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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. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosures: All authors report no conflicts of interest.

Abstarct: BACKGROUND: Early recurrence after esophagectomy is often used as a surrogate for aggressive tumor biology and treatment failure. However, there is no standardized definition of early recurrence, and predictors for early recurrence are unknown. Therefore, we aimed to define an evidence-based cutoff to discriminate early and late recurrence and assess the influence of neoadjuvant treatment modalities for patients with esophageal or gastroesophageal-junction adenocarcinoma (EAC)., Patients and Methods: This dual-center retrospective cohort study included patients who underwent esophagectomy for stage II-III EAC after neoadjuvant treatment with chemotherapy using 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) or radiochemotherapy according to the Chemoradiotherapy for Esophageal Cancer followed by Surgery Study (CROSS) protocol from 2012 to 2022. The optimal cutoff for early versus late recurrence was calculated by using the most significant difference in survival after recurrence (SAR). Multivariable logistic regression was used to identify variables associated with early recurrence., Results: Of 334 included patients, 160 (47.9%) were diagnosed with recurrence. Most patients had systemic (60.5%) or multiple sites of recurrence (21.1%), whereas local-only recurrence (9.2%) and carcinomatosis (9.2%) were rare. The optimal interval between surgery and recurrence for distinguishing early and late recurrence was 18 months (median SAR: 9.1 versus 17.8 months, p = 0.039) with only 24% of recurrences diagnosed after the calculated cutoff. Advanced pathologic tumor infiltration (ypT3-4, p = 0.006), nodal positivity (p = 0.013), poor treatment response (>10% residual tumor, p = 0.015), and no adjuvant treatment (p = 0.048) predicted early recurrence., Conclusion: Early recurrence can be defined as recurrent disease within 18 months. Hallmarks for early recurrence are poor response to neoadjuvant therapy with persisting advanced disease. In those patients, adjuvant therapy and closer follow-up should be considered., Competing Interests: Disclosures: There are no conflicts of interest for any authors., (© 2024. The Author(s).)

Background: Early recurrence in intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) is poorly defined. Predictors are lacking and needed for patient counseling, risk stratification, and postoperative management. This study aimed to define and predict early recurrence for patients in resected IPMN-derived PDAC and guide management., Methods: A lowest p value for survival after recurrence (SAR) was used to define early recurrence in resected IPMN-derived PDAC from five international centers. Overall survival (OS) and SAR were compared using log-rank tests. A multivariable logistic regression identified odds ratios (ORs) with 95 % confidence intervals (CIs) for early recurrence. Rounded ORs were used to stratify patients into low-, intermediate-, and high-risk groups using upper and lower quartile score distributions. Adjuvant chemotherapy was assessed by Cox regression and log-rank tests for OS in risk groups., Results: Recurrence developed in 160 (42 %) of 381 patients. Early recurrence was defined at 10.5 months and observed in 61 patients (38 % of recurrences). The median SAR for the patients with early recurrence was 8.3 months (95 % CI, 3.1-16.1 months) compared with 12.9 months (95 % CI, 5.2-27.5 months) for the patients with late recurrence. The independent predictors of early recurrence were CA19-9 (OR, 3.80; 95 % CI, 1.54-9.41) and N2 disease (OR, 7.29; 95 % CI, 3.22-16.49). The early recurrence rates in the low-, intermediate-, and high-risk groups were respectively 1 %, 14 %, and 32 %. Adjuvant chemotherapy was associated with improved OS only for the high-risk patients (hazard ratio, 0.50; 95 % CI, 0.32-0.79)., Conclusion: In IPMN-derived PDAC, the optimal cutoff for early recurrence is 10.5 months. Both CA19-9 and N stage predict early recurrence. Adjuvant chemotherapy is associated with survival benefit only for high-risk patients., Competing Interests: Disclosure: There are no conflicts of interest., (© 2024. Society of Surgical Oncology.)

Competing Interests: Disclosure: The authors declare no conflicts of interest.

Competing Interests: Disclosure: There are no conflicts of interest for any of the authors. This work was supported by the Ben and Rose Cole Charitable PRIA Foundation. Joseph R. Habib was supported by the NIH T32 grant T32CA193111.

