S1. DSC and DSG isoforms expressed in MCF-7 cells.

S2. Predicted orientation of the F57 side chain in the apoFABP4 form.

BACKGROUND:Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database.METHODS:Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling.RESULTS:We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05).CONCLUSIONS:NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.

Abstract Fatty acid binding protein 4 (FABP4) is a secreted adipokine linked to obesity and progression of a variety of cancers. Obesity increases extracellular FABP4 (eFABP4) levels in animal models and in obese breast cancer patients compared with lean healthy controls. Using MCF-7 and T47D breast cancer epithelial cells, we show herein that eFABP4 stimulates cellular proliferation in a time and concentration dependent manner while the non-fatty acid-binding mutant, R126Q, failed to potentiate growth. When E0771 murine breast cancer cells were injected into mice, FABP4 null animals exhibited delayed tumor growth and enhanced survival compared with injections into control C57Bl/6J animals. eFABP4 treatment of MCF-7 cells resulted in a significant increase in phosphorylation of extracellular signal-regulated kinase 1/2 (pERK), transcriptional activation of nuclear factor E2-related factor 2 (NRF2) and corresponding gene targets ALDH1A1, CYP1A1, HMOX1, SOD1 and decreased oxidative stress, while R126Q treatment did not show any effects. Proximity-labeling employing an APEX2–FABP4 fusion protein revealed several proteins functioning in desmosomes as eFABP4 receptor candidates including desmoglein (DSG), desmocollin, junction plankoglobin, desomoplankin, and cytokeratins. AlphaFold modeling predicted an interaction between eFABP4, and the extracellular cadherin repeats of DSG2 and pull-down and immunoprecipitation assays confirmed complex formation that was potentiated by oleic acid. Silencing of DSG2 in MCF-7 cells attenuated eFABP4 effects on cellular proliferation, pERK levels, and ALDH1A1 expression compared with controls. Implications: These results suggest desmosomal proteins, and in particular desmoglein 2, may function as receptors of eFABP4 and provide new insight into the development and progression of obesity-associated cancers.

BACKGROUND:Obesity and diabetes are associated with an increased incidence of pancreatic cancer. Fatty acid binding protein 4 (FABP4), noted to be higher in patients with severe obesity, is linked to the development and progression of several cancers, and its level in the circulation decreases after bariatric surgery.OBJECTIVE:In this paper, we evaluate the role of FABP4 in pancreatic cancer progression.SETTING:University Hospital and Laboratories, United States.METHODS AND RESULTS:When Panc-1 (human) and Pan02 (mouse) pancreatic cancer cells were treated with FABP4 or the-single-point mutant FABP4 (R126Q, fatty acid binding site mutant), only FABP4 stimulated cellular proliferation. The transcriptional activity of nuclear factor E2-related factor 2 (NRF2) was increased in response to FABP4 but not the R126Q. FABP4 treatment also led to downregulation of reactive oxygen species (ROS) activity. Consistent with induced cell propagation by FABP4, the growth of Pan02 tumor was decreased in FABP4-null animals compared with C57BL/6J controls.CONCLUSION:These results suggest that FABP4 increases pancreatic cancer proliferation via activation of NRF2 and downregulation of ROS activity.

The obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show that VSG confers weight loss and durable metabolic benefit, where equivalent caloric intake in shams resulted in significant weight gain following surgery. Furthermore, we show that VSG is associated with early, weight-independent increases in bile acids, short-chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes toward highly regulatory myeloid cells and Tregs. These data demonstrate that this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.

Background Excess body weight has been associated with worsening breast cancer survival. While bariatric surgery has been associated with less incident of breast cancer, the role that bariatric surgery plays after breast cancer diagnosis in terms of both feasibility and in preventing breast cancer recurrence is unclear. Methods We report the outcomes of 13 individuals who underwent bariatric surgery after definitive breast cancer treatment at a single institution. Results Thirteen females diagnosed with breast cancer (69.2% stage I, 23.1% stage II) at a median age of 42 years received bariatric surgery between 2001 and 2017. The median age of bariatric surgery was 52 years. Of the 13 patients, 46.2% underwent laparoscopic Roux-en-Y gastric bypass and 38.5% laparoscopic sleeve gastrectomy. The median time from breast cancer treatment to bariatric surgery was 3 years. The procedures were well tolerated. One female developed an abdominal wall hematoma. The average weight loss after 1 year and 2 years was 28.1% and 28.2%, respectively. There was a single breast cancer recurrence with a median follow-up of 11.7 years after breast cancer diagnosis and 5.3 years after bariatric surgery. Conclusions Bariatric surgery after breast cancer treatment is feasible and well tolerated. Prospective trials evaluating bariatric surgery in obese breast cancer survivors should be considered.

