A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1.

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer.

Breaking down barriers to bariatric care: a qualitative study on how telemedicine could transform patient experiences in a Swiss monocentric setting.

OBJECTIVE: Telemedicine is becoming an increasingly feasible option for patients with chronic diseases due to its convenience, cost-effectiveness and ease of access. While there are certain limitations, the benefits can be appreciated by those seeking repetitive care. The perception of telemedicine as an alternative to recurrent, in-person appointments for patients with obesity in structured bariatric programmes is still unclear. This content analysis' primary endpoint was to explore how patients within our bariatric programme perceived telemedicine and virtual consultations as a new way of communication during COVID-19. DESIGN: A qualitative study using semistructured interviews and qualitative content analysis method by Elo and Kyngäs following four steps: data familiarisation, coding and categorising with Quirkos software and final interpretation guided by developed categories. SETTING: University Hospital, Switzerland. PARTICIPANTS: We conducted 33 interviews with 19 patients from a structured bariatric programme. RESULTS: Most patients shared positive experiences, acknowledging the convenience and accessibility of virtual appointments. Others voiced concerns, especially regarding telemedicine's limitations. These reservations centred around the lack of physical examinations, difficulties in fostering connections with healthcare providers, as well as barriers stemming from language and technology. The research identified a spectrum of patient preferences in relation to telemedicine versus in-person visits, shaped by the immediacy of their concerns and their availability. CONCLUSION: While telemedicine is increasingly accepted by the public and provides accessible and cost-effective options for routine follow-up appointments, there are still obstacles to overcome, such as a lack of physical examination and technological limitations. However, integrating virtual alternatives, like phone or video consultations, into routine bariatric follow-ups could improve continuity and revolutionise bariatric care.

Educational challenges and opportunities for the future generation of surgeons: a scoping review.

PURPOSE: Surgery offers exciting opportunities but comes with demanding challenges that require attention from both surgical program administrators and aspiring surgeons. The hashtag #NoTrainingTodayNoSurgeonsTomorrow on 𝕏 (previously Twitter) underscores the importance of ongoing training. Our scoping review identifies educational challenges and opportunities for the next generation of surgeons, analyzing existing studies and filling gaps in the literature. METHODS: Following the PRISMA guidelines, MEDLINE/PubMed was searched in February 2022, using the MeSH terms "surgeons/education," for articles in English or German on general, abdominal, thoracic, vascular, and hand surgery and traumatology targeting medical students, surgical residents, future surgeons, and fellows. RESULTS: The initial search yielded 1448 results. After a step-by-step evaluation process, 32 publications remained for complete review. Three main topics emerged: surgical innovations and training (n = 7), surgical culture and environment (n = 19), and mentoring (n = 6). The articles focusing on surgical innovations and training mainly described the incorporation of structured surgical training methods and program initiatives. Articles on surgical culture examined residents' burnout, well-being, and gender issues. Challenges faced by women, including implicit bias and sexual harassment, were highlighted. Regarding mentoring, mentees' needs, training challenges, and the qualities expected of both mentors and mentees were addressed. CONCLUSION: At a time of COVID-19-driven surgical innovations, the educational and working environment of the new generation of surgeons is changing. Robotic technology and other innovations require future surgeons to acquire additional technological and digital expertise. With regard to the cultural aspects of training, surgery needs to adapt curricula to meet the demands of the new generation of surgeons, but even more it has to transform its culture.

Hepatic Artery Infusion Chemotherapy for Primary and Secondary Malignancies of the Liver: State of the Art and Current High-Level Evidence.

BACKGROUND: Hepatic artery infusion chemotherapy (HAI) has been proposed as a valuable adjunct for multimodal therapy of primary and secondary liver malignancies. This review provides an overview of the currently available evidence of HAI, taking into account tumor response and long-term oncologic outcome. SUMMARY: In colorectal liver metastases (CRLM), HAI in combination with systemic therapy leads to high response rates (85-90%) and conversion to resectablity in primary unresectable disease in up to 50%. HAI in combination with systemic therapy in CRLM in the adjuvant setting shows promising long-term outcomes with up to 50% 10-year survival in a large, non-randomized single-center cohort. For hepatocellular carcinoma patients, response rates as high as 20-40% have been reported for HAI and long-term outcomes compare well to other therapies. Similarly, survival for patients with unresectable intrahepatic cholangiocarcinoma 3 years after treatment with HAI is reported as high as 34%, which compares well to trials of systemic therapy where 3-year survival is usually below 5%. However, evidence is mainly limited by highly selected, heterogenous patient groups, and outdated chemotherapy regimens. The largest body of evidence stems from small, often non-randomized cohorts, predominantly from highly specialized single centers. KEY MESSAGE: In well-selected patients with primary and secondary liver malignancies, HAI might improve response rates and, possibly, long-term survival. Results of ongoing randomized trials will show whether a wider adoption of HAI is justified, particularly to increase rates of resectability in advanced malignant diseases confined to the liver.

