Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells.

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.

Fatty acid binding protein 4 regulates pancreatic cancer cell proliferation via activation of nuclear factor E2-related factor 2.

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.

A nonhuman primate model of vertical sleeve gastrectomy facilitates mechanistic and translational research in human obesity.

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.

Bariatric surgery outcomes in Medicare beneficiaries.

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.

Systemic therapy without radiation may be appropriate as neoadjuvant therapy for localized pancreas cancer.

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.

Bariatric Surgery is Associated With Decreased Progression of Nonalcoholic Fatty Liver Disease to Cirrhosis: A Retrospective Cohort Analysis.

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.

The Impact of Bariatric Surgery on Breast Cancer Recurrence: Case Series and Review of Literature.

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.

Completion of Adjuvant Chemotherapy After Upfront Surgical Resection for Pancreatic Cancer Is Uncommon Yet Associated With Improved Survival.

BACKGROUND: 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. METHODS: The Surveillance Epidemiology and End Results Medicare-linked data was used to identify patients who underwent upfront resection for pancreatic adenocarcinoma from 2004 to 2013. Billing codes were used to quantify receipt and completion of chemotherapy. Factors associated with completion of chemotherapy were identified using multivariable regression. Kaplan-Meier and Cox proportional-hazards modeling were used to examine survival. RESULTS: The inclusion criteria were met by 2440 patients. Of these patients, 65% received no adjuvant chemotherapy, 28% received incomplete therapy, and 7% completed chemotherapy. The factors associated with chemotherapy completion were nodal metastases and treatment at a National Cancer Institute-designated cancer center (p ≤ 0.05). Comorbidities decreased the odds of completion (p ≤ 0.05). The median overall survival (OS) was 14 months for the patients who received no adjuvant chemotherapy, 17 months for those who received incomplete adjuvant chemotherapy, and 22 months for those who completed adjuvant chemotherapy (p ≤ 0.05). More recent diagnosis, comorbidities, T stage, nodal metastases, and no adjuvant chemotherapy were associated with an increased hazard ratio for death (p ≤ 0.05). Evaluation of 15 or more nodes and completion of chemotherapy decreased the hazard ratio for death (p ≤ 0.05). CONCLUSIONS: Only 7% of the Medicare patients who underwent upfront resection for pancreatic cancer completed adjuvant chemotherapy, yet completion of adjuvant chemotherapy was associated with improved OS. Completion of adjuvant chemotherapy should be the goal after upfront resection, but neoadjuvant chemotherapy may ensure that patients receive systemic chemotherapy.

Racial disparities in perioperative outcomes after bariatric surgery.

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/m2; SG: 46.8 versus 44.9 kg/m2; 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.

Surgical resection of lymph node positive intrahepatic cholangiocarcinoma may not improve survival.

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.

Role of Gene Therapy in Pancreatic Cancer-A Review.

Mortality from pancreatic ductal adenocarcinoma (PDAC) has remained essentially unchanged for decades and its relative contribution to overall cancer death is projected to only increase in the coming years. Current treatment for PDAC includes aggressive chemotherapy and surgical resection in a limited number of patients, with median survival of optimal treatment rather dismal. Recent advances in gene therapies offer novel opportunities for treatment, even in those with locally advanced disease. In this review, we summarize emerging techniques to the design and administration of virotherapy, synthetic vectors, and gene-editing technology. Despite these promising advances, shortcomings continue to exist and here will also be highlighted those approaches to overcoming obstacles in current laboratory and clinical research.

Liver Regeneration in the Acute Liver Failure Patient.

Liver regeneration after simple resection represents a unique process in which the organ returns to its original size and histologic structure. Over the past 30 years, there has been significant progress in elucidating the mechanisms associated with regeneration after loss of hepatic mass. Liver regeneration after acute liver failure shares several of these classical pathways. It differs, however, in key processes, including the role of both differentiated and stemlike cells. This article outlines these differences in addition to new molecular mechanisms, including immunomodulation, microRNAs, and the gut-liver axis. In addition, applications to the patient population, including prognostication and stem cell therapies, are explored.

