Postoperative complications after metabolic and bariatric surgery (MBS) increase with age, yet data on bone health in older postmenopausal women remain limited. The 2022 European Calcified Tissue Society (ECTS) position statement recommend anti-osteoporotic medication (AOM) for patients with a T-score ≤ −2 and/or a fragility fracture within the past two years. This study evaluated the prevalence of AOM eligibility according to age (< 60 vs. ≥ 60 years) in postmenopausal women and identified associated risk factors. We conducted a cross-sectional, observational, single-center study at Lille University Hospital including postmenopausal women referred for bone health evaluation before or after MBS. AOM eligibility was defined according to the 2022 ECTS criteria. Among 306 postmenopausal women, 173 were < 60 years (group 1) and 133 were ≥ 60 years (group 2). Overall, 69 patients (22.5

BACKGROUND AND AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD), the most common chronic liver disease worldwide, is closely linked to obesity and metabolic syndrome. The reason some patients with MASLD develop metabolic dysfunction-associated steatohepatitis (MASH) and which metabolic changes in the liver are linked to its progression are unclear. METHODS:A non-targeted metabolomics analysis was performed on liver samples from 106 Finnish patients with severe obesity (71 females, mean age ± SD: 48.6 ± 8.7 years, body mass index: 41.6 ± 5.2 kg/m2) selected for laparoscopic gastric bypass surgery. Liver metabolomics and liver RNA sequencing data were used to study metabolic differences between those with steatosis and those with MASH. Validation was performed in a French cohort of 227 patients with obesity and MASLD. RESULTS:Overall, 45 metabolites differed between patients with steatosis and those with MASH. Novel MASH-associated metabolites included n-acetylneuraminate (β = 0.276), pentose acid (β = -0.290), UDP-galactose (β = -0.413), gamma/beta-tocopherol (β = -0.317), and guanidinosuccinate (β = -0.289) (all p < 0.05). In the validation cohort, 8 of 20 metabolites, including n-acetylneuraminate and plasmalogens 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE(P-16:0/20:4) and 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE(P-18:0/20:4), were linked to MASH (p < 0.05). The 45 significantly altered metabolites formed two clusters with different associations with metabolic parameters, depending on their correlation with liver histological features. Kyoto Encyclopedia of Genes and Genomes analysis revealed that elevated metabolites in MASH were associated with inflammatory pathways; those decreased in MASH were linked to fatty acid degradation and amino acid and pyruvate metabolism. CONCLUSION:Transitioning from simple steatosis to MASH is associated with distinct alterations in liver metabolites and systemic metabolic traits, highlighting disease progression-associated pathways.

Objective: To evaluate predictors of ideal postoperative trajectories after minimally invasive left pancreatectomy (MILP). Summary Background Data: Postoperative course after MILP can be assessed through the Ideal Outcome (IO), but no predictive tool is currently available. Methods: MILP performed between 2010–2022 across 55 French centers were included. 90-days IO required absence of mortality, severe complications, postoperative pancreatic fistula grade B/C (CR-POPF), reoperation, readmission, and length of stay (LOS)≤75 th percentile; Best Performer (BP) was IO with LOS≤25 th p. Predictors were evaluated using multivariable logistic regression and extreme gradient boosting (XGB). Model performance was assessed with nested cross-validation and 1,000-iteration bootstrap resampling. Results: Among 2,092 MILP, mortality was 1.3%, reoperation 5.6%, severe morbidity 17.9%, CR-POPF 18.8%, and readmission 15.3%; median LOS 9 days [IQR 7–13]. IO and BP occurred in 59.6% and 28.1%. Following a stepwise strategy, starting with a preoperative multivariable logistic regression model (AUC 0.57), then a preoperative-only XGBoost model (AUC 0.59), improved by inclusion of intraoperative variables (AUC 0.62); finally, after refining the endpoint to Best Performer (IO+LOS ≤25th percentile), the final XGBoost model achieved an AUC of 0.72 (95%CI 0.70–0.74). SHAP analysis identified center-volume and operative duration as the strongest contributors, followed by age, BMI, conversion, blood loss, and splenectomy. At the optimal threshold, sensitivity reached 0.78, specificity 0.57, PPV 0.41, and NPV 0.87. An online risk calculator is at disposal. Conclusions: Predicting ideal postoperative trajectory after MILP remains challenging; identifying determinants may help optimize postoperative pathways by integrating preoperative and intraoperative determinants of recovery.

