Outcomes after Surgical Microwave Ablation for the Treatment of Colorectal Liver Metastasis.

BACKGROUND: Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Of these, approximately 25% will have liver metastasis. We performed 394 microwave ablations (MWA) and analyzed outcomes for survival and ablation failure. STUDY DESIGN: Retrospective review of patients who underwent a surgical microwave ablation at a single center high-volume institution from October 2006 through September 2022 using a prospectively maintained database. Primary outcome was overall survival. RESULTS: A total of 394 operations were performed on 328 patients with 842 tumors undergoing MWA. Median tumor size was 1.5 cm (range 0.4-7.0 cm), with the median number of tumors ablated per operation being 1 (range 1-11). A laparoscopic approach was used 77.9% of the time. Concomitant procedures were performed 63% of the time, most commonly hepatectomy (22.3%), cholecystectomy (17.5%), and colectomy (6.6%). Clavien-Dindo Grade III or IV complications occurred in 12 patients (3.6%), and all of these patients had undergone concomitant procedures. Mortality within 30 days occurred in 4 patients (1.2%). The rate of incomplete ablation (IA) was 1.5% per tumor. Local recurrence (LR) occurred at a rate of 6.3% per tumor. African Americans were found to have a higher incidence of IA and LR. One year survival probability was 91% [95% CI: 87.9 -94.3], with a mean overall survival of 57.6 months [95% CI: 49.9-65.4 months]. CONCLUSION: Surgical MWA offers a low-morbidity approach to treatment of colorectal liver metastasis (CRLM), with low rates of failure. This large series reviews the outcomes of MWA as definitive treatment for CRLM.

Alcohol-Associated Liver Disease Outcomes: Critical Mechanisms of Liver Injury Progression.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Harnessing the Electrochemical Effects of Electroporation-Based Therapies to Enhance Anti-tumor Immune Responses.

This study introduces a new method of targeting acidosis (low pH) within the tumor microenvironment (TME) through the use of cathodic electrochemical reactions (CER). Low pH is oncogenic by supporting immunosuppression. Electrochemical reactions create local pH effects when a current passes through an electrolytic substrate such as biological tissue. Electrolysis has been used with electroporation (destabilization of the lipid bilayer via an applied electric potential) to increase cell death areas. However, the regulated increase of pH through only the cathode electrode has been ignored as a possible method to alleviate TME acidosis, which could provide substantial immunotherapeutic benefits. Here, we show through ex vivo modeling that CERs can intentionally elevate pH to an anti-tumor level and that increased alkalinity promotes activation of naïve macrophages. This study shows the potential of CERs to improve acidity within the TME and that it has the potential to be paired with existing electric field-based cancer therapies or as a stand-alone therapy.

Assessing Platelet Mitochondrial Dysfunction in a Murine Model of Acute Acetaminophen Toxicity.

INTRODUCTION: Acetaminophen (APAP) toxicity remains a significant cause of adult and pediatric liver failure in North America and Europe. Previous research has evaluated the impaired mitochondrial function associated with APAP toxicity. The primary aim of this study was to evaluate the effects of APAP toxicity on platelet mitochondrial function using platelet oxygen consumption in a murine model in vivo. Our secondary objectives were to determine the effect of 4-MP on platelet mitochondrial function and hepatic toxicity in the setting of APAP overdose, and to correlate platelet mitochondrial function with other markers of APAP toxicity. METHODS: Male C57Bl/6 mice were randomized to receive APAP (300 or 500 mg/kg) or vehicle followed 90 minutes later by either 4-MP (50 mg/kg) or vehicle via intraperitoneal injection. Mice were euthanized 0, 12, or 24 hours later and platelets isolated from cardiac blood and counted. Platelet oxygen consumption (POC) was determined using a closed-system respirometer. Liver injury was assessed by measuring alanine transferase (ALT) and histological evaluation. RESULTS: Injection of 500 mg/kg APAP led to increased POC versus pair-matched control (vehicle) (p < 0.001). Administration of 4-MP did not affect POC in control or 300 mg/kg APAP mice. In mice receiving 500 mg/kg APAP and 4-MP, POC decreased significantly compared to mice receiving 500 mg/kg APAP alone (p < 0.01). Serum and histological analysis confirmed APAP-induced hepatic damage in mice receiving 500 mg/kg APAP and these effects blunted by treatment with 4-MP. CONCLUSIONS: Platelet oxygen consumption as a measure of mitochondrial function may be useful as a biomarker of hepatic APAP toxicity in the setting of moderate to severe overdose. Treatment with 4-MP decreases hepatic necrosis and may mitigate the harmful effects of APAP on platelet mitochondrial function detected via POC.

