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BackgroundCurrent diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) has important limitations and better biomarkers are needed to guide initial therapy. We investigated the performance of circulating tumour cells (CTCs) as an adjunctive biomarker at the time of disease presentation.MethodsVenous blood (VB) was collected prospectively from 100 consecutive, pre-treatment patients with PDAC. Utilising the microfluidic NanoVelcro CTC chip, samples were evaluated for the presence and number of CTCs. KRAS mutation analysis was used to compare the CTCs with primary tumour tissue. CTC enumeration data was then evaluated as a diagnostic and staging biomarker in the setting of PDAC.ResultsWe found 100% concordance for KRAS mutation subtype between primary tumour and CTCs in all five patients tested. Evaluation of CTCs as a diagnostic revealed the presence of CTCs in 54/72 patients with confirmed PDAC (sensitivity=75.0%, specificity=96.4%, area under the curve (AUROC)=0.867, 95% CI=0.798-0.935, and P

Purpose: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE., Methods: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE., Results: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE., Conclusions: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging., (© 2024. Society of Surgical Oncology.)

Background: Pancreaticoduodenectomy is a highly morbid operation with significant resource utilization. Using a national cohort, we examined the interhospital variation in pancreaticoduodenectomy hospitalization cost in the United States., Methods: Adults undergoing elective pancreaticoduodenectomy in the setting of pancreatic cancer were tabulated from the 2016-2020 Nationwide Readmissions Database. A 2-level mixed-effects model was developed to evaluate the interhospital variation in pancreaticoduodenectomy hospitalization costs. Institutions within the top decile of risk-adjusted expenditures were defined as high-cost hospitals. Multivariable regression models were fitted to examine the association between high-cost hospital status and outcomes of interest. To account for the effects of complications on expenditures, a subgroup analysis comprising of patients with no adverse events was conducted., Results: The study included an estimated 24,779 patients with a median hospitalization cost of $38,800. After mixed-effects modeling, 40.9% of the cost variation was attributable to hospital, rather than patient, factors. Multivariable regression models revealed an association between high-cost hospital status and greater odds of complications and longer length of stay. Among patients without an adverse event, interhospital cost variation remained significant at 61.0%, and treatment at high-cost hospitals was similarly linked to longer length of stay., Conclusion: Our study identified significant interhospital variation in pancreaticoduodenectomy hospitalization costs in the United States. Although high-cost hospital status was associated with increased odds of complications, variation remained significant even among patients without an adverse event. These results suggest the important role of hospital practices as contributors to expenditures. Further efforts to identify drivers of costs and standardize pancreatic surgical care are warranted., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pancreatic neuroendocrine tumors (pNETs) are genomically diverse tumors. The management of newly diagnosed well-differentiated pNETs is limited by a lack of sensitivity of existing biomarkers for prognostication. Our goal was to investigate the potential utility of genetic markers as a predictor of progression-free survival (PFS) and recurrence-free survival (RFS)., Methods: Whole-exome sequencing of resected well-differentiated, low and intermediate-grade (G1 and G2) pNETs and normal adjacent tissue from patients who underwent resection from 2005 to 2015 was performed. Genetic alterations were classified using pan-genomic and oncogenic pathway classifications. Additional samples with genetic and clinicopathologic data available were obtained from the publicly available International Cancer Genome Consortium (ICGC) database and included in the analysis. The prognostic relevance of these genomic signatures on PFS and RFS was analyzed., Results: Thirty-one patients who underwent resection for pNET were identified. Genomic analysis of mutational, copy number, cytogenetic, and complex phenomena revealed similar patterns to prior studies of pNETs with relatively few somatic gene mutations but numerous instances of copy number changes. Analysis of genomic and clinicopathologic outcomes using the combined data from our study as well as the ICGC pNET cohort (n = 124 patients) revealed that the recurrent pattern of whole chromosome loss (RPCL) and metastatic disease were independently associated with disease progression. When evaluating patients with local disease at the time of resection, RPCL and alterations in the TGFβ oncogenic pathway were independently associated with the risk of recurrence., Conclusions: Well-differentiated pNETs are genomically diverse tumors. Pathway signatures may be prognostic for predicting disease progression and recurrence., (© 2024 Wiley Periodicals LLC.)