Metabolic syndrome (MetS) presents a global health challenge characterized by cardiometabolic risk factors like central obesity, elevated blood pressure, dyslipidemia, and high fasting glucose levels. Despite lifestyle interventions and medications, the increasing prevalence of MetS calls for effective treatments. Sleeve gastrectomy (SG) has emerged as a promising intervention. This review examines the role of SG in improving MetS outcomes, drawing from a PubMed/Medline literature search. It highlights SG's multifaceted metabolic effects, including hormonal changes and improved insulin sensitivity, contributing to improved metabolic outcomes. Additionally, SG leads to significant weight loss and effectively addresses comorbidities like hypertension, dyslipidemia, and type 2 diabetes mellitus (T2DM), with low rates of early morbidity and mortality. However, long-term studies indicate that Roux-en-Y gastric bypass (RYGB) provides more sustained weight loss and superior resolution of metabolic comorbidities, whereas SG is associated with fewer early complications and a lower risk of nutritional deficiencies. In conclusion, SG offers a valuable option for managing MetS, providing significant weight loss and comorbidity improvement. Nevertheless, potential long-term complications, such as gastroesophageal reflux disease (GERD) and suboptimal weight response, emphasize careful patient selection and monitoring., Competing Interests: Declarations. Conflict of interest: All authors declared that there are no conflicts of interest. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable. Informed consent: Not applicable., (© 2024. The Author(s).)

Liver fibrosis is characterized by excessive deposition of extracellular matrix due to chronic inflammation of the liver. Hepatic stellate cells (HSCs) become activated and produce excessive amounts of extracellular matrix. It was previously shown that loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. Thus, the protective effect of PHD1 deficiency (PHD1 -/- ) in an additional (toxic) model of liver fibrosis was validated and the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis, was evaluated. Liver fibrosis was induced utilizing carbon tetrachloride in wild-type (WT), PHD1 -/- , vehicle-treated, and DMOG-treated mice. Livers were further analyzed by Sirius red staining and gene expression analysis of profibrotic genes to assess fibrosis development. When compared with WT mice, PHD1 -/- mice developed less-severe liver fibrosis. By contrast, DMOG treatment did not prevent liver fibrosis. PHD1 -/- mice showed fewer α-SMA +  cells and less macrophage infiltration compared with WT mice. Gene expression of profibrogenic and proinflammatory genes was reduced in livers from carbon tetrachloride-exposed PHD1 -/- mice. In vitro analyses of PHD1-deficient human HSCs revealed attenuated mRNA levels of profibrotic genes, as well as impaired migration and invasion. Although PHD1 deficiency attenuates activation of HSCs, pharmacologic PHD inhibition does not ameliorate fibrosis development. Selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers., Summary Background Data: RDP is an emerging minimally invasive approach; however, only limited, mostly single center data are available on its safe implementation, including the learning curve., Methods: Consecutive patients undergoing elective RDP from 16 expert centers across three continents were included to assess the learning curve. Based on the first 100 RDPs at each center, three cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade ≥III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared., Results: The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P=0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P=0.012), and mastery was associated with a higher proportion of patients with textbook outcome (71% vs. 63%; P=0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications., Conclusion: Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP., Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest. Conflict of interest: The authors declare that no conflict of interest exists. No grants and financial support were received for this study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The risk for recurrence in patients with distal gastric cancer can be reduced by surgical radicality. However, dispute exists about the value of the proposed minimum proximal margin distance (PMD). Here, we assess the prognostic value of the safety distance between the proximal resection margin and the tumor., Patients and Methods: This is a single-center cohort study of patients undergoing distal gastrectomy for gastric adenocarcinoma (2001-2021). Cohorts were defined by adequacy of the PMD according to the European Society for Medical Oncology (ESMO) guidelines (≥ 5 cm for intestinal and ≥ 8 cm for diffuse Laurén's subtypes). Overall survival (OS) and time to progression (TTP) were assessed by log-rank and multivariable Cox-regression analyses., Results: Of 176 patients, 70 (39.8%) had a sufficient PMD. An adequate PMD was associated with cancer of the intestinal subtype (67% vs. 45%, p = 0.010). Estimated 5-year survival was 63% [95% confidence interval (CI) 51-78] and 62% (95% CI 53-73) for adequate and inadequate PMD, respectively. Overall, an adequate PMD was not prognostic for OS (HR 0.81, 95% CI 0.48-1.38) in the multivariable analysis. However, in patients with diffuse subtype, an adequate PMD was associated with improved oncological outcomes (median OS not reached versus 131 months, p = 0.038, median TTP not reached versus 88.0 months, p = 0.003)., Conclusion: Patients with diffuse gastric cancer are at greater risk to undergo resection with an inadequate PMD, which in those patients is associated with worse oncological outcomes. For the intestinal subtype, there was no prognostic association with PMD, indicating that a distal gastrectomy with partial preservation of the gastric function may also be feasible in the setting where an extensive PMD is not achievable., (© 2024. The Author(s).)