Irreversible Electroporation-Assisted Resection for Locally Advanced Pancreas Cancer.

BACKGROUND: A significant number of patients with advanced pancreatic cancer are unable to undergo resection due to vascular involvement. Irreversible electroporation (IRE) has shown promise in improving survival. This study sought to assess a novel IRE application whereby IRE was performed pre-resection to alter tissue plasticity and assist tumor removal from underlying vasculature when surgical excision was otherwise precluded. METHODS: After multidisciplinary evaluation appropriate patients were consented for IRE therapy. All IRE cases were tracked prospectively using an institutional review board-approved database that was retrospectively queried for patients undergoing IRE-assisted resection (IRE-AR) for pancreatic adenocarcinoma located in the head/uncinate process. Patients who underwent other IRE therapy or had disease location elsewhere were excluded. RESULTS: 5 patients met the study inclusion criteria with a mean tumor size of 3.2 cm (range 2.4-4.1 cm). Using IRE-AR median recurrence free survival was 10.6 months, with 21.6 month overall survival. The average comprehensive complication index score was 23.23. One patient had grade 3 [or higher] complications and there were no 90 day mortalities. DISCUSSION: Employing a high-starting voltage for ablation along resection margins allows for resection when margins are anticipated to be positive. Patients with locally advanced pancreatic adenocarcinoma who underwent IRE-AR had promising outcomes. CONCLUSION: This study reports IRE-AR as a novel approach for resecting locally advanced pancreatic adenocarcinoma. A prospective trial of IRE-AR for inoperable pancreatic adenocarcinoma will provide additional data for the long-term application of this approach.

African American Patients Experience Worse Outcomes than Hispanic Patients Following Bariatric Surgery: an Analysis Using the MBSAQIP Data Registry.

BACKGROUND: Obesity rates in Hispanics and African Americans (AAs) are higher than in Caucasians in the USA, yet the rate of metabolic and bariatric surgery (MBS) for weight loss remains lower for both Hispanics and AAs. METHODS: Patient demographics and outcomes of adult AA and Hispanic patients undergoing sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) procedures were analyzed using the MBSAQIP dataset [2015-2018] using unmatched and propensity-matched data. RESULTS: In total, 173,157 patients were included, of whom 98,185 were AA [56.7%] [21,163-RYGB; 77,022-SG] and 74,972 were Hispanic [43.3%] [20,282-RYGB; 54,690-SG]). Preoperatively, the AA cohort was older, had more females, and higher BMIs with higher rates of all tracked obesity-related medical conditions except for diabetes, venous stasis, and prior foregut surgery. Intra- and postoperatively, AAs were more likely to experience major complications including unplanned ICU admission, 30-day readmission/reintervention, and mortality. After propensity matching, the differences in ED visits, treatment for dehydration, 30-day readmission, 30-day intervention, and pulmonary embolism remained for both SG and RYGB cohorts. Progressive renal insufficiency and ventilator use lost statistical significance in both cohorts. Conversely, 30-day reoperation, postoperative ventilator requirement, unplanned intubation, unplanned ICU admission, and mortality lost significance in the RYGB cohort, but not SG patients. CONCLUSION: Outcomes for AA patients were worse than for Hispanic patients, even after propensity matching. After matching, differences in major complications and mortality lost significance for RYGB, but not SG. These data suggest that outcomes for RYGB may be driven by the presence and severity of pre-existing patient-related factors.

Robotic Revision of Hepaticojejunostomy for Benign Biliary Stricture.

Surgical revision of biliary enteric anastomoses (BEA) can be a challenging undertaking and a robotic platform may provide advantages that address many of the technical obstacles. We present our technical approach and outcomes for patients undergoing robotic revision of BEA for benign strictures. A retrospective review was performed for robot-assisted benign BEA revision at our institution. Operative details, perioperative metrics, and outcomes are reported. Four patients underwent anastomotic revision following previously failed non-operative management. There were no intraoperative complications, mean length of stay was 4-days, and all patients experienced resolution of presenting clinical signs and symptoms. No patients required reoperation and there was no mortality. Postoperative outcomes were consistent with findings reported for other interventional modalities. Based on our experience we conclude robotic intervention in this context is safe and improves the technical feasibility of this complex procedure.

Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism.