Background and Objectives: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation., Methods: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis., Results: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001)., Conclusions: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody-drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2-307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies., (©2023 American Association for Cancer Research.)

Purpose: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity., Experimental Design: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo., Results: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation., Conclusions: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition., (©2023 American Association for Cancer Research.)

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Background: With a large body of literature demonstrating positive volume-outcome relationships for most major operations, minimum volume requirements have been suggested for concentration of cases to high-volume centers (HVCs). However, data are limited regarding disparities in access to these hospitals for pancreatectomy patients., Methods: The 2005-2018 National Inpatient Sample (NIS) was queried for all elective adult hospitalizations for pancreatectomy. Hospitals performing more than 20 annual cases were classified as HVCs. Mixed-multivariable regression models were developed to characterize the impact of demographic factors and case volume on outcomes of interest., Results: Of an estimated 127,527 hospitalizations, 79.8% occurred at HVCs. Patients at these centers were more frequently white (79.0 vs 70.8%; p < 0.001), privately insured (39.4 vs 34.2%; p < 0.001), and within the highest income quartile (30.5 vs 25.0%; p < 0.001). Adjusted analysis showed that operations performed at HVCs were associated with reduced odds of in-hospital mortality (adjusted odds ratio [AOR], 0.43; 95% confidence interval [CI], 0.34-0.55), increased odds of discharge to home (AOR, 1.17; 95% CI, 1.04-1.30), shorter hospital stay (β, -0.81 days; 95% CI, -1.2 to -0.40 days), but similar costs. Patients who were female (AOR, 0.88; 95% CI, 0.79-0.98), non-white (black: AOR, 0.66; 95% CI, 0.59-0.75; Hispanic: AOR, 0.56; 95% CI, 0.47-0.66; reference, white), insured by Medicaid (AOR, 0.63; 95% CI, 0.56-0.72; reference, private), and within the lowest income quartile (AOR, 0.73; 95% CI, 0.59-0.90; reference, highest) had decreased odds of treatment at an HVC., Conclusions: For those undergoing pancreatectomies, HVCs realize superior clinical outcomes but treat lower proportions of female, non-white, and Medicaid populations. These findings may have implications for improving access to high-quality centers., (© 2023. The Author(s).)

Background: Pancreaticoduodenectomy (PD) is complex procedure with high morbidity in the elderly. This retrospective study aimed to compare post-operative outcomes in patients ≥75 years of age who underwent robot-assisted (RA)PD and open PD., Methods: We analyzed 2502 patients ≥75 years of age who underwent PD from 2015 to 2018 in the National Surgical Quality Improvement Program (NSQIP) database. RAPD and open PD patients were propensity score matched 1:5 to assess the 30-day outcomes of interest: postoperative complications, length of stay, discharge destination, and readmissions., Results: Of 725 matched patients, 110 underwent RAPD, 615 OPD, and 12 were converted to an open operation. Post-operative outcomes were largely similar between cohorts. RAPD was associated a shorter length of stay (median 8 days, interquartile range [IQR] 6 to 11) than OPD (median 8 days, IQR 7 to 13) (p = 0.003). However, RAPD was associated with more readmissions (28.1% vs. 17.7%; p = 0.02)., Conclusions: RAPD in patients ≥75 years of age appears to be safe and has a similar complication profile to open PD. Randomized or well-designed prospective matched studies are needed to confirm these findings., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Pancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC., Methods: In this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast-enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses., Results: Survival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P < 0.05)., Conclusions: A CT-transcriptomic RG map for PDAC composed of semantic and quantitative traits with associated biology processes predictive of overall survival, was constructed, that serves as a reference for further mechanistic studies for non-invasive phenotyping of pancreatic tumors., (© 2023. The Author(s).)