Aim: To investigate the impact of total pancreatectomy (TP) on oncological outcomes for patients at high-risk of local recurrence or secondary progression in the remnant gland after partial pancreatectomy (PP) for IPMN-associated cancer., Summary Background Data: Major risk factors for invasive progression in the remnant gland include multifocality, diffuse main duct dilation, and the presence of invasive cancer. In these high-risk patients, a TP may be oncologically beneficial. However, current guidelines discourage TP, especially in elderly patients., Methods: This international multicenter study compares TP versus PP in patients with adenocarcinoma arising from multifocal or diffuse IPMN (2002-2022). Log-rank test and multivariable Cox-analysis with interaction analysis was performed to assess overall survival (OS), disease-free survival (DFS), and local-DFS., Results: Of 359 included patients, 162 (45%) were treated with TP, whereas 197 (55%) underwent PP. Despite TP and PP having similar R0-rates (59% vs. 58%, P=0.866), patients undergoing a TP had significantly longer local-DFS compared to PP (P=0.039). However, no difference in OS was observed between the two surgical approaches (P=0.487). In a multivariable analysis, young age (optimal cut-off ≤63.6 yrs) was associated with an OS benefit derived from TP (HR:0.44, 95%CI:0.22-0.89), whereas no significant difference was observed in elderly patients (HR:1.24, 95%CI:0.92-1.67, Pinteraction=0.007)., Conclusion: Since overall, patients with diffuse or multifocal IPMN with an invasive component do not benefit from TP in terms of OS, the indication for TP may be individualized to young patients who have sufficient life expectancy to benefit from the prevention of secondary progression or local recurrence., Competing Interests: Conflicts of Interest: None declared. Disclosures: There are no conflicts of interest for any of the authors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess the prognostic impact of margin status in patients with resected intraductal papillary mucinous neoplasms (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and to inform future intraoperative decision-making on handling differing degrees of dysplasia on frozen section., Summary Background Data: The ideal oncologic surgical outcome is a negative transection margin with normal pancreatic epithelium left behind. However, the prognostic significance of reresecting certain degrees of dysplasia or invasive cancer at the pancreatic neck margin during pancreatectomy for IPMN-derived PDAC is debatable., Methods: Consecutive patients with resected and histologically confirmed IPMN-derived PDAC (2002-2022) from six international high-volume centers were included. The prognostic relevance of a positive resection margin (R1) and degrees of dysplasia at the pancreatic neck margin were assessed by log-rank test and multivariable Cox-regression for overall survival (OS) and recurrence-free survival (RFS)., Results: Overall, 832 patients with IPMN-derived PDAC were included with 322 patients (39%) having an R1-resection on final pathology. Median OS (mOS) was significantly longer in patients with an R0 status compared to those with an R1 status (65.8 vs. 26.3 mo P<0.001). Patients without dysplasia at the pancreatic neck margin had similar OS compared to those with low-grade dysplasia (mOS: 78.8 vs. 66.8 months, P=0.344). However, high-grade dysplasia (mOS: 26.1 mo, P=0.001) and invasive cancer (mOS: 25.0 mo, P<0.001) were associated with significantly worse OS compared to no or low-grade dysplasia. Patients who underwent conversion of high-risk margins (high-grade or invasive cancer) to a low-risk margin (low-grade or no dysplasia) after intraoperative frozen section had significantly superior OS compared to those with a high-risk neck margin on final pathology (mOS: 76.9 vs. 26.1 mo P<0.001)., Conclusions: In IPMN-derived PDAC, normal epithelium or low-grade dysplasia at the neck have similar outcomes while pancreatic neck margins with high-grade dysplasia or invasive cancer are associated with poorer outcomes. Conversion of a high-risk to low-risk margin after intraoperative frozen section is associated with survival benefit and should be performed when feasible., Competing Interests: Disclosures: There are no conflicts of interest for any of the authors.Funding: Joseph R. Habib is supported by the NIH T32 grant T32CA193111. Ingmar F. Rompen is supported by the Swiss National Science Foundation (SNSF, grant number 217684). This work was also supported by the Ben and Rose Cole Charitable PRIA Foundation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim was to analyze the learning curves of minimal invasive liver surgery(MILS) and propose a standardized reporting., Summary Background Data: MILS offers benefits compared to open resections. For a safe introduction along the learning curve, formal training is recommended. However, definitions of learning curves and methods to assess it lack standardization., Methods: A systematic review of PubMed, Web of Science, and CENTRAL databases identified studies on learning curves in MILS. The primary outcome was the number needed to overcome the learning curve. Secondary outcomes included endpoints defining learning curves, and characterization of different learning phases(competency, proficiency and mastery)., Results: 60 articles with 12'241 patients and 102 learning curve analyses were included. The laparoscopic and robotic approach was evaluated in 71 and 18 analyses and both approaches combined in 13 analyses. Sixty-one analyses (60%) based the learning curve on statistical calculations. The most often used parameters to define learning curves were operative time (n=64), blood loss (n=54), conversion (n=42) and postoperative complications (n=38). Overall competency, proficiency and mastery were reached after 34 (IQR 19-56), 50 (IQR 24-74), 58 (IQR 24-100) procedures respectively. Intraoperative parameters improved earlier (operative time: competency to proficiency to mastery: -13%, 2%; blood loss: competency to proficiency to mastery: -33%, 0%; conversion rate (competency to proficiency to mastery; -21%, -29%), whereas postoperative complications improved later (competency to proficiency to mastery: -25%, -41%)., Conclusions: This review summarizes the highest evidence on learning curves in MILS taking into account different definitions and confounding factors. A standardized three-phase reporting of learning phases (competency, proficiency, mastery) is proposed and should be followed., Competing Interests: Compliance with Ethical Standards: Conflict of interest: The authors declare that they have no conflict of interest. Conflict of interest: The authors declare no conflict of interest. No grants and financial support were received for this study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s).)