Bariatric Surgery: A Perspective for Primary Care.

IN BRIEF Bariatric surgery is the most efficacious treatment for obesity, type 2 diabetes, and other obesity-related comorbidities. In this article, the authors review the current indications for bariatric surgery and discuss the most commonly performed procedures. They analyze medical outcomes of bariatric procedures by reviewing key prospective trials and discuss changes in physiology after these procedures. They conclude by discussing long-term management of bariatric patients by reviewing current guidelines for nutritional support and listing common complications related to these procedures.

A structured teaching curriculum for medical students improves their performance on the National Board of Medical Examiners shelf examination in surgery.

BACKGROUND: The aim of this study was to evaluate the effect of a resident-driven, student taught educational curriculum on the medical students' performance on the National Board of Medical Examiners surgery subject examination (NBME). METHODS: On daily morning rounds, medical students or the chief resident delivered preassigned brief presentations on 1 or 2 of the 30 common surgical topics selected for the curriculum. An initial assessment of student knowledge and an end-rotation in-house examination (multiple choice question examination) were conducted. The mean scores on the NBME examination were compared between students in teams using this teaching curriculum and those without it. RESULTS: A total of 57 third-year medical students participated in the study. The mean score on the in-house postclerkship multiple choice question examination was increased by 23.5% (P < .05). The mean NBME scores were significantly higher in the students who underwent the teaching curriculum when compared with their peers who were not exposed to the teaching curriculum (78 vs 72, P < .05). CONCLUSION: The implementation of a resident-driven structured teaching curriculum improved performance of medical students on the NBME examination.

Is there a place for medical students as teachers in the education of junior residents?

BACKGROUND: The aim of this study was to investigate a novel resident education model that turns the traditional surgical hierarchy upside down, termed a "reverse" peer-assisted learning curriculum. METHODS: Thirty surgical topics were randomized between medical students and chief residents on each clinical team, with 1 topic being presented briefly during morning rounds. An exam evaluating junior residents' knowledge of these topics was administered before and after 1 month of presentations. A questionnaire was distributed to evaluate the junior residents' perceptions of this teaching model. RESULTS: Thirty-four residents participated. There was a significant improvement in the mean examination score (54 vs 74, P < .05). No significant difference was noted in the mean score differentials of topics presented by either the medical students or the chief resident (21 vs 18, P = .22). More than 80% of the residents responded positively about the effectiveness of this exercise and agreed that they would like to see this model used on other services. CONCLUSIONS: This study confirms the hypothesis that medical students can teach surgical topics to junior residents at least as effectively as their chief residents.

Epidural catheter placement in morbidly obese parturients with the use of an epidural depth equation prior to ultrasound visualization.

BACKGROUND: Previously, Balki determined the Pearson correlation coefficient with the use of ultrasound (US) was 0.85 in morbidly obese parturients. We aimed to determine if the use of the epidural depth equation (EDE) in conjunction with US can provide better clinical correlation in estimating the distance from the skin to the epidural space in morbidly obese parturients. METHODS: One hundred sixty morbidly obese (≥40 kg/m(2)) parturients requesting labor epidural analgesia were enrolled. Before epidural catheter placement, EDE was used to estimate depth to the epidural space. This estimation was used to help visualize the epidural space with the transverse and midline longitudinal US views and to measure depth to epidural space. The measured epidural depth was made available to the resident trainee before needle insertion. Actual needle depth (ND) to the epidural space was recorded. RESULTS: Pearson's correlation coefficients comparing actual (ND) versus US estimated depth to the epidural space in the longitudinal median and transverse planes were 0.905 (95% CI: 0.873 to 0.929) and 0.899 (95% CI: 0.865 to 0.925), respectively. CONCLUSION: Use of the epidural depth equation (EDE) in conjunction with the longitudinal and transverse US views results in better clinical correlation than with the use of US alone.