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies., Significance: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247., (©2022 The Authors; Published by the American Association for Cancer Research.)

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18 F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18 F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18 F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18 F-FDG uptake in the spleen. The average spleen SUV max in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice ( P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18 F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18 F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Emotional regulation is increasingly gaining acceptance as a means to improve well-being, performance, and leadership across high-stakes professions, representing innovation in thinking within the field of surgical education. As one part of a broader cognitive skill set that can be trained and honed, emotional regulation has a strong evidence base in high-stress, high-performance fields. Nevertheless, even as Program Directors and surgical educators have become increasingly aware of this data, with emerging evidence in the surgical education literature supporting efficacy, hurdles to sustainable implementation exist. In this white paper, we present evidence supporting the value of emotional regulation training in surgery and share case studies in order to illustrate practical steps for the development, adaptation, and implementation of emotional regulation curricula in three key developmental contexts: basic cognitive skills training, technical skills acquisition and performance, and preparation for independence. We focus on the practical aspects of each case to elucidate the challenges and opportunities of introducing and adopting a curricular innovation into surgical education. We propose an integrated curriculum consisting of all three applied contexts for emotional regulation skills and advocate for the dissemination of such a longitudinal curriculum on a national level., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.

Background: General surgery residents commonly engage in research years after the second (Post-postgraduate year 2 [PostPGY2]) or third (PostPGY3) clinical training year. The impact of dedicated research training timing on training experience is unknown. Our aim was to examine the progression of residents' perceived meaningful operative autonomy and evaluate career satisfaction, in relation to research timing., Methods: Categorical surgery residents with 2-year research requirements were surveyed regarding perceived autonomy for laparoscopic appendectomy, laparoscopic cholecystectomy, and right hemicolectomy and satisfaction with the impact of dedicated research training on professional development. Meaningful operative autonomy was defined as Zwisch scores ≥3 (passive help or supervision only)., Results: Residents from 17 programs participated (n = 233, 30.6%); 48% were PostPGY2. PostPGY3 residents were more likely to perceive meaningful operative autonomy when starting dedicated research training (laparoscopic appendectomy: 98% vs 74%, P < .001; laparoscopic cholecystectomy: 87% vs 48%, P < .001; right hemicolectomy: 27% vs 3%, P < .001). Meaningful operative autonomy declined during dedicated research training but was still higher for PostPGY3 residents for laparoscopic appendectomy (84% vs 42%, P < .001) and laparoscopic cholecystectomy (68% vs 30%, P < .001). By PGY4, PostPGY2 residents reported rates of meaningful operative autonomy comparable to PostPGY3 through training completion. A higher proportion of PostPGY3 residents reported dedicated research training satisfaction (90% vs 78%, P = .01). Training at PostPGY3 programs (odds ratio, 3.06, 95% confidence interval, 1.38-6.80) and postresearch training stage (compared with preresearch residents, odds ratio, 3.25, 95% confidence interval, 1.06-10.0) were independently associated with satisfaction., Conclusion: Significant differences existed in the progression of perceived operative autonomy and dedicated research training satisfaction between PostPGY2 and PostPGY3 residents. These results could help surgical educators make individualized decisions regarding research timing to promote surgical skill acquisition and resident well-being., (Copyright © 2022 Elsevier Inc. All rights reserved.)