Background and Aims: Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-β is the pivotal profibrogenic cytokine that activates HSC, yet other molecules can modulate TGF-β 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-β-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., (Copyright © 2023 American Association for the Study of Liver Diseases.)

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/m 2 . 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., (© 2023. The Author(s).)

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., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing Interests: G.M. H. reported to having received the following funding unrelated to this manuscript: Consulting or Advisory Role: Bristol-Myers Squibb; MSD Sharp & Dohme; Lilly; Novartis; Daiichi Sankyo. Honoraria: Servier; MSD Sharp & Dohme; Lilly; Targos; Bristol-Myers Squibb; IOMEDICO, MCI Conventions. Research Funding (not related to this manuscript): Nordic Pharma; Taiho Pharmaceutical; MSD Sharp & Dohme; Janssen; Astra Zeneca; Bristol-Myers Squibb; IKF Klinische Krebsforschung Frankfurt. Travel; Accommodations: Bristol-Myers Squibb; Lilly; Servier; MSD Sharp & Dohme. All other authors stated no conflict of interest., (© The author(s).)

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/m 2 ] 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/m 2 in the SG and 42.0 kg/m 2 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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-71/coif). The authors have no conflicts of interest to declare., (2022 Hepatobiliary Surgery and Nutrition. All rights reserved.)