Fatty acid binding protein-4 (FABP4) is not normally expressed in the liver but is induced in alcohol-dependent liver disease (ALD)). This study sought to identify mechanisms whereby ethanol (EtOH) metabolism alters triglyceride accumulation and FABP4 production. Human hepatoma cells which were stably transfected to express alcohol dehydrogenase (ADH) or cytochrome P4502E1 (CYP2E1) were exposed to EtOH in the absence/presence of inhibitors of ADH (4-methylpyrazole) or CYP2E1 (chlormethiazole). Cells were analyzed for free fatty acid (FFA) content and FABP4 mRNA, then culture medium assayed for FABP4 levels. Cell lysates were analyzed for AMP-activated protein kinase-α (AMPKα), Acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein-1c (SREBP-1c), and Lipin-1ß activity and localization in the absence/presence of EtOH and pharmacological inhibitors. CYP2E1-EtOH metabolism led to increased FABP4 mRNA/protein expression and FFA accumulation. Analysis of signaling pathway activity revealed decreased AMPKα activation and increased nuclear-SREBP-1c localization following CYP2E1-EtOH metabolism. The role of AMPKα-SREBP-1c in regulating CYP2E1-EtOH-dependent FFA accumulation and increased FABP4 was confirmed using pharmacological inhibitors and over-expression of AMPKα. Inhibition of ACC or Lipin-1ß failed to prevent FFA accumulation or changes in FABP4 mRNA expression or protein secretion. These data suggest that CYP2E1-EtOH metabolism inhibits AMPKα phosphorylation to stimulate FFA accumulation and FABP4 protein secretion via an SREBP-1c dependent mechanism.

Ectodysplasin-A mRNA in exosomes released from activated hepatic stellate cells stimulates macrophage response.

INTRODUCTION: The interaction between activated hepatic stellate cells (aHSCs) and macrophages is central to liver fibrosis development. The cargo contained within aHSC exosomes (aHSC-EXOs) and how aHSC-EXOs affect macrophage function is poorly understood. METHODS: RNA from aHSC-EXOs was separated into small (<200-basepairs) and large (≥200-basepairs) RNA species, transfected into macrophages, and macrophage IL-6 and TNFα mRNA expression and protein secretion measured. Next generation sequencing was performed on EXOs from rat quiescent and aHSCs and human aHSCs. aHSCs were transfected with siRNA against ectodysplasin-A (EDA), EXOs collected, and their effect on macrophage function analyzed. Human cirrhotic liver was analyzed for EDA mRNA expression and compared to non-tumor liver (NTL). RESULTS: Transfection with large RNA from aHSC-EXOs stimulated macrophage IL-6 and TNFα mRNA expression and protein secretion. EDA mRNA was highly expressed in aHSCs and transfection of aHSCs with EDA-siRNA decreased aHSC-EXO EDA mRNA and blunted the effect of aHSC-EXOs on macrophage function (IL-6/TNFα expression and macrophage migration). Human cirrhotic liver exhibited high EDA mRNA compared to NTL. CONCLUSIONS: HSC activation leads to altered EXO mRNA/miRNA profiles with aHSC-EXOs mRNAs exerting a dominant role in altering macrophage function. Ectodysplasin-A mRNA is an important component in aHSC-EXOs in regulating macrophage function.

Cytochrome P450 2E1-dependent hepatic ethanol metabolism induces fatty acid-binding protein 4 and steatosis.

BACKGROUND: Hepatic steatosis is an early pathology of alcohol-associated liver disease (ALD). Fatty acid-binding protein-4 (FABP4, a FABP not normally produced in the liver) is secreted by hepatocytes in ALD and stimulates hepatoma proliferation and migration. This study sought to investigate the mechanism[s] by which hepatic ethanol metabolism regulates FABP4 and steatosis. METHODS: Human hepatoma cells (HepG2/HuH7) and cells stably transfected to express cytochrome P450 2E1 (CYP2E1), were exposed to ethanol in the absence or presence of chlormethiazole (a CYP2E1-inhibitor; CMZ) and/or EX-527 (a sirtuin-1 [SIRT1] inhibitor). The culture medium was analyzed for ethanol metabolism and FABP4 protein abundance. Cells were analyzed for FABP4 mRNA expression, SIRT1 protein abundance, and neutral lipid accumulation. In parallel, cells were analyzed for forkhead box O1 [FOXO1], ß-catenin, peroxisome proliferator-activated receptor-α [PPARα], and lipin-1α protein abundance in the absence or presence of ethanol and pharmacological inhibitors of the respective target proteins. RESULTS: CYP2E1-dependent ethanol metabolism inhibited the amount of SIRT1 protein detected, concomitant with increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation, effects abolished by CMZ. Analysis of pathways associated with lipid oxidation revealed increased FOXO1 nuclear localization and decreased ß-catenin, PPARα, and lipin-1α protein levels in CYP2E1-expressing cells in the presence of ethanol. Pharmacological inhibition of SIRT1 mimicked the effects of ethanol, while inhibition of FOXO1 abrogated the effect of ethanol on FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation in CYP2E1-expressing cells. Pharmacological inhibition of ß-catenin, PPARα, or lipin-1α failed to alter the effects of ethanol on FABP4 or neutral lipid accumulation. CONCLUSION: CYP2E1-dependent ethanol metabolism inhibits SIRT1-FOXO1 signaling, which leads to increased FABP4 mRNA expression, FABP4 protein secretion, and neutral lipid accumulation. These data suggest that FABP4 released from steatotic hepatocytes could play a role in promoting tumor cell expansion in the setting of ALD and represents a potential target for therapeutic intervention.