WNT signaling promotes pancreatic ductal adenocarcinoma (PDAC) through diverse effects on proliferation, differentiation, survival, and stemness. A subset of PDAC with inactivating mutations in ring finger protein 43 (RNF43) show growth dependency on autocrine WNT ligand signaling and are susceptible to agents that block WNT ligand acylation by Porcupine O-acyltransferase, which is required for proper WNT ligand processing and secretion. For this study, global transcriptomic, proteomic, and metabolomic analyses were performed to explore the therapeutic response of RNF43-mutant PDAC to the Porcupine inhibitor (PORCNi) LGK974. LGK974 disrupted cellular bioenergetics and mitochondrial function through actions that included rapid mitochondrial depolarization, reduced mitochondrial content, and inhibition of oxidative phosphorylation and tricarboxylic acid cycle. LGK974 also broadly altered transcriptional activity, downregulating genes involved in cell cycle, nucleotide metabolism, and ribosomal biogenesis and upregulating genes involved in epithelial-mesenchymal transition, hypoxia, endocytosis, and lysosomes. Autophagy and lysosomal activity were augmented in response to LGK974, which synergistically inhibited tumor cell viability in combination with chloroquine. Autocrine WNT ligand signaling dictates metabolic dependencies in RNF43-mutant PDAC through a combination of transcription dependent and independent effects linked to mitochondrial health and function. Metabolic adaptations to mitochondrial damage and bioenergetic stress represent potential targetable liabilities in combination with PORCNi for the treatment of WNT ligand-addicted PDAC., (©2022 American Association for Cancer Research.)