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 β-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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: Competing interests: The authors declare that they have no conflicts of interest or relevant financial ties to disclose. FN reports support for courses and travel from Johnson & Johnson, Medtronic, Intuitive Surgical, Cambridge Medical Robotics and KARL STORZ as well as consultancy fees from KARL STORZ., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-5/coif). The authors have no conflicts of interest to declare., (2022 Hepatobiliary Surgery and Nutrition. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obesity is a major health burden worldwide and is associated with nonalcoholic fatty liver disease, which can lead to cirrhosis. Bariatric surgery is increasingly being used to treat obesity, and the number of patients with obesity and cirrhosis undergoing bariatric surgery is also rising. However, the safety and feasibility of bariatric surgery in patients with obesity and cirrhosis are controversial., Objectives: In this meta-analysis, we compared postoperative complications, mortality, and weight loss between patients with and without cirrhosis undergoing bariatric surgery., Setting: An electronic search of Medline, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL)., Methods: Patient morbidity and mortality odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were assessed. Intraoperative and overall complications, length of hospital stay, in-hospital mortality, long-term mortality, and total weight loss were recorded., Results: The literature search yielded 2977 articles. Eight studies were included in the analysis. Meta-analysis showed that the overall complications (OR: 2.1; 95% CI: 1.47-3.00; P < .0001), postoperative bleeding (OR: 2.22; 95% CI: 1.95-2.54; P < .00001), length of hospital stay (MD: .68; 95% CI: .14-1.19; P = .01), and in-hospital/90-day mortality (OR: 3.59; 95% CI: 2.84-4.54; P < .00001) were significantly higher in patients with compensated cirrhosis than in patients without cirrhosis. Intraoperative complications, operation time, major complications, and long-term mortality were similar between the groups. Total weight loss was also not significantly different between the groups., Conclusion: Bariatric surgery can be considered only in highly selected patients with obesity and compensated cirrhosis., (Copyright © 2022 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the long-term outcomes of patients with end-stage organ failure (ESOF) undergoing obesity surgery., Objective: To investigate the perioperative and mid-term outcomes of patients with ESOF undergoing obesity surgery., Setting: University hospital, Germany., Methods: A total of 1 094 patients undergoing obesity surgery from 2006 to 2019 were screened. Inclusion criteria were ejection fraction <30%, continuous oxygen/noninvasive ventilation therapy, liver cirrhosis, or kidney failure stage 4/5. ESOF patients were compared with matched standard (MS) patients without advanced organ failure and matched for age, gender, body mass index (BMI), operation type, diabetes, arterial hypertension, and sleep apnea., Results: Twenty-seven ESOF patients (56% female, age 50.3 ± 8.6, BMI 53.8 ± 8.7 kg/m 2 ) were identified. Eighty-five percent had a sleeve gastrectomy. Mid-term total weight loss was 26.6% ± 9.0% in the ESOF patients versus 17.8% ± 11.1% in MS patients (P = .181). Long-term improvement of type 2 diabetes was comparable (ESOF: HbA1C 8.79 ± 2.06% to 6.25±1.17%, P = .047; MS: HbA1C 7.94 ± 2.02% to 7.2 ± 1.28%; P = .343). Depression scores (Patient Health Questionnaire 9) among ESOF patients improved from 13.0 ± 6.3 to 6.1 ± 5.8 (P = .004) but without significant change in MS patients (9.4 ± 7.3 to 4.3 ± 5.7; P = .082). Lung function improved in all patients although only 15% were off oxygen therapy. Treatment goals were achieved in >50% of the other groups. Major complications occurred in 11% (ESOF) versus 4% (MS) of patients (P = .299) with one death in the ESOF group (4%)., Conclusion: Both groups had similar outcomes regarding weight loss and co-morbidity improvement. Depression only improved significantly in the ESOF group. Patients with ESOF should not be precluded from obesity surgery. Further investigation is needed to define optimized selection criteria., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Gastric staple line leakage (GL) is a serious complication of laparoscopic sleeve gastrectomy (LSG), with a specific mortality ranging from 0.2 to 3.7%. The current treatment of choice is stent insertion. However, it is unclear whether the type of stent which is inserted affects treatment outcome. Therefore, we aimed not only to determine the effectiveness of stent treatment for GL but also to specifically clarify whether treatment outcome was dependent on the type of stent (small- (SS) or megastent (MS)) which was used., Patients and Methods: A single-centre retrospective study of 23 consecutive patients was conducted to compare the outcomes of SS (n = 12) and MS (n = 11) for the treatment of GL following LSG. The primary outcome measure was the success rate of stenting, defined as complete healing of the GL without changing the treatment strategy. Treatment change or death were both coded as failure., Results: The success rate of MS was 91% (10/11) compared to only 50% (6/12) for SS (p = 0.006). An average of 2.3 ± 0.5 and 6.8 ± 3.7 endoscopies were required to achieve healing in the MS and SS groups respectively (p < 0.001). The average time to resumption of oral nutrition was shorter in the MS group (1.4 ± 1.1 days vs. 23.1 ± 33.1 days, p = 0.003)., Conclusions: Stent therapy is only effective and safe for the treatment of GL after LSG if a MS is used. Treatment with a MS may not only increase treatment success rates but may also facilitate earlier resumption of oral nutrition and shorten the duration of hospitalization., (© 2021. The Author(s).)