Evidence mapping on how to perform an optimal surgical repair of large hiatal hernias.

BACKGROUND: Symptomatic and large hiatal hernia (HH) is a common disorder requiring surgical management. However, there is a lack of systematic, evidence-based recommendations summarizing recent reviews on surgical treatment of symptomatic HH. Therefore, this systematic review aimed to create evidence mapping on the key technical issues of HH repair based on the highest available evidence. METHODS: A systematic review identified studies on eight key issues of large symptomatic HH repair. The literature was screened for the highest level of evidence (LE from level 1 to 5) according to the Oxford Center for evidence-based medicine's scale. For each topic, only studies of the highest available level of evidence were considered. RESULTS: Out of the 28.783 studies matching the keyword algorithm, 47 were considered. The following recommendations could be deduced: minimally invasive surgery is the recommended approach (LE 1a); a complete hernia sac dissection should be considered (LE 3b); extensive division of short gastric vessels cannot be recommended; however, limited dissection of the most upper vessels may be helpful for a floppy fundoplication (LE 1a); vagus nerve should be preserved (LE 3b); a dorso-ventral cruroplasty is recommended (LE 1b); routine fundoplication should be considered to prevent postoperative gastroesophageal reflux (LE 2b); posterior partial fundoplication should be favored over other forms of fundoplication (LE 1a); mesh augmentation is indicated in large HH with paraesophageal involvement (LE 1a). CONCLUSION: The current evidence mapping is a reasonable instrument based on the best evidence available to guide surgeons in determining optimal symptomatic and large HH repair.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

The role of bariatric surgery on beta-cell function and insulin resistance in patients with nonalcoholic fatty liver disease and steatohepatitis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are strongly associated with obesity, metabolic syndrome, and insulin resistance (IR). OBJECTIVE: The aim of this study was to investigate the effects of metabolic surgery on pancreatic beta cell function and IR in patients with obesity and NAFLD. SETTING: University Hospital, Germany. METHODS: Liver biopsies were taken intraoperatively from 112 patients undergoing sleeve gastrectomy (n = 68) or Roux-en-Y gastric bypass (n = 44) and analyzed histologically for the presence of simple steatosis (NAFL) or NASH. Clinical and biochemical parameters were collected over up to 2 years. Beta cell function and IR were assessed using the homeostasis model assessment of beta-cell function (HOMA2-%B) and insulin resistance (HOMA2-IR) index. RESULTS: NASH was present in 53.6% (n = 60) of the patients and NAFL in 25.9% (n = 29). Liver enzymes, adiponectin/leptin ratio, triglycerides, and HbA1C were improved at 6 months, 1, and 2 years after surgery. HOMA2-IR was significantly lower in patients without NAFLD while HOMA2-IR did not differ between patients with NAFL and/or NASH. HOMA2-%B was highest in the NAFLD group and lowest in patients with NASH. While there was no change in HOMA2-%B and HOMA2-IR in the No-NAFLD group, HOMA2-%B decreased and IR improved in the NAFL and NASH groups. CONCLUSION: Insufficient compensatory beta-cell function may contribute to the progression from NAFL alongside with IR to NASH. Our findings suggest that bariatric surgery decreases IR while at the same time reducing compensatory insulin oversecretion. These results are associated with beneficial changes in adipose tissue function after bariatric surgery.

Age-dependent benefit of neoadjuvant treatment in adenocarcinoma of the esophagus and gastroesophageal junction: a multicenter retrospective observational study of young versus old patients.