Islet transplantation, a validated therapy for type 1 diabetes, shows heterogeneous clinical outcomes. There is an unmet need for actionable biomarkers predicting islet graft potency before transplantation. We leveraged a comprehensive set of clinical data and islet samples to explore the relation between islet NKX6.1 gene expression and clinical transplantation outcomes. We measured NKX6.1 copy number with digital PCR in 114 clinical islet preparations and showed its linear correlation with islet graft function in a mouse bioassay, independently of islet mass, purity, and viability (P < 0.01). Analyzing the clinical outcomes of 34 patients who received two or three islet preparations, we showed the added value of total NKX6.1 copy number to predict primary graft function, as compared with islet mass alone (Delong test, P < 0.001). Using a multiple regression Cox model, adjusted for islet mass, purity, and viability, a high total NKX6.1 copy number was independently correlated with 10-year survival of islet graft success [adjusted hazard ratio (HR) [95% CI]: 0.63 [0.43; 0.92], P < 0.017] and insulin independence (HR [95% CI]: 0.70 [0.52; 93], P < 0.01). This relation was confirmed in an independent cohort of nine patients receiving a single islet transplantation in other centers. Genetic silencing with anti-NKX6.1 shRNA or pharmacological induction of NKX6.1 with silymarin in vitro indicated a causal link between NKX6.1 gene expression and islet graft function. These results suggest that NKX6.1 mRNA expression can predict islet graft function and may serve as an actionable biomarker of graft potency in β cell replacement.

BACKGROUND:Pancreatic resection (PR) may require portal/superior mesenteric vein resection (VR). Outcomes of minimally invasive PR (MIPR) with VR are poorly studied. METHODS:Multicentric retrospective cohort of MI pancreatoduodenectomy (MIPD) and left pancreatectomy (MILP) with or without VR between 2010 and 2021. Propensity score matching analysis stratified on age, sex, BMI, pancreas texture, tumor type, ASA score, conversion and surgical approach was performed. RESULTS:After matching, 234 MIPD were included, 78 (33.3%) with and 156 (66.7%) without VR. VR had greater blood loss (400 vs 300 mL; p = 0.033) and operative time (471 vs 430 min; p = 0.012). VR had 10.3% mortality compared to 4.5% (p = 0.097), similar severe morbidity (30.8% vs 37.8%: p = 0.313) and R0 resection rate (84.9% vs 90.8%: p = 0.252). After matching, 275 MILP, 25 (9%) with and 250 (91%) without VR were compared. VR had greater blood loss (350 vs 150mL; p = 0.019) and operative time (300 vs 240 min; p = 0.005). VR had 8% mortality versus 2% (p = 0.126), 19.2% severe morbidity versus 8% (p = 0.274) and lower R0 resection rate (58.3% vs 94.9%; p <0.001). CONCLUSION:MIPR with VR has non-significant increased postoperative mortality, lower R0 resection rate and therefore cannot be considered as a standard of care.

Surgical management of pheochromocytoma has evolved from a high-risk, open procedure to a nuanced, minimally invasive practice guided by multidisciplinary care. This review synthesizes contemporary advances in diagnostics, genetics, perioperative medicine, and surgical techniques. Definitive treatment remains complete resection, with minimally invasive adrenalectomy (transabdominal or retroperitoneal, laparoscopic, or robotic) now the standard for localized tumors, offering comparable oncologic outcomes when selected based on tumor size, anatomy, and expertise. Genomic characterization is integral to management, as approximately 40% of cases harbor germline mutations, influencing imaging strategies and surgical planning, particularly in advocating for cortical-sparing adrenalectomy in hereditary settings to avoid lifelong steroid dependence. Despite technical progress, perioperative hemodynamic crisis remains a key concern. While the necessity of universal preoperative α-adrenergic blockade is debated for low-risk patients, it remains the guideline-backed standard to mitigate cardiovascular morbidity. For metastatic disease, surgery retains a role within a multimodal framework, offering symptomatic and potential survival benefit in select cases. Future directions will further integrate molecular profiling, advanced imaging, and surgical innovation to optimize long-term oncologic and functional outcomes.

