports benefit while contrasting the benefits to the unique challenges associated with MIPD that may lead to unacceptable rates of complications and death. We conclude that in a handful of centers, MIPD confers an iterative but not transformative benefit. Significant barriers to the wide-spread acceptance of MIPD are apparent and persist, including: lack of high level data confirming clinical benefit, well defined patient selection criteria, formal education programs that address challenges of the learning curve, and ultimately value.

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.

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.