OBJECTIVES: The objective was to provide evidence for age-dependent use of neoadjuvant treatment by clinical comparisons of young (lower quartile, <56.6 years) versus old (upper quartile, >71.3 years) patients with esophageal and esophagogastric-junction adenocarcinoma. BACKGROUND: Neoadjuvant treatment is the standard of care for locally advanced and node-positive EAC. However, the effect of age on oncological outcomes is disputable as they are underrepresented in treatment defining randomized controlled trials. METHODS: Patients with EAC undergoing esophagectomy between 2001 and 2022 were retrospectively analyzed from three centers. Patients having distant metastases or clinical UICC-stage I were excluded. Cox proportional hazards regression was used to identify the variables associated with survival benefit. RESULTS: Neoadjuvant treatment was administered to 185/248 (74.2%) young and 151 out of 248 (60.9%) elderly patients ( P =0.001). Young age was associated with a significant overall survival (OS) benefit (median OS: 85.6 vs. 29.9 months, hazard ratio 0.62, 95% CI: 0.42-0.92) after neoadjuvant treatment versus surgery alone. In contrast, elderly patients did only experience a survival benefit equaling the length of neoadjuvant treatment itself (median OS: neoadjuvant 32.8 vs. surgery alone 29.3 months, hazard ratio 0.89, 95% CI: 0.63-1.27). Despite the clear difference in median OS benefit, histopathological regression was similar ((Mandard-TRG-1/2: young 30.7 vs. old 36.4%, P= 0.286). More elderly patients had a dose reduction or termination of neoadjuvant treatment (12.4 vs. 40.4%, P <0.001). CONCLUSION: Old patients benefit less from neoadjuvant treatment compared to younger patients in terms of gain in OS. Since they also experience more side effects requiring dose reduction, upfront surgery should be considered as the primary treatment option in elderly patients.

Mid-Term Outcomes After Conversion Procedures Following Laparoscopic Sleeve Gastrectomy.

PURPOSE: In the long term, laparoscopic sleeve gastrectomy (SG) may be associated with insufficient weight loss (IWL), gastroesophageal reflux disease (GERD), and persistence or relapse of associated medical problems. This study's objective is to present mid-term results regarding weight loss (WL), evolution of associated medical problems, and reoperation rate of patients who underwent a conversion after SG. METHODS: Retrospective single-center analysis of patients with a minimal follow-up of 2 years after conversion. RESULTS: In this series of 549 SGs, 84 patients (15.3%) underwent a conversion, and 71 met inclusion criteria. They were converted to short biliopancreatic limb Roux-en-Y gastric bypass (short BPL RYGB) (n = 28, 39.4%), biliopancreatic diversion with duodenal switch (BPD/DS) (n = 19, 26.8%), long biliopancreatic limb Roux-en-Y gastric bypass (long BPL RYGB) (n = 17, 23.9%), and re-sleeve gastrectomy (RSG) (n = 7, 9.9%). Indications were GERD (n = 24, 33.8%), IWL (n = 23, 32.4%), IWL + GERD (n = 22, 31.0%), or stenosis/kinking of the sleeve (n = 2, 2.8%). The mean pre-revisional body mass index (BMI) was 38.0 ± 7.5 kg/m2. The mean follow-up time after conversion was 5.1 ± 3.1 years. The overall percentage of total weight loss (%TWL) was greatest after BPD/DS (36.6%) and long BPL RYGB (32.9%) compared to RSG (20.0%; p = 0.004; p = 0.049). In case of GERD, conversion to Roux-en-Y gastric bypass (RYGB) led to a resolution of symptoms in 79.5%. 16.9% of patients underwent an additional revisional procedure. CONCLUSION: In the event of IWL after SG, conversion to BPD/DS provides a significant and sustainable additional WL. Conversion to RYGB leads to a reliable symptom control in patients suffering from GERD after SG.

Clinical Characteristics and Oncological Outcomes of Surgically Treated Early-Onset Gastric Adenocarcinoma - a Retrospective Cohort Study.