Background: The utility of neoadjuvant treatment for resectable pancreas cancer is yet to be determined, but has commonly included chemoradiation. We evaluated outcomes in patients with radiographically resectable pancreatic adenocarcinoma treated with neoadjuvant chemotherapy without chemoradiation. Methods: A retrospective review of patients in our institutional pancreatic cancer registry was performed, which identified 36 patients who received neoadjuvant chemotherapy alone for resectable pancreatic adenocarcinoma between 2012 and 2016. Results: Median age at diagnosis was 66.3 years. Chemotherapy regimens included gemcitabine (n=17), gemcitabine/nab-paclitaxel (n=8), or 5-FU/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) (n=11). Surgical resection was performed in 69％ of patients (n=25), with an R0 resection rate of 92％(n=23 patients). During chemotherapy, distant disease became apparent in 19％ of patients (n=7), while no patients had evidence of local progression. Resection rates were similar between chemotherapy regimens (single agent =59％, multiple agent =79％). Median overall survival for all patients who received neoadjuvant chemotherapy was 30.3 and 34.4 months for those who underwent surgical resection. There was no difference in median survival for patients treated with gemcitabine (31.3 months) or multi-agent chemotherapy (29.7 months). Conclusions: A short course of neoadjuvant chemotherapy without chemoradiation may improve patient selection prior to surgical resection for pancreas cancer. Further, local disease progression did not limit surgical resection in this small series.

Objective: This study sought to compare trends in the development of cirrhosis between patients with NAFLD who underwent bariatric surgery and a well-matched group of nonsurgical controls. Summary of Background Data: Patients with NAFLD who undergo bariatric surgery generally have improvements in liver histology. However, the long-term effect of bariatric surgery on clinically relevant liver outcomes has not been investigated. Methods: From a large insurance database, patients with a new NAFLD diagnosis and at least 2 years of continuous enrollment before and after diagnosis were identified. Patients with traditional contraindications to bariatric surgery were excluded. Patients who underwent bariatric surgery were identified and matched 1:2 with patients who did not undergo bariatric surgery based on age, sex, and comorbid conditions. Kaplan-Meier analysis and Cox proportional hazards modeling were used to evaluate differences in progression from NAFLD to cirrhosis. Results: A total of 2942 NAFLD patients who underwent bariatric surgery were identified and matched with 5884 NAFLD patients who did not undergo surgery. Cox proportional hazards modeling found that bariatric surgery was independently associated with a decreased risk of developing cirrhosis (hazard ratio 0.31, 95% confidence interval 0.19-0.52). Male gender was associated with an increased risk of cirrhosis (hazard ratio 2.07, 95% confidence interval 1.31-3.27). Conclusions: Patients with NAFLD who undergo bariatric surgery are at a decreased risk for progression to cirrhosis compared to well-matched controls. Bariatric surgery should be considered as a treatment strategy for otherwise eligible patients with NAFLD. Future bariatric surgery guidelines should include NAFLD as a comorbid indication when determining eligibility.

Nugent, Julia MD; Staley, Christopher PhD; Wirth, Keith MD; Sheka, Adam C. MD; Ramachandran, Sabarinathan PhD; Singh, Amar PhD; Hocum Stone, Laura PhD; Hering, Bernhard MD; Graham, Melanie MPH, PhD; Ikramuddin, Sayeed MD, FACS Author Information

Nugent, Julia MD; Singh, Amar PhD; Hocum Stone, Laura PhD; Sheka, Adam C. MD; Wirth, Keith MD; Hering, Bernhard MD; Graham, Melanie L. MPH, PhD; Ikramuddin, Sayeed MD, FACS; Ramachandran, Sabarinathan PhD Author Information