OBJECTIVE:To evaluate predictors of ideal postoperative trajectories after minimally invasive left pancreatectomy (MILP). SUMMARY BACKGROUND DATA:Postoperative course after MILP can be assessed through the Ideal Outcome (IO), but no predictive tool is currently available. METHODS:MILP performed between 2010-2022 across 55 French centers were included. 90-days IO required absence of mortality, severe complications, postoperative pancreatic fistula grade B/C (CR-POPF), reoperation, readmission, and length of stay (LOS)≤75 th percentile; Best Performer (BP) was IO with LOS≤25 th p. Predictors were evaluated using multivariable logistic regression and extreme gradient boosting (XGB). Model performance was assessed with nested cross-validation and 1,000-iteration bootstrap resampling. RESULTS:Among 2,092 MILP, mortality was 1.3%, reoperation 5.6%, severe morbidity 17.9%, CR-POPF 18.8%, and readmission 15.3%; median LOS 9 days [IQR 7-13]. IO and BP occurred in 59.6% and 28.1%. Following a stepwise strategy, starting with a preoperative multivariable logistic regression model (AUC 0.57), then a preoperative-only XGBoost model (AUC 0.59), improved by inclusion of intraoperative variables (AUC 0.62); finally, after refining the endpoint to Best Performer (IO+LOS ≤25th percentile), the final XGBoost model achieved an AUC of 0.72 (95%CI 0.70-0.74). SHAP analysis identified center-volume and operative duration as the strongest contributors, followed by age, BMI, conversion, blood loss, and splenectomy. At the optimal threshold, sensitivity reached 0.78, specificity 0.57, PPV 0.41, and NPV 0.87. An online risk calculator is at disposal. CONCLUSIONS:Predicting ideal postoperative trajectory after MILP remains challenging; identifying determinants may help optimize postoperative pathways by integrating preoperative and intraoperative determinants of recovery.

Objective To describe surgical indications, procedures and outcomes in patients operated for Zollinger-Ellison syndrome (ZES) in multiple endocrine neoplasia type 1 (MEN1) using a large nationwide cohort. Background Management of ZES in MEN1 remains controversial. Methods All patients with ZES diagnosed through the MEN1 AFCE/GTE network from 1985 to 2015.Results Among 233 ZES patients, 66 (28%) were operated for ZES-related gastrinomas. Thirty-three (51%) procedures aimed to remove gastrinomas and associated pancreatic neuroendocrine tumors (pNET(s)) with appropriate resection. Thirty-two procedures (49%) aimed to remove gastrinomas alone (ZES group). Survival was decreased in patients metastatic at ZES diagnosis (p < 0.001). Fifteen-year survival among non-metastatic patients was not significantly better in operated patients (82% vs. 70%, p = 0.2). Perioperative mortality was nil. Metastatic lymph nodes were found in 30/42 lymphadenectomies (71%). The choice between pancreaticoduodenectomy versus duodenal focused surgery in the ZES group was associated with pre-operative detection of adenopathies (p > 0.001), leading to more frequent lymphadenectomies (p < 0.01). Previous pancreatic surgeries (30%) may have influenced the choice of ZES procedures. Gastrin levels were more frequently normalized when the duodenum and the head of pancreas were removed versus more localized duodenal surgeries (p < 0.01). Conclusion The high rate of invaded nodes in lymphadenectomies in MEN1 patients operated for ZES, the absence of operative mortality, and the decreased survival in metastatic patients are indirect arguments for surgery. Pancreaticoduodenectomy may be indicated in young and fit individuals to better control hypergastrinemia and to prevent metastatic progression in the ZES group. Gastrinoma removal is justified when associated with large pNETs.

BACKGROUND:Metabolic-bariatric surgery is an efficient therapy in selected adolescents with severe obesity. However, predicting the postoperative weight loss is challenging. A machine learning calculator predicting 5-year weight loss trajectory has been developed in adults, based on seven preoperative features. The aim of the present study was to adapt and test it in adolescents. METHODS:Retrospective cohort study in patients aged 12-20 years undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric band (AGB) in France and Sweden between 2001 and 2022. Primary outcome was the accuracy of 5-year BMI prediction, expressed as the median absolute deviation (MAD) between predicted and observed BMI. The model developed in adults, was trained in a subset of 80% of randomly selected adolescents, and secondly tested in the remaining 20%. RESULTS:We enrolled a total of 2255 patients (1705 female [75.6%], 12-20 years [median 19]). Five-year follow-up data were available for 59% of French and 38% of Swedish patients. The median (IQR) 5-year total weight loss was 30.2% (23.9-38.6) for RYGB, 23.4% (13.7-32.8) for SG, and 13.4% (0.0-30.1) for AGB. The adapted model predicted the observed 5-year BMI with a MAD of 3.7 kg/m² (95% CI [3.3-3.9]). The accuracy of the model was maximal for bypass (3.2 kg/m² [3.0-3.7]), good for SG (3.9 kg/m² [3.1-5.0]), and lower for AGB (7.3 kg/m² [5.5-8.4]), and accuracy decreased with time and in adolescents under 19 years. Age, height, weight, and type of intervention influenced 5-year weight loss. Type 2 diabetes influenced weight loss until 2 years after surgery, but not later. CONCLUSION:The model had an acceptable accuracy for adolescents to predict 5-year postoperative weight loss trajectory. Accuracy decreased over time and was influenced by type of intervention and age. This calculator is available online: https://bariatric-weight-trajectory-prediction.univ-lille.fr/ .