Introduction: The incidence of early-onset gastric adenocarcinoma (patients <50 years, EOGA) is rising. Tumors in younger patients are associated with prognostically unfavorable features. The impact of EOGA on patient survival, however, remains unclear. The aim of this study is to evaluate early-onset age as a prognostic factor compared to late-onset gastric adenocarcinoma (LOGA, >50years) in a surgical cohort and assess treatment options. Methods: We analyzed 738 patients (129 early-onset/609 late-onset) operated in curative intent from 2002 to 2021. Data was extracted from a prospectively managed database of an academic tertiary referral hospital. Differences in perioperative as well as oncological outcomes were calculated by chi-square test. Cox regression analysis was performed to assess disease-free survival (DFS) and overall survival (OS). Results: EOGA patients were more often treated with neoadjuvant therapy (62.8% vs. 43.7%, p<0.001) and extended surgical resections e.g. through additional resections (36.4% vs. 26.8%, p=0.027). EOGA was more often metastasized into regional lymph nodes (pN+ 67.4% vs. 55.3%, p=0.012) and to distant sites (pM+: 23.3% vs. 12.0%, p=0.001) and was more often poorly differentiated (G3/G4: 91.1% vs. 67.2%, p<0.001). There were no significant differences in overall complication rates (31.0% vs. 36.6%, p=0.227). Survival analysis showed shorter DFS (median DFS 25.6 months vs. not reached, p=0.006) but similar OS (median OS: 50.5 months vs. not reached, p=0.920) in EOGA compared to LOGA. Conclusions: This analysis confirmed that EOGA is associated with more aggressive tumor characteristics. Early-Onset was not a prognostic factor in the multivariate analysis. EOGA patients may be more capable to undergo intensive multimodal therapy including perioperative chemotherapy and extended surgery.

Semaphorin 3C exacerbates liver fibrosis.

BACKGROUND AND AIMS: Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-ß is the pivotal profibrogenic cytokine that activates HSC, yet other molecules can modulate TGF-ß signaling during liver fibrosis. Expression of the axon guidance molecules semaphorins (SEMAs), which signal through plexins and neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs. APPROACH AND RESULTS: We analyzed publicly available patient databases and liver biopsies. We used transgenic mice, in which genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the semaphorin family in liver samples from patients with cirrhosis. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis, or HBV-induced hepatitis discriminates those with a more profibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs on activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-ß-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained on activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. CONCLUSION: SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.

Bariatric surgery in patients with obesity and end-stage renal disease.

BACKGROUND: Bariatric surgery has been suggested as a treatment for obesity and end-stage renal disease (ESRD). Although the number of bariatric surgeries in patients with ESRD is increasing, its safety and effectiveness in these patients are still controversial and the surgical method of choice in these patients is under debate. OBJECTIVES: To compare the outcomes of bariatric surgery between patients with and without ESRD and to assess different methods of bariatric surgery in patients with ESRD. SETTING: Meta-analysis. METHODS: A comprehensive search was conducted in Web of Science and Medline (via Pubmed) until May 2022. Tow meta-analyses were performed: A) to compare bariatric surgery outcomes among patients with and without ESRD, and B) to compare outcomes of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in patients with ESRD. Using a random-effect model, odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were computed for surgical and weight loss outcomes. RESULTS: Of 5895 articles, 6 studies were included in meta-analysis A and 8 studies in meta-analysis B. The risk of bias was moderate to serious among studies. Major postoperative complications (OR = 2.82; 95% CI = 1.66-4.77; P = .0001), reoperation (OR = 2.66; 95% CI = 1.99-3.56; P < .00001), readmission (OR = 2.37; 95% CI = 1.55-3.64; P < .0001), and in-hospital/90-d mortality (OR = 4.03; 95% CI = 1.80-9.03; P = .0007) were higher in patients with ESRD. Patients with ESRD also had a longer hospital stay (MD = 1.23; 95% CI = .32-2.14; P = .008). Bleeding, leakage, and total weight loss were comparable among groups. SG showed a 10% lower rate of overall complications and significantly shorter hospital stay than RYGB did. The quality of evidence was very low for the outcomes CONCLUSIONS: Bariatric surgery in patients with ESRD seems to have higher rates of major complications and perioperative mortality than in patients without ESRD, but a comparable rate of overall complications. SG has fewer postoperative complications and could be the method of choice in these patients. These findings should be interpreted cautiously in light of the moderate to high risk of bias in most included studies.

Outcome and prognostic factors in patients undergoing salvage therapy for recurrent esophagogastric cancer after multimodal treatment.

PURPOSE: Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. METHODS: Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. RESULTS: Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (< 6 months) had an inferior overall survival (OS 6.3 vs. 13.8 months, p < 0.001) after relapse than those with a late relapse (> 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p < 0.0001). Multivariate analysis confirmed the prognostic benefit of the MSI status and a local intervention. CONCLUSION: Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Combined non-alcoholic fatty liver disease and type 2 diabetes in severely obese patients-medium term effects of sleeve gastrectomy versus Roux-en-Y-gastric bypass on disease markers.