Background: Primary hyperaldosteronism is a recognized risk factor for myocardial infarction, stroke, and atrial fibrillation. Minimally invasive adrenalectomy is the first-line treatment for localized primary hyperaldosteronism. Whether minimally invasive adrenalectomy should be performed using a cortex-sparing technique (partial minimally invasive adrenalectomy) or not (total minimally invasive adrenalectomy) remains a subject of debate. The aim of our study was to evaluate the clinical and biochemical efficacy of both procedures and to examine the morbidity associated with partial minimally invasive adrenalectomy versus total minimally invasive adrenalectomy in a multicenter study., Methods: Using a retrospective study design, we determined the efficacy, morbidity, and mortality of partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy. The Primary Aldosteronism Surgical Outcome Study classification was used to explore clinical and biochemical success. Matched-pair analysis was used in order to address possible bias., Results: We evaluated 234 matched patients with unilateral primary hyperaldosteronism: 78 (33.3%) underwent partial minimally invasive adrenalectomy, and 156 (66.7%) were treated with total minimally invasive adrenalectomy. Complete clinical success was achieved in 40.6%, and partial clinical success in an additional 52.6% of patients in the entire cohort. Complete biochemical success was seen in 94.0% of patients. Success rates and the incidence of perioperative complications were comparable between groups. Both postoperative hypocortisolism (11.5% vs 25.0% after partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy, respectively; P < .001) and postoperative hypoglycemia (2.6% vs 7.1% after partial minimally invasive adrenalectomy and total minimally invasive adrenalectomy; P = .039) occurred more frequently after total minimally invasive adrenalectomy., Conclusion: Our study provides evidence that patients with unilateral primary hyperaldosteronism are good surgical candidates for partial minimally invasive adrenalectomy. Not only is the surgical outcome comparable to that of total minimally invasive adrenalectomy, but also postsurgical morbidity, particularly in terms of hypocortisolism and hypoglycemia, may be reduced., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Non-alcoholic steatohepatitis (NASH) associated hepatocellular carcinomas (NASH-HCC) are increasing. NASH-HCC often develops in the fibrotic liver. Several analyses report conflicting results regarding the outcome of non-cirrhotic NASH-HCC. Furthermore, type 2 diabetes (T2D) is considered a risk factor for poor survival. The aim of this study was to investigate oncological outcomes of non-cirrhotic NASH-HCC and the impact of T2D., Methods: Patients with non-cirrhotic NASH-HCC with T2D as determined by an expert pathologist conducting histological slide review were matched for risks factors for poor outcome (age, gender, body mass index) with patients with NASH-HCC without T2D. These patients were then matched 1:1 with HCCs of other underlying liver diseases with and without T2D. Oncological outcomes were assessed using Kaplan-Meier curves., Results: Out of 365 HCCs resected between 2001 and 2017, 34 patients with non-cirrhotic NASH-HCC were selected (17 with T2D, 17 without T2D) and matched with 26 patients with hepatitis-HCC and 28 patients with alcohol-related HCC. Oncological risk factors such as tumor size, resection margin, and vessel invasion were comparable. There was no difference in overall survival (5-year survival 71.3% for NASH-HCC, 60.4% for hepatitis-HCC, 79.9% for alcohol-HCC). NASH-HCC was associated with longer disease-specific survival than hepatitis-HCC (5-year 87.5% vs. 63.7%, p = 0.048), while recurrence-free survival was identical. T2D had no impact on oncological outcomes in either liver disease., Conclusion: Non-cirrhotic NASH-HCC has outcomes comparable with other underling etiologies. Despite a lack of cirrhosis, patients with non-cirrhotic NASH-HCC have the same risks of HCC recurrence as patients with cirrhotic liver disease of other etiologies.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1,2 . The accumulation of metabolites leads to cell stress and inflammation in the liver 3 , but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 + CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 + CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 + CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Background: This study aimed to evaluate changes in body tissue composition with obesity surgery regarding visceral fat, subcutaneous fat, and skeletal muscle., Design: Prospective non-randomized single-center cohort study METHODS: Whole-body magnetic resonance imaging (MRI) measured volumes of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle (SM) in 31 patients with laparoscopic sleeve gastrectomy (LSG, 20) or Roux-en-Y gastric bypass (RYGB, 11) preoperatively, at three- and 12-months follow-up., Results: Body mass index (BMI) went down from 45.2 ± 6.5 preoperatively to 37.2 ± 5.6 (p < 0.001) at three months and 32.2 ± 5.3 kg/m 2 (p < 0.001) at 12 months. SAT went down from 55.0 ± 14.0 L (liter) to 42.2 ± 13.3 L (p < 0.001) at three months and 31.7 ± 10.5 L (p < 0.001) at 12 months (- 42.3%). VAT went down from 6.5 ± 2.3 to 4.5 ± 1.7 (p < 0.001) at three months and 3.1 ± 1.7 L (p < 0.001) at 12 months (- 52.3%). SM went down from 22.7 ± 4.8 to 20.4 ± 3.6 (p = 0.008) at three months and remained 20.2 ± 4.6 L at 12 months (p = 0.17 relative three-month; p = 0.04 relative preop, - 11.1%). Relative loss was higher for VAT than that for SAT (52.3 ± 18.2% vs. 42.3 ± 13.8%; p = 0.03). At 12 months, there was no difference between LSG and RYGB for relative changes in BMI or body tissue composition., Conclusion: Postoperatively, there was higher net loss of SAT but higher relative loss of VAT with weight loss. SM was lost only during the first three months. MRI provides accurate evaluation of surgeries' effect on individual patients' tissue composition. This can benefit risk assessment for related cardiovascular and metabolic health but cost-related factors will likely reserve the used methods for research.