Background: The Medicare population is increasing while the prevalence of obesity remains high. Bariatric surgery is the most efficacious treatment of obesity and its comorbidities. The objective of this investigation was to assess trends in utilization, readmission, mortality, and cost of bariatric surgery in the Medicare population. Methods: Utilizing the Medicare Provider Analysis and Review database, patients with clinically severe obesity undergoing laparoscopic Roux-en-Y gastric bypass (RYGB), laparoscopic sleeve gastrectomy (SG), and laparoscopic adjustable gastric banding (LAGB) from 2011-2015 were identified. Trends in procedure selection, readmissions, mortality, and cost were examined. A multivariable logistic regression analysis to evaluate factors associated with readmission and mortality was performed. Results: Of the 73,718 patients identified, 53,949 (73%) of patients were enrolled in Medicare due to disability, 19,191 (26%) due to age, and 578 (<1%) due to end stage renal disease (ESRD). Utilization of SG increased (1% in 2011 to 61% in 2015), while utilization of RYGB (68% to 32%) and LAGB (31% to 1%) decreased. Length of stay (LOS) was highest after RYGB (2.54 days), and lowest after LAGB (1.32 days). LOS decreased from 2.23 days in 2011 to 2.12 days in 2015. Thirty-day readmissions were 8.24% for the disabled, 5.5% for the elderly, 12.8% with ESRD. Odds of readmission increased with black race, higher body mass index (BMI), and RYGB. Readmission decreased from 8% in 2011 to 7% in 2015. Thirty-day mortality was 0.22% in the disabled, and 0.28% in the elderly. Odds of 30-day mortality increased among men, those with higher BMI, some comorbidities, and those who underwent RYGB. Cost of SG decreased while cost of RYGB increased. Conclusions: Among the Medicare population, an increase in SG while a decrease in RYGB and LAGB utilization was noted from 2011-2015. Readmissions and cost have decreased, while mortality has remained low.

Background: Nodal positivity is a predictor of poor survival following resection for intrahepatic cholangiocarcinoma (ICC). The aim of this study was to evaluate the impact of surgical resection on survival in patients with lymph node (LN) positive ICC. Methods: An augmented version of the Surveillance, Epidemiology, and End Results program database was utilized to identify patients with LN-positive ICC without distant metastases from 2000 to 2014. Patients were stratified by treatment: chemotherapy alone or surgical resection with/without chemotherapy. Survival was evaluated using Kaplan-Meier and Cox proportional hazard models. Results: 169 patients who underwent treatment for LN-positive ICC were identified. 88% underwent surgical resection and 12% underwent chemotherapy alone. The median survival for patients who underwent surgical resection was not different from patients treated with chemotherapy alone (19 months 95% Confidence Interval (CI) 17-33 versus 20 months CI 10-27, p = 0.323). A cox-proportional hazard ratio model demonstrated that black race was associated with worse survival (p < 0.05), while surgical resection was not independently associated with survival. Conclusion: Surgical resection for patients with LN-positive ICC may not improve survival compared to chemotherapy alone. Pathologic LN evaluation should be performed prior to surgical resection, to improve patient selection and ensure receipt of optimal therapy.

Multiple trials have demonstrated a survival benefit for adjuvant chemotherapy after resection of pancreatic adenocarcinoma. This study aimed to identify the rate for completion of adjuvant chemotherapy, factors associated with completion, and its impact on survival after surgical resection.

Background: Multiple randomized trials have demonstrated that adjuvant chemotherapy improves survival following upfront surgical resection for pancreatic cancer, but institutional series have reported that many patients do not complete adjuvant chemotherapy. We sought to identify the rate of completion of adjuvant chemotherapy, the factors associated with completion, and its impact on survival in a population-based sample.

Altman, Ariella M. MD; Shukla, Dip M.; Sheka, Adam MD; Wirth, Keith MD; Marmor, Schelomo MPH, PhD; Lou, Emil MD; Hui, Jane Y.C. MD, FACS; Tuttle, Todd M. MD, FACS; Jensen, Eric H. MD, FACS; Denbo, Jason W. MD Author Information

Background: NonHispanic black patients bear a disproportionate burden of the obesity epidemic and its related medical co-morbidities. While bariatric surgery is the most effective treatment for morbid obesity, black patients access bariatric surgery at lower rates than nonHispanic white patients. Objectives: To examine racial differences before bariatric surgery and in short-term perioperative outcomes and complications, and the extent to which race is independently associated with perioperative morbidity and mortality. Setting: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database. Methods: Data were extracted from the 2015 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program Participant Use File. Multivariate analysis was used to identify differences in mortality, length of stay, readmission, and reintervention by race in patients undergoing laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy (SG). Results: A total of 108,198 patients were included in the analysis. There were significant differences in perioperative disease burden. Black patients had a higher body mass index at the time they underwent surgery (laparoscopic Roux-en-Y gastric bypass: 48.0 versus 45.7 kg/m(2); SG: 46.8 versus 44.9 kg/m(2); P<.001). Black patients had significantly longer length of stay and higher rates of readmission in both the laparoscopic Roux-en-Y gastric bypass and SG groups. In the SG group, black patients had significantly higher 30-day mortality (.2% versus .1%, odds ratio=3.613, 95% confidence interval 1.990-6.558, P<.001) and higher rates of reoperation or reintervention. Conclusions: We found significant racial disparities in bariatric surgery outcomes, including higher mortality in black patients undergoing SG. The specific causes of these disparities remain unclear and must be the subject of future research. (C) 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.