Background: Pathological treatment effect of resected pancreatic adenocarcinoma after neoadjuvant therapy has prognostic implications. The impact for patients who received chemotherapy alone or chemoradiotherapy is not well defined., Methods: Patients with localized pancreatic adenocarcinoma who had pancreatectomy after neoadjuvant therapy at 3 centers from 2011 to 2017 were retrospectively analyzed. The chemotherapy and chemoradiotherapy groups were evaluated separately., Results: Of 525 patients, 148 received neoadjuvant chemotherapy and 377 received chemoradiotherapy. The chemoradiotherapy group had a better treatment effect (score 0: 10%, score 1: 30%, score 2: 42%, and score 3: 18%) than the chemotherapy group (score 0: 2%, score 1: 8%, score 2: 35%, and score 3: 55%) (P < .001). Median overall survival was similar between the 2 groups (25.8 vs 26.4 months). Median overall survival for score 0/1, 2, or 3 was 72.2, 38.5, and 20.0 months in the chemotherapy group and 37.9, 24.5, and 19.0 months in the chemoradiotherapy group. Score 2 in the chemotherapy group was associated with better overall survival compared to score 3 (adjusted hazard ratio: 0.49, P = .005), whereas only combined score 0/1 reached significance over score 2 for the chemoradiotherapy group (hazard ratio: 0.63, P = .006)., Conclusion: The prognostic significance of pathological treatment effect for localized pancreatic adenocarcinoma differs for patients receiving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The purpose of this study was to evaluate 18 F-FDG PET/CT as an early and late interim imaging biomarker in patients with pancreatic ductal adenocarcinoma who undergo first-line systemic therapy. Methods: This was a prospective, single-center, single-arm, open-label study (IRB12-000770). Patient receiving first-line chemotherapy were planned to undergo baseline 18 F-FDG PET/CT, early interim 18 F-FDG PET/CT, and late interim 18 F-FDG PET/CT. Cutoffs for metabolic and radiographic tumor response assessment as selected and established by receiver-operating-characteristic analysis were applied (modified PERCIST/RECIST1.1). Patients were followed to collect data on further treatments and overall survival. Results: The study population consisted of 28 patients who underwent baseline 18 F-FDG PET/CT. Twenty-three of these (82%) underwent early interim 18 F-FDG PET/CT, and 21 (75%) underwent late interim 18 F-FDG PET/CT. Twenty-three deaths occurred during a median follow-up period of 14 mo (maximum follow-up, 58.3 mo). The median overall survival was 36.2 mo (95% CI, 28 mo to not yet reached [NYR]) in early metabolic responders (6/23 [26%], P = 0.016) and 25.4 mo (95% CI, 19.6 mo-NYR) in early radiographic responders (7/23 [30%], P = 0.16). The median overall survival was 27.4 mo (95% CI, 21.4 mo-NYR) in late metabolic responders (10/21 [48%], P = 0.058) and 58.2 mo (95% CI, 21.4 mo-NYR) in late radiographic responders (7/21 [33%], P = 0.008). Conclusion: 18 F-FDG PET may serve as an early interim imaging biomarker (at ∼4 wk) for evaluation of response to first-line chemotherapy in patients with pancreatic ductal adenocarcinoma. Radiographic changes might be sufficient for response evaluation after the completion of first-line chemotherapy., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors., Competing Interests: Declaration of interests C.G.R. and J. Czernin are co-founders of Sofie Biosciences and Trethera Corporation. They and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. T.R.D. is an executive board member and holds equity in Trethera Corporation. The intellectual property developed by C.G.R. and J. Czernin and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Female surgeons face gender-specific obstacles during residency training, yet longitudinal data on gender bias experienced by female surgery residents are lacking. We aimed to investigate the evolution of gender bias, identify obstacles experienced by female general surgery residents, and discuss approaches to supporting female surgeons during residency training., Methods: Between August 2019 and January 2021, we conducted a retrospective cohort study using structured telephone interviews of female graduates of the UCLA General Surgery Residency training program. Responses of early graduates (1981-2009) were compared with those of recent graduates (2010-2020). Quantitative data were compared with Fisher's exact tests and Chi-squared tests. Interview responses were reviewed to catalog gender bias, obstacles experienced by female surgeons, and advice offered to training programs to address women's concerns., Results: Of 61 female surgery residency graduates, 37 (61%) participated. Compared to early graduates (N = 20), recent graduates (N = 17) were significantly more likely to pursue fellowship training (100% vs. 65%, p < 0.01) and have children before or during residency (65% vs. 25%, p = 0.02). A substantial proportion in each cohort experienced some form of gender bias (71% vs. 85%, p = 0.43). Compared to early graduates, recent graduates were significantly less likely to report experiencing explicit gender bias (12% vs. 50%, p = 0.02) but equally likely to report implicit gender bias (71% vs. 55%, p = 0.50). Female graduates across the decades advocated for specific measures to champion work-life balance in residency (51%), strengthen female mentorship (49%), increase childcare support (41%), and promote women into leadership positions (32%)., Conclusions: While having children during residency has become more common and accepted over the decades, female surgery residents continue to experience implicit gender bias in the workplace. Female surgeons advocate for targeted interventions to establish systems for parental leave, address gender bias, and strengthen female mentorship., Competing Interests: Declarations of Interest None., (Copyright © 2021 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT). Accordingly, IFN treatment up-regulates cancer cell [ 18 F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [ 18 F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [ 18 F]FLT uptake in vivo following systemic treatment. These findings indicate that [ 18 F]FLT accumulation in tumors is sensitive to IFN signaling and that [ 18 F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression., Competing Interests: Competing interest statement: C.G.R. and J. Czernin are cofounders of Sofie Biosciences and the Trethera Corporation. They and the University of California hold equity in Sofie Biosciences and the Trethera Corporation. T.R.D. is an executive board member and holds equity in the Trethera Corporation.