Background: Metabolic surgery is the most effective therapy for patients with type 2 diabetes (T2D), also improving diabetic kidney disease. Whether these effects depend on weight loss is currently unknown., Objectives: To assess the correlation between weight loss and improvement of diabetic kidney disease in patients with T2D undergoing metabolic surgery., Setting: University of Heidelberg, Germany., Methods: A systematic literature search was performed in December 2018 using the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases without language restrictions or time limit. Studies reporting exact data on change in urinary albumin-creatinine ratio (uACR) or albuminuria as well as change in body mass index in patients with T2D undergoing metabolic surgery were included. Out of 2145 potentially eligible hits, 15 studies were included. Study quality was assessed using the Downs and Black score. Data were pooled using a random-effects model, and a Spearman's rank correlation was performed., Results: No correlation was found between improved renal injury (change in uACR or albuminuria) and weight loss (change in body mass index) (r s = -.306, P = 0.504, and r s = -.086, P = .872), and no significant correlation was found between improved renal injury (change in uACR or albuminuria) and improved glycemic control (change in A1C) (r s = .378, P = .403, and r s = .500, P = .391., Conclusion: Metabolic surgery can improve diabetic kidney disease independent of weight loss and glycemic control. Other mechanisms, including modified adipokine balance, signaling pathways of fat tissue and gut hormones, or reduced systemic inflammation, contribute to improved renal injury, while weight loss seems to play a lesser role than expected., (Copyright © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Bariatric surgery gains attention as a potential treatment for non-alcoholic fatty liver disease (NAFLD). The present study aimed to evaluate improvement of NAFLD after the two most common bariatric procedures with validated non-invasive instruments., Material and Methods: N = 100 patients scheduled for laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB) were included. NAFLD was evaluated preoperatively and postoperatively with liver stiffness measurement by transient elastography and laboratory-based fibrosis scores. Clinical data included body mass index (BMI), total weight loss (%TWL), excess weight loss (%EWL), age, gender, comorbidities, and the Edmonton obesity staging system (EOSS)., Results: There were significant improvements of BMI, %TWL, %EWL, and EOSS after bariatric surgery. Liver stiffness was significantly improved from pre- to postoperative (12.9 ± 10.4 vs. 7.1 ± 3.7 kPa, p < 0.001) at median follow-up of 12.5 months. Additionally, there were significant improvements of liver fibrosis scores (aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio 0.8 ± 0.3 vs. 1.1 ± 0.4, p < 0.001; NAFLD fibrosis score - 1.0 ± 1.8 vs. - 1.7 ± 1.3, p < 0.001; APRI score 0.3 ± 0.2 vs. 0.3 ± 0.1, p = 0.009; BARD score 2.3 ± 1.2 vs. 2.8 ± 1.1, p = 0.008) and laboratory parameters (ALT, AST, and GGT). After adjustment for baseline liver stiffness, RYGB showed higher improvements than LSG, and there was no gender difference. Improvement of liver stiffness was not correlated to improvement of BMI, %TWL, %EWL, or EOSS., Conclusions: NAFLD seems to be improved by bariatric surgery as measured by validated non-invasive instruments. Furthermore, it appears that RYGB is more effective than LSG. No correlation could be detected between NAFLD and weight loss. The present study highlights the potential of bariatric surgery for successful treatment of NAFLD. Further research is required to understand the exact mechanisms.

