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Obesity has become a global epidemic with a soaring economic encumbrance due to its related morbidity and mortality. Amongst obesity-related conditions, cancer is indeed the most redoubtable. Bariatric surgery has been proven to be the most effective treatment for obesity and its associated metabolic and cardiovascular disorders. However, the understanding of whether and how bariatric surgery determines a reduction in cancer risk is limited. Obesity-related malignancies primarily include colorectal and hormone-sensitive (endometrium, breast, prostate) cancers. Additionally, esophago-gastric tumors are growing to be recognized as a new category mainly associated with post-bariatric surgery outcomes. In fact, certain types of surgical procedures have been described to induce the development and subsequent progression of pre-cancerous esophageal and gastric lesions. This emerging category is of great concern and further research is required to possibly prevent such risks. Published data has generated conflicting results. In fact, while overall cancer risk reduction was reported particularly in women, some authors showed no improvement or even increased cancer incidence. Although various studies have reported beneficial effects of surgery on risk of specific cancer development, fundamental insights into the pathogenesis of obesity-related cancer are indispensable to fully elucidate its mechanisms.

ObjectiveClinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis.DesignThis multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16− monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis.ResultsThe algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography.ConclusionsThe proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers.Clinical trialsDiscovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

ObjectiveTo assess the role of jejunum in insulin resistance in humans and in experimental animals.DesignTwenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling.ResultsWhole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans.ConclusionProximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity.Trial registration numberNCT03111953.

Background: Gastric bypass surgery is a very effective treatment of obesity and type 2 diabetes. However, very few eligible patients are offered surgery. Some patients also prefer less invasive approaches. We aimed to study the effects of the Sleeveballoona new device combining an intragastric balloon with a connecting sleeve, which covers the duodenal and proximal jejunal mucosaon insulin sensitivity, glycemic control, body weight and body fat distribution. Methods: We compared the effects of Sleeveballoon, Roux-en-Y Gastric-Bypass (RYGB) and sham-operation in 30 high-fat diet (HFD) fed Wistar rats. Whole body and hepatic insulin sensitivity and insulin signaling were studied. Transthoracic echocardiography was performed using a Vevo 2100 system (FUJIFILM VisualSonics Inc., Canada). Gastric emptying was measured using gastrografin. Findings: Hepatic (P = .023) and whole-body (P = .011) insulin sensitivity improved in the Sleeveballoon and RYGB groups compared with sham-operated rats. Body weight reduced in both Sleeveballoon and RYGB groups in comparison to the sham-operated group (503.1 ± 8.9 vs. 614.4 ± 20.6 g, P = .006 and 490.0 ± 17.7 vs. 614.4 ± 20.6 g, P = .006, respectively). Ectopic fat deposition was drastically reduced while glycogen content was increased in both liver and skeletal muscle. Gastric emptying (T 1/2) was longer (157.7 ± 29.2 min, P = .007) in the Sleeveballoon than in sham-operated rats (97.1 ± 26.3 min), but shorter in RYGB (3.5 ± 1.1 min, P b .0001). Cardiac function was better in Sleeveballoon and RYGB versus sham-operated rats. Interpretation: The Sleeveballoon reduces peripheral and hepatic insulin resistance, glycaemia, body weight and ectopic fat deposition to a similar level as RYGB, although the contribution of gastric emptying to blood glucose reduction is different.

(1) Background: Fluorescence cholangiography has been proposed as a method for improving the visualization and identification of extrahepatic biliary anatomy in order to possibly reduce injuries and related complications. The most common method of indocyanine green (ICG) administration is the intravenous route, whereas evidence on direct ICG injection into the gallbladder is still quite limited. We aimed to compare the two different methods of ICG administration in terms of the visualization of extrahepatic biliary anatomy during laparoscopic cholecystectomy (LC), analyzing differences in the time of visualization, as well as the efficacy, advantages, and disadvantages of both modalities. (2) Methods: A total of 35 consecutive adult patients affected by acute or chronic gallbladder disease were enrolled in this prospective case–control study. Seventeen patients underwent LC with direct gallbladder ICG injection (IC-ICG) and eighteen subjects received intravenous ICG administration (IV-ICG). (3) Results: The groups were comparable with regard to their demographic and perioperative characteristics. The IV-ICG group had a significantly shorter overall operative time compared to the IC-ICG group (p = 0.017). IV-ICG was better at delineating the duodenum and the common hepatic duct compared to the IC-ICG method (p = 0.009 and p = 0.041, respectively). The cystic duct could be delineated pre-dissection in 76.5% and 66.7% of cases in the IC-ICG and IV-ICG group, respectively, and this increased to 88.2% and 83.3% after dissection. The common bile duct could be highlighted in 76.5% and 77.8% of cases in the IC-ICG and IV-ICG group, respectively. Liver fluorescence was present in one case in the IC-ICG group and in all cases after IV-ICG administration (5.8% versus 100%; p < 0.0001). (4) Conclusions: The present study demonstrates how ICG-fluorescence cholangiography can be helpful in identifying the extrahepatic biliary anatomy during dissection of Calot’s triangle in both administration methods. In comparison with intravenous ICG injection, the intracholecystic ICG route could provide a better signal-to-background ratio by avoiding hepatic fluorescence, thus increasing the bile duct-to-liver contrast.

Nonalcoholic fatty-liver disease (NAFLD) is the most common cause of liver-related mortality. NAFLD is associated with obesity, hepatic fat accumulation and insulin-resistance, all of which contribute to its pathophysiology. Weight-loss is the main therapy for NAFLD and metabolic surgery is the most effective treatment for morbid obesity and its metabolic comorbidities. Although has been reported that Roux-en-Y gastric bypass can reverse NAFLD, it is unclear if such effects result from reduced weight, from a less calorie-intake or from the direct influence of surgery on mechanisms contributing to NAFLD. We aim to investigate whether gastrointestinal (GI) bypass surgery can induce direct effects on hepatic fat accumulation and insulin-resistance, independently of weight reduction. Twenty Wistar rats under a high-fat diet underwent duodenal-jejunal-bypass (DJB) or sham-operation and were pair-fed (PF) for 15 weeks after surgery to obtain a matched weight. Outcome measures include ectopic fat deposition, expression of genes and proteins involved in fat metabolism, insulin-signaling and gluconeogenesis in liver and muscle. Despite no differences in body-weight and calorie-intake, DJB showed lower ectopic fat accumulation, improved peripheral and hepatic insulin-sensitivity, and enhanced lipid droplet degradation. In both tissues DJB increased insulin-signaling while hepatic key enzymes involved in gluconeogenesis and de novo lipogenesis were decreased. These findings suggest that DJB can reverse, independently of weight loss, ectopic fat deposition and insulin-resistance, two features of NAFLD that share a mutual pathway, in which Perilipin-2 (PLIN2) seems to be the main player, supporting further investigation into strategies that target the gut to treat metabolic liver diseases.

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