Importance: The suspension of elective operations in March 2020 to prepare for the COVID-19 surge posed significant challenges to resident education. To mitigate the potential negative effects of COVID-19 on surgical education, it is important to quantify how the pandemic influenced resident operative volume., Objective: To examine the association of the pandemic with general surgical residents' operative experience by postgraduate year (PGY) and case type and to evaluate if certain institutional characteristics were associated with a greater decline in surgical volume., Design, Setting, and Participants: This retrospective review included residents' operative logs from 3 consecutive academic years (2017-2018, 2018-2019, and 2019-2020) from 16 general surgery programs. Data collected included total major cases, case type, and PGY. Faculty completed a survey about program demographics and COVID-19 response. Data on race were not collected. Operative volumes from March to June 2020 were compared with the same period during 2018 and 2019. Data were analyzed using Kruskal-Wallis test adjusted for within-program correlations., Main Outcome and Measures: Total major cases performed by each resident during the first 4 months of the pandemic., Results: A total of 1368 case logs were analyzed. There was a 33.5% reduction in total major cases performed in March to June 2020 compared with 2018 and 2019 (45.0 [95% CI, 36.1-53.9] vs 67.7 [95% CI, 62.0-72.2]; P < .001), which significantly affected every PGY. All case types were significantly reduced in 2020 except liver, pancreas, small intestine, and trauma cases. There was a 10.2% reduction in operative volume during the 2019-2020 academic year compared with the 2 previous years (192.3 [95% CI, 178.5-206.1] vs 213.8 [95% CI, 203.6-223.9]; P < .001). Level 1 trauma centers (49.5 vs 68.5; 27.7%) had a significantly lower reduction in case volume than non-level 1 trauma centers (33.9 vs 63.0; 46%) (P = .03)., Conclusions and Relevance: In this study of operative logs of general surgery residents in 16 US programs from 2017 to 2020, the first 4 months of the COVID-19 pandemic was associated with a significant reduction in operative experience, which affected every PGY and most case types. Level 1 trauma centers were less affected than non-level 1 centers. If this trend continues, the effect on surgical training may be even more detrimental.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with KRAS, NRAS, NF1, BRAF non-V600 , and BRAF V600 mutations. Tumor cell-intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8 + T cells, and durable tumor regression elicited by this combination requires CD8 + T cells, which can be reinvigorated by anti-PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy. SIGNIFICANCE: Type I RAFi + MEKi are indicated only in certain BRAF V600MUT cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8 + T cells are mechanisms that may be further exploited. This article is highlighted in the In This Issue feature, p. 521 ., (©2020 American Association for Cancer Research.)

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo., Competing Interests: Competing interest statement: C.G.R. is a cofounder of Sofie Biosciences and Trethera Corporation. He and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. The intellectual property developed by C.G.R. and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study.

Background: In patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who undergo neoadjuvant therapy, CT imaging is the standard of care for restaging. However, differentiating residual tumor from post-treatment inflammation with CT is unreliable. The diagnosis of periarterial soft tissue cuffing (PSTC) near major vessels is key to guiding resectability. The goal of this study was to assess the utility of EUS-FNA in determining the etiology of PSTC in BRPC or LAPC after neoadjuvant treatment., Methods: We performed a retrospective analysis of patients referred for EUS-FNA of PSTC following downstaging therapy for LAPC or BRPC at our tertiary medical center. Negative EUS-FNA cytology results were compared with surgical pathology after resection. Patients with positive EUS-FNA cytology results were either followed clinically or results were compared to surgical pathology if surgery was attempted despite the positive cytology., Results: Fourteen patients were included in the study of whom four had positive cytology. Two of these patients had progression of disease, and two had attempted resection with positive surgical pathology (100% true positives). All ten patients with negative cytology underwent attempted surgical resection. Nine patients (90%) achieved negative margins, and one patient (10%) had a positive surgical margin. The sensitivity, specificity, and accuracy of EUS-FNA for determining resectability were 80%, 100%, and 92.9%, respectively., Conclusions: In this series of patients with BRPC or LAPC and persistent PSTC after downstaging neoadjuvant treatment, EUS-FNA accurately determined surgical resectability and should be considered as part of the evaluation of such patients.