Objective: The underlying causes of type 2 diabetes (T2DM) remain poorly understood. Adipose tissue dysfunction with high leptin, inflammation, and increased oxidative stress may play a pivotal role in T2DM development in obese patients. Little is known about the changes in the adipose tissue after Roux-Y gastric bypass (RYGB) in non-severely obese patients (BMI < 35 kg/m 2 ) and since these patients have more T2DM-associated complications than obese patients ("obesity paradox"), we investigated changes in adipose tissue function in a cohort of BMI <35 kg/m 2 with insulin-dependent T2DM after RYGB surgery which resolves T2DM., Methods: Twenty patients with insulin-dependent T2DM and BMI <35 kg/m 2 underwent RYGB. Insulin-resistance, leptin, oxidative stress, and cytokines were determined over 24 months. Expression of cytokines and NF-kappaB pathway genes were measured in leukocytes (PBMC). Adipose tissue inflammation was examined histologically preoperatively and 24 months after RGYB in subcutaneous adipose tissue., Results: Insulin-resistance, leptin, oxidative stress as well as adipose tissue inflammation decreased significantly after RYGB. Similarly, systemic inflammation was reduced and peripheral blood mononuclear cells (PBMCs) were reprogrammed towards an M2-type inflammation. Loss of BMI correlated with leptin levels (r = 0.891, p < 0.0001), insulin resistance (r = 0.527, p = 0.003), and oxidative stress (r = 0.592, p = 0.016). Leptin correlated with improved insulin resistance (r = 0.449, p = 0.032) while reduced leptin showed a strong association with improved oxidative stress (r = 0.809, p = 0.001). Lastly, reduced oxidative stress correlated strongly with improved insulin-resistance (r = 0.776, p = 0.001)., Conclusions: RYGB improves adipose tissue function and inflammation. Leptin as marker for adipose tissue dysfunction may be the mediating factor between insulin resistance and oxidative stress and thereby likely improving T2DM.