The Association Between Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease Diagnosis Varies by Race.

Objectives: This study investigated how the association between metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD) diagnosis varies between non-Hispanic African American and white patients. Methods: A retrospective cohort study was performed using electronic medical records from an integrated health care system (2010-2018). Adults with records for all MetS measurements (body mass index, lipids, blood pressure, and blood glucose) in 2011, who did not have a NAFLD diagnosis before their last MetS measurement, were included. Results: The study cohort consisted of 139,336 patients (age 56.1 ± 15.2 years, 57.9% female, 79.4% non-Hispanic white). The rate of NAFLD diagnosis was higher in MetS patients compared with non-MetS patients [adjusted hazards ratio (AHR) = 1.99, 95% CI = 1.91-2.09] with a significant interaction by race (AHR = 2.05, 95% CI = 1.95-2.15 in non-Hispanic whites vs. AHR = 1.76, 95% CI = 1.58-1.96 non-Hispanic African Americans, P = 0.017). Secondary analyses revealed that the relative NAFLD diagnosis rate was higher in non-Hispanic whites with MetS compared with non-Hispanic African Americans with MetS among females and patients 18-39 years of age and 40-59 years, but not among males and those ≥60 years of age. Conclusions: Non-Hispanic white patients with MetS, particularly females and those <60 years of age, may be at increased risk of NAFLD compared with non-Hispanic African American MetS patients and may benefit from extra attention regarding NAFLD screening.

The role of total alimentary limb length in Roux-en-Y gastric bypass: a systematic review.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is an established surgical treatment for obesity. Variations in limb length during RYGB procedures have been investigated for optimizing weight loss while minimizing nutritional deficiencies. The role of the total alimentary limb length (TALL; Roux limb plus common channel [CC]), however, is poorly defined. OBJECTIVE: Compare TALL in RYGB procedures for weight loss outcomes and malnutrition. SETTING: Systematic review. METHODS: Ovid Medline and PubMed databases were searched for entries between 1993 and 2020. Search terms included "gastric bypass" and "TALL." Two independent reviewers screened the results. RESULTS: A total of 21 studies measured TALL in RYGB. Of these, 4 of 6 reported a relationship between TALL and weight loss. Additionally, 11 studies reported that when TALL was ≤400 cm and CC <200 cm, 3.4% to 63.6% of patients required limb lengthening for protein malnutrition. CONCLUSIONS: The majority of studies on RYGB do not report TALL length. There is some evidence that weight loss is affected by shortening TALL, while a TALL ≤400 cm with CC<200 should be avoided due to severe protein malnutrition. More studies on the effect of TALL are needed.

Safety of Primary Versus Revisional Biliopancreatic Diversion with Duodenal Switch in Patients with Super Obesity Using the MBSAQIP database.