Background: Pancreatic enucleation (PE) is a viable option for the removal of non-malignant pancreatic masses leading to complete preservation of organ function. Nevertheless, PE is associated with substantial rates of post-operative pancreatic fistula (POPF), particularly when the mass is close to the main pancreatic duct (MPD). Preoperative stenting of the MPD may prevent its injury when performing PE. This paper describes a novel technique of "deep" PE preceded by endoscopic stenting of the MPD., Methods: From January 2017 to May 2019, patients with small pancreatic neuroendocrine tumors proximal to the MPD were candidates for PE with previous stenting of the MPD at the University of Verona, Italy, and at the UCLA Medical Center, Los Angeles, California. The endoscopic stenting was scheduled either the day before or 3 weeks before surgery, depending on the participating institute., Results: Ten patients were included in this pilot study. The endoscopic procedure was successful and well tolerated in all cases. Open, laparoscopic and robotic PE were performed. Seven patients had surgical complications. Among these, six developed a post-operative pancreatic fistula (POPF), but neither grade C fistulas nor disruptions of the MPD were detected. At pathology, a low grade pancreatic neuroendocrine tumor was confirmed in all cases., Conclusion: In the setting of high-volume centers, this procedure is safe, and it is associated with acceptable short-term surgical morbidity. The preoperative stenting of the MPD might extend the surgical indications for PE.

Background: Resection margin status has been recognized as an independent prognostic factor on overall survival in pancreatic cancer patients undergoing surgical resection. However, its impact after neoadjuvant treatment remains uncertain., Methods: We analyzed 305 patients with resectable or borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatoduodenectomy at 3 tertiary referral centers between 2010 and 2017. Positive resection margin was defined as 1 or more cancer cells at any margin. Overall survival was measured from the date of surgery until death or last follow-up., Results: One hundred and seventy-eight patients received neoadjuvant chemotherapy and 127 received neoadjuvant chemoradiotherapy. The median overall survival was 29.8 months. The 1-, 3-, and 5-year overall survival rates were 79.2%, 44.0%, and 23.5%, respectively. Negative margin was achieved in 275 (90.2%) patients. Negative margin resection patients had a significantly longer overall survival than positive resection margin patients (31.3 vs 16.3 months, P < .001). In univariate analyses, overall survival was associated with age, margin status, histologic grade, ypT, number of positive lymph nodes, perineural invasion, treatment effect, postoperative carbohydrate antigen 19-9, and adjuvant therapy. Positive margin resection, poorly differentiated carcinoma, treatment effect score of 3, postoperative carbohydrate antigen 19-9 of 37 U/mL or higher, and lack of adjuvant therapy were predictive of poor overall survival in multivariate Cox regression analysis., Conclusion: Margin status was an independent predictor of overall survival in patients treated with neoadjuvant therapy and pancreatoduodenectomy, supporting the use of a negative margin resection as a surrogate of adequate oncological resection in this setting. Our findings may also have significant implications for patient stratification in future randomized trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13 , was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC 50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice., (This journal is © The Royal Society of Chemistry 2020.)

Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity. The JNK inhibitor JNK-IN-8 was found to potently inhibit nucleoside transport and engage ENT1. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant de novo pathway enzyme DHODH and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH., Competing Interests: Declaration of Interests C.G.R. and J.C. are co-founders of Sofie Biosciences and Trethera Corporation. M.E.J. is a co-founder of Trethera Corporation. They and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. The intellectual property developed by C.G.R., J.C., and M.E.J. and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Although most surgery residents pursue fellowships, data regarding those decisions are limited. This study describes associations with interest in fellowship and specific subspecialties., Methods: Anonymous surveys were distributed to 607 surgery residents at 19 US programs. Subspecialties were stratified by levels of burnout and quality of life using data from recent studies., Results: 407 (67%) residents responded. 372 (91.4%) planned to pursue fellowship. Fellowship interest was lower among residents who attended independent or small programs, were married, or had children. Residents who received AOA honors or were married were less likely to choose high burnout subspecialties (trauma/vascular). Residents with children were less likely to choose low quality of life subspecialties (trauma/transplant/cardiothoracic)., Conclusions: Surgery residents' interest in fellowship and specific subspecialties are associated with program type and size, AOA status, marital status, and having children. Variability in burnout and quality of life between subspecialties may affect residents' decisions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Consistent and reliable tumor staging is a critical factor in determining treatment strategy, selection of patients for adjuvant therapy, and for therapeutic clinical trials. The aim of this study was to evaluate the number and extent of pancreatic ductal adenocarcinoma (PDAC) cases that would have a different pT, pN, and overall stages based on the new eighth edition American Joint Committee on Cancer staging system when compared with the seventh edition., Methods: Patients diagnosed with PDAC who underwent pancreaticoduodenectomy, total pancreatectomy, or distal pancreatectomy from 2007 to 2017 were retrospectively reviewed. A total of 340 cases were included., Results: According to the seventh edition, the vast majority of tumors in our cohort were staged as pT3 tumors (88.2%). Restaging these cases with the new size-based pT system resulted in a more equal distribution among the 3 pT categories, with higher percentage of pT2 cases (55%)., Conclusions: The newly adopted pT stage protocol for PDAC is clinically relevant, ensures a more equal distribution among different stages, and allows for a significant prognostic stratification. In contrast, the new pN classification (pN1 and pN2) based on the number of positive lymph nodes failed to show survival differences and remains controversial.