Background: We aimed to evaluate the medium-term efficacy of sleeve gastrectomy (SG) vs. Roux-en-Y gastric bypass (RYGB) on remission of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Methods: We identified severely obese patients [body mass index (BMI) >35 kg/m2] with NAFLD (as defined by the Longitudinal Assessment of Bariatric Surgery Study) and T2DM (as defined by the American Association of Clinical Endocrinologists and the American College of Endocrinology) who underwent SG or RYGB in a single university surgical centre. The cohorts were match-paired and data were analysed after at least 3 years of follow up. The key outcomes measured were: (I) the improvement of liver function tests and NAFLD markers; (II) glycemic control and insulin resistance. Results: Ninety-six patients were investigated; 44 (45.8%) were women. The mean pre-operative BMI was 45.2 kg/m2 in the SG and 42.0 kg/m2 in the RYGB group. SG and RYGB both significantly reduced serum liver enzyme concentrations. NAFLD markers resolved 2 years after SG in all patients. In contrast, only 78% and 80% of patients achieved remission of NAFLD 2 and 3 years after RYBG respectively. Both procedures resulted in comparable rates of remission of T2DM. Conclusions: Bariatric surgery with SG may be preferable to RYGB for obese patients with NAFLD and T2DM based on the rates of remission of markers of these co-morbidities. However, our results need to be confirmed in prospective trials. Understanding the metabolic effects of specific bariatric surgical procedures may facilitate the development of a personalised approach to weight-loss surgery.

Comparative effectiveness of medical treatment vs. metabolic surgery for histologically proven non-alcoholic steatohepatitis and fibrosis: a matched network meta-analysis.

Background: Non-alcoholic steatohepatitis (NASH) comprises a major healthcare problem affecting up to 30% of patients with obesity and the associated risk for cardiovascular and liver-related mortality. Several new drugs for NASH-treatment are currently investigated. No study thus far directly compared surgical and non-surgical therapies for NASH. This network meta-analysis compares for the first time the effectiveness of different therapies for NASH using a novel statistical approach. Methods: The study was conducted according to the PRISMA guidelines for network meta-analysis. PubMed, CENTRAL and Web of Science were searched without restriction of time or language using a validated search strategy. Studies investigating therapies for NASH in adults with liver biopsies at baseline and after at least 12 months were selected. Patients with liver cirrhosis were excluded. Risk of bias was assessed with ROB-2 and ROBINS-I-tools. A novel method for population-adjusted indirect comparison to include and compare single-arm trials was applied. Main outcomes were NASH-resolution and improvement of fibrosis. Results: Out of 7,913 studies, twelve randomized non-surgical studies and twelve non-randomized surgical trials were included. NASH-resolution after non-surgical intervention was 29% [95% confidence interval (CI): 23-40%] and 79% (95% CI: 72-88%) after surgery. The network meta-analysis showed that surgery had a higher chance of NASH-resolution than medication [odds ratio (OR) =2.68; 95% CI: 1.44-4.97] while drug treatment was superior to placebo (OR =2.24; 95% CI: 1.55-3.24). Surgery (OR =2.18; 95% CI: 1.34-3.56) and medication (OR =1.79; 95% CI: 1.39-2.31) were equally effective to treat fibrosis compared to placebo without difference between them. The results did not change when only new drugs specifically developed for the treatment of NASH were included. Conclusions: Metabolic surgery has a higher effectiveness for NASH-therapy than medical therapy while both were equally effective regarding improvement of fibrosis. Trials directly comparing surgery with medication must be urgently conducted. Patients with NASH should be informed about surgical treatment options.

Minimally invasivE versus open total GAstrectomy (MEGA): study protocol for a multicentre randomised controlled trial (DRKS00025765).

INTRODUCTION: The only curative treatment for most gastric cancer is radical gastrectomy with D2 lymphadenectomy (LAD). Minimally invasive total gastrectomy (MIG) aims to reduce postoperative morbidity, but its use has not yet been widely established in Western countries. Minimally invasivE versus open total GAstrectomy is the first Western multicentre randomised controlled trial (RCT) to compare postoperative morbidity following MIG vs open total gastrectomy (OG). METHODS AND ANALYSIS: This superiority multicentre RCT compares MIG (intervention) to OG (control) for oncological total gastrectomy with D2 or D2+LAD. Recruitment is expected to last for 2 years. Inclusion criteria comprise age between 18 and 84 years and planned total gastrectomy after initial diagnosis of gastric carcinoma. Exclusion criteria include Eastern Co-operative Oncology Group (ECOG) performance status >2, tumours requiring extended gastrectomy or less than total gastrectomy, previous abdominal surgery or extensive adhesions seriously complicating MIG, other active oncological disease, advanced stages (T4 or M1), emergency setting and pregnancy.The sample size was calculated at 80 participants per group. The primary endpoint is 30-day postoperative morbidity as measured by the Comprehensive Complications Index. Secondary endpoints include postoperative morbidity and mortality, adherence to a fast-track protocol and patient-reported quality of life (QoL) scores (QoR-15, EUROQOL EuroQol-5 Dimensions-5 Levels (EQ-5D), EORTC QLQ-C30, EORTC QLQ-STO22, activities of daily living and Body Image Scale). Oncological endpoints include rate of R0 resection, lymph node yield, disease-free survival and overall survival at 60-month follow-up. ETHICS AND DISSEMINATION: Ethical approval has been received by the independent Ethics Committee of the Medical Faculty, University of Heidelberg (S-816/2021) and will be received from each responsible ethics committee for each individual participating centre prior to recruitment. Results will be published open access. TRIAL REGISTRATION NUMBER: DRKS00025765.