INTRODUCTION: For patients with super obesity (BMI > 50 kg/m2), biliopancreatic diversion/duodenal switch (BPD/DS) can be an effective bariatric operation. Technical challenges and patient safety concerns, however, have limited its use as a primary procedure. This study sought to assess the safety of primary versus revisional BPD/DS. MATERIALS AND METHODS: The MBSAQIP database was queried for primary and revisional BPD/DS (2015-2018). Inclusion criteria were patients ≥ 18 years of age, BMI > 50 kg/m2, and with no concurrent procedures. Preoperative variables were compared using a chi-square test or Wilcoxon two-sample tests. Multivariate logistic or robust linear regression models were used to compare outcomes. RESULTS: There were 3,378 primary BPD/DS and 487 revisional BPD/DS patients. Primary BPD/DS patients had higher BMI (56.5 [IQR4.4] versus 54.8 [IQR4] kg/m2, p < 0.0001) and had more diabetes mellitus type II (29.1% versus 17.2%, p < 0.0001). Intraoperatively, revisional BPD/DS had longer operative time (165 [IQR47] min versus 139 [IQR100] min, p < 0.0001). After adjusting for preoperative characteristics, there was no difference in 30-day readmission or ED visits (primary 12.9% versus revisional 14.6%), reoperation or reintervention (primary 5.7% versus revisional 7.8%), or mortality (primary 0.4% versus revisional 0.6%). In contrast, the revisional BPD/DS patients had higher odds of major morbidity (primary 3.4% versus revisional 5.3%, OR 1.9, CI 1.1-3.2, p = 0.019). CONCLUSIONS: Revisional BPD/DS is associated with higher morbidity than primary BPD/DS in patients with super obesity. These patients should thus be counselled appropriately when choosing a primary or revisional bariatric procedure.

Why Size Matters: an Evaluation of Gastric Pouch Size in Roux-en-Y Gastric Bypass Using CT Volumetric Analysis and its Effect on Marginal Ulceration.

PURPOSE: Marginal ulceration (MU) is a common long-term complication following Roux-en-Y gastric bypass (RYGB). The causes of MU after RYGB are multifactorial and include surgical technique of constructing the gastrojejunal anastomosis (GJA). The purpose of this study is to evaluate the relationship between gastric pouch size in RYGB and MU using CT volumetrics. MATERIAL AND METHODS: Patients were retrospectively identified who underwent esophagogastroduodenoscopy (EGD) following RYGB at a tertiary care teaching hospital. Measurement of gastric pouch size was performed using 3-D CT software. Standard statistical methods were used, a univariate comparison was performed between MU and non-MU patients followed by a propensity-matched comparison to control for factors known to affect MU, and a propensity-matched subgroup analysis was also performed. RESULTS: In total, 122 patients met criteria, 57 of which had MU on EGD and 65 who did not. The MU group had more smokers and patients with PPI use than the non-MU group, and the mean time from operation to CT scan was 26.6 months (range: 0-108 months). The MU group had a larger gastric pouch size than the non-MU group (34.1 ± 11.8 versus 20.1 ± 6.8 cm3). When analyzed for matched patient cohorts, this difference remained for the MU group that included smokers and PPI use. When stratified for pouch size, for each 5 cm3 increase in pouch size, patients had 2.4 times odds increase of MU formation. CONCLUSIONS: CT volumetric analysis demonstrated that a larger gastric pouch size was associated with MU following RYGB.

Modeling of a single bipolar electrode with tines for irreversible electroporation delivery.

Irreversible electroporation (IRE) is a non-thermal tumor ablation technology employed to treat solid tumors not amenable to resection or thermal ablation. The IRE systems currently in clinical use deliver electrical pulses via multiple monopolar electrodes. This approach can present significant technical challenges due to the requirement for accurate placement of multiple electrodes and maintenance of parallel electrode alignment during pulse delivery. In this study, we sought to evaluate a novel IRE electrode configuration consisting of a single bipolar electrode with deployable tines. Using commercial finite element software predicted ablation outcomes, thermal damage, ablation sphericity, and energy delivery were calculated for existing monopolar and bipolar electrodes, and bipolar electrodes with either 4 or 8 deployable tines. The bipolar electrodes with tines generated larger predicted ablations compared to existing monopolar (>100%) and bipolar (>10%) arrangements, and the ablation shape using bipolar electrodes with tines were more spherical than those modeled for bipolar electrodes. Thermal damage modeled for bipolar electrodes and bipolar electrodes with tines was less than that of monopolar electrodes (using identical pulse parameters), and bipolar electrodes with tines delivered less energy than monopolar or bipolar electrodes. These studies using a single point of device insertion suggest the potential for developing alternative IRE delivery techniques, and may simplify clinical use and increase the predicted ablation shape/volume.

Platelet Aggregation, Mitochondrial Function and Morphology in Cold Storage: Impact of Resveratrol and Cytochrome c Supplementation.