Background: Patients with early-stage pancreatic neuroendocrine tumors (PNETs) may develop metastatic recurrences despite undergoing potentially curative pancreas resections. We sought to identify factors predictive of metastatic recurrences and develop a prognostication strategy to predict recurrence-free survival (RFS) in resected PNETs., Methods: Patients with localized PNETs undergoing surgical resection between 1989 and 2015 were identified. Univariate and multivariate analysis were used to identify potential predictors of post-resection metastasis. A score-based prognostication system was devised using the identified factors. The bootstrap model validation methodology was utilized to estimate the external validity of the proposed prognostication strategy., Results: Of the 140 patients with completely resected early-stage PNETs, overall 5- and 10-year RFS were 84.6% and 67.1%, respectively. The median follow-up was 56 months. Multivariate analysis identified tumor size > 5 cm, Ki-67 index 8-20%, lymph node involvement, and high histologic grade (G3, or Ki-67 > 20%) as independent predictors of post-resection metastatic recurrence. A scoring system based on these factors stratified patients into three prognostic categories with distinct 5-year RFS: 96.9%, 54.8%, and 33.3% (P < 0.0001). The bootstrap model validation methodology projected our proposed prognostication strategy to retain a high predictive accuracy even when applied in an external dataset (validated c-index of 0.81)., Conclusions: The combination of tumor size, LN status, grade, and Ki-67 was identified as the most highly predictive indicators of metastatic recurrences in resected PNETs. The proposed prognostication strategy may help stratify patients for adjuvant therapies, enhanced surveillance protocols and future clinical trials.

Objective: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis., Design: DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo., Results: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates., Conclusion: Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1,2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance 3-7 . Furthermore, PSC activation occurs very early during PDAC tumorigenesis 8-10 , and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Objectives: The aim of this study was to evaluate the impact of epidural analgesia (EA) on postoperative length of stay (LOS), expeditious discharge, and pain relief after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP)., Methods: Retrospective reviews of 2014-2015 American College of Surgeons National Surgical Quality Improvement Program databases and our institutional pancreatic surgery database were conducted., Results: On univariate analysis, EA was associated with statistically significant longer lengths of stay for both PD and DP. On comparative analysis at mode LOS, discharged before versus after 7 days for PD and 6 days for DP, EA was a significant predictor for the longer groups for both procedures on multivariable analysis (PD, odds ratio of 1.465, P < 0.001; DP, odds ratio of 1.471, P = 0.004). On review of our institution's pancreatic surgery database, patient-reported pain scores were significantly lower in the EA groups than intravenous narcotics groups on the day of surgery only for both PD and DP., Conclusions: Epidural analgesia was associated with longer LOS with a most pronounced effect on early discharge after surgery for patients undergoing open PD and DP. It only resulted in superior pain control on the day of surgery.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors., Competing Interests: The authors declare no conflict of interest.