Study protocol of REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I): a prospective observational study of antibiotic prophylaxis practice for patients undergoing major abdominal surgery.

INTRODUCTION: Surgical site infections (SSIs) are among the most common complications after abdominal surgery and develop in approximately 20% of patients. These patients suffer a 12% increase in mortality, underlying the need for strategies reducing SSI. Perioperative antibiotic prophylaxis is paramount for SSI prevention in major abdominal surgery. Yet, intraoperative redosing criteria are subjective and whether patients benefit from it remains unclear. METHODS AND ANALYSIS: The REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I) study is a single-centre, prospective, observational study investigating redosing of antibiotic prophylaxis in 300 patients undergoing major abdominal surgery. Adult patients scheduled for major abdominal surgery will be included. Current practice of redosing regarding number and time period will be recorded. Postoperative SSIs, nosocomial infections, clinically relevant infection-associated bacteria, postoperative antibiotic treatment, in addition to other clinical, pharmacological and economical outcomes will be evaluated. Differences between groups will be analysed with analysis of covariance. ETHICS AND DISSEMINATION: RESISTAAS I will be conducted in accordance with the Declaration of Helsinki and internal, national and international standards of GCP. The Medical Ethics Review Board of Heidelberg University has approved the study prior to initiation (S-404/2021). The study has been registered on 7 February 2022 at German Clinical Trials Register, with identifier DRKS00027892. We plan to disseminate the results of the study in a peer-reviewed journal. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00027892.

Gastric Bypass Resolves Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) in Low-BMI Patients: A Prospective Cohort Study.

OBJECTIVE: Metabolic dysfunction-associated fatty liver disease (MAFLD) reflects the multifactorial pathogenesis of fatty liver disease in metabolically sick patients. The effects of metabolic surgery on MAFLD have not been investigated. This study assesses the impact of Roux-en-Y gastric bypass (RYGB) on MAFLD in a prototypical cohort outside the guidelines for obesity surgery. METHODS: Twenty patients were enrolled in this prospective, single-arm trial investigating the effects of RYGB on advanced metabolic disease (DRKS00004605). Inclusion criteria were an insulin-dependent type 2 diabetes, body mass index of 25 to 35 kg/m 2 , glucagon-stimulated C-peptide of >1.5 ng/mL, glycated hemoglobin >7%, and age 18 to 70 years. A RYGB with intraoperative liver biopsies and follow-up liver biopsies 3 years later was performed. Steatohepatitis was assessed by expert liver pathologists. Data were analyzed using the Wilcoxon rank sum test and a P value <0.05 was defined as significant. RESULTS: MAFLD completely resolved in all patients 3 years after RYGB while fibrosis improved as well. Fifty-five percent were off insulin therapy with a significant reduction in glycated hemoglobin (8.45±0.27% to 7.09±0.26%, P =0.0014). RYGB reduced systemic and hepatic nitrotyrosine levels likely through upregulation of NRF1 and its dependent antioxidative and mitochondrial genes. In addition, central metabolic regulators such as SIRT1 and FOXO1 were upregulated while de novo lipogenesis was reduced and ß-oxidation was improved in line with an improvement of insulin resistance. Lastly, gastrointestinal hormones and adipokines secretion were changed favorably. CONCLUSIONS: RYGB is a promising therapy for MAFLD even in low-body mass index patients with insulin-treated type 2 diabetes with complete histologic resolution. RYGB restores the oxidative balance, adipose tissue function, and gastrointestinal hormones.