Donated platelets are critical components of hemostasis management. Extending platelet storage beyond the recommended guidelines (5 days, 22 °C) is of clinical significance. Platelet coagulation function can be prolonged with resveratrol (Res) or cytochrome c (Cyt c) at 4 °C. We hypothesized that storage under these conditions is associated with maintained aggregation function, decreased reactive oxygen species (ROS) production, increased mitochondrial respiratory function, and preserved morphology. Donated platelets were stored at 22 °C or 4 °C supplemented with 50 µM Res or 100 µM Cyt c and assayed on days 0 (baseline), 5, 7 and 10 for platelet aggregation, morphology, intracellular ROS, and mitochondrial function. Declining platelet function and increased intracellular ROS were maintained by Res and Cyt c. Platelet respiratory control ratio declined during storage using complex I + II (CI + CII) or CIV substrates. No temperature-dependent differences (4 °C versus 22 °C) in respiratory function were observed. Altered platelet morphology was observed after 7 days at 22 °C, effects that were blunted at 4 °C independent of exposure to Res or Cyt c. Storage of platelets at 4 °C with Res and Cyt c modulates ROS generation and platelet structural integrity.

Gastrojejunal Anastomotic Stricture Following Roux-en-Y Gastric Bypass: an Analysis of Anastomotic Technique at a Single Institution.

PURPOSE: Patients undergoing laparoscopic Roux-en-Y gastric bypass (RYGB) are at risk of developing strictures of the gastrojejunal anastomosis (GJA). Several variables can affect this, one of which may be the method of anastomosis. Between 2010 and 2014, our institution utilized three different anastomotic techniques for creating the GJA (25 mm end-to-end circular-stapled (CS), linear-stapled (LS), and robotic hand sewn (HS)). Our objectives were to compare the method of GJA relative to the subsequent development of anastomotic stricture. METHODS: We queried our electronic health record for all patients who underwent an upper endoscopy (EGD) after RYGB (2010-2014). Patient charts were retrospectively reviewed for type of GJA, weight loss, complications, interventions, and revisions of the GJA. RESULTS: In total, 1112 RYGB were performed at our institute, and 17.4% of patients (194/1112) had an upper endoscopy (EGD). Overall, 3.1% (34/1112) were found to have a stricture of the GJA. Patients undergoing a CS, LS, and HS anastomosis had GJA stricture rates of 4.9%, 0.5%, and 1.2% respectively (CS to LS (p < 0.05), p = NS among CS vs. HS, and LS vs. HS). The rate of GJA revision was 1.5%, 0.5%, and 0.1% (p = NS). In patients who had an EGD, excess BMI loss was 57.4%, 64.6%, and 59.2% (p = NS). In patients symptomatic from strictures, excess BMI loss was 69.4%, 83%, and 63.5% respectively (p = NS). CONCLUSION: The anastomotic technique for creating of the GJA may impact the formation of strictures. Based on our experience, gastrojejunostomies created with a 2-mm EEA-stapling technique are at higher risk of strictures.

Hepatic stellate cell-derived exosomes modulate macrophage inflammatory response.

BACKGROUND: Hepatic stellate cell (HSC) differentiation/activation is central to liver fibrosis and is innately linked to the immune response to liver injury. Exosomes (EXOs) are important means of communication between cell populations. This study sought to characterize EXO release from HSCs and the effect of HSC-EXOs on macrophage cytokine release/function. METHODS: Liver from a rat fibrosis model was analyzed for EXO expression and localization. Quiescent and culture-activated rat and mouse HSCs and activated human HSCs were analyzed for microRNA expression. Mouse, rat, and human HSCs were culture-activated and EXOs purified from culture medium prior to addition to macrophages, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) mRNA and protein measured. The effect of activated HSC-EXOs on macrophage migration was assayed. RESULTS: Activation of rat HSCs led to increased EXO production in vivo, an effect mirrored by in vitro rat HSC culture-activation. Culture activation of mouse and rat HSCs led to altered EXO microRNA profiles, with a similar microRNA profile detected in activated human HSCs. Addition of activated HSC-EXOs to macrophages stimulated IL-6 and TNFα mRNA expression and protein secretion in mouse and human macrophages, but not for rat HSC-EXO-macrophages. Addition of human EXOs to macrophages stimulated migration, effects mirrored by the direct addition of rhIL-6 and rhTNFα. CONCLUSIONS: HSC-EXOs associate with macrophages and stimulate cytokine synthesis-release and macrophage migration. Constructing a comprehensive understanding of EXO interactions between liver cell populations in the setting of inflammation/fibrosis increases the potential for developing new diagnostic/therapeutic approaches.