Importance:Metabolic bariatric surgery (MBS) is the most effective treatment for severe obesity, yet patient selection and prioritization remain largely based on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) thresholds rather than clinical conditions. The Lancet Diabetes and Endocrinology Commission recently proposed distinguishing clinical obesity (adiposity with obesity-related organ dysfunction) from preclinical obesity (excess adiposity with preserved function). The implications of this framework for MBS practice have not been evaluated. Objective:To assess the prevalence of clinical and preclinical obesity among MBS candidates and examine their demographic and clinical profiles, perioperative risk, and long-term prognosis. Design, Setting, and Participants:This retrospective, multicenter, cross-sectional study audited data of adults (aged ≥18 years) undergoing primary MBS (laparoscopic gastric bypass or sleeve gastrectomy) between January 1, 2014, and December 31, 2025, at 4 high-volume tertiary centers in the UK, Spain, France, and Brazil. Patients who underwent revisional procedures or multiple bariatric operations within the same year were excluded. Exposures:Classification of obesity as clinical or preclinical using a pragmatic operationalization. Main Outcomes and Measures:The primary outcome was the prevalence of clinical obesity. Secondary outcomes were patterns of organ dysfunction, BMI levels, baseline American Society of Anesthesiologists classification and Charlson Comorbidity Index, estimated 10-year cardiovascular risk (Framingham risk score), and 30-day major postoperative complications (Clavien-Dindo grade ≥3). Comparative analyses between patients with clinical obesity vs those with preclinical obesity were performed only within each individual cohort. No direct statistical comparisons were performed between centers as patient-level data were not shared across cohorts. Results:Among the 2316 patients included, 1709 (73.8%) had clinical obesity (mean [SD] age across cohorts, 45.6 [11.0] to 48.9 [11.7] years; 1149 women [67.2%]) and 607 (26.2%) had preclinical obesity (mean [SD] age across cohorts, 34.7 [10.4] to 40.0 [9.8] years; 486 women [80.1%]). Clinical obesity was the most prevalent category across all centers (from 62.7% in the Brazilian cohort to 79.3% in the UK cohort). Mean (SD) BMI ranged from 40.2 (4.9) (preclinical obesity in the Brazilian cohort) to 48.5 (9.0) (preclinical obesity in the UK cohort), and BMI levels and BMI category distributions (<40, 40-49, ≥50) were similar between clinical and preclinical obesity. Patients with clinical obesity were significantly older compared with those with preclinical obesity (UK cohort: mean [SD], 48.9 [11.7] vs 39.5 [9.7] years; French cohort: mean [SD], 45.6 [11.0] vs 34.7 [10.4] years; Spanish cohort: mean [SD], 47.1 [9.3] vs 40.0 [9.8] years; Brazilian cohort: mean [SD], 48.3 [11.7] vs 40.0 [9.4] years (all P < .001) and had a higher American Society of Anesthesiologists classification (UK cohort: median [IQR], 3 [2-3] vs 2 [2-3]; P < .001; French cohort: median [IQR], 3 [3-3] vs 2 [2-3]; P < .001; Spanish cohort: median [IQR], 2 [2-3] vs 2 [1-2]; P < .001; Brazilian cohort: median [IQR], 2 [2-2] vs 2 [2-2]; P = .02), as well as higher estimated cardiovascular Framingham risk score (Spanish cohort: median [IQR], 1.31 [0.20-4.34] vs 0.20 [0.20-1.68]; Brazilian cohort: median [IQR], 1.57 [0.20-5.28] vs 0.20 [0.20-0.20]; French cohort: median [IQR], 8.00 [3.00-13.00] vs 2.00 [1.00-4.00]) (all P < .001) and all-cause mortality risk (Charlson Comorbidity Index score) (UK cohort: median [IQR], 1 [0-2] vs 0 [0-0]; Spanish cohort: median [IQR], 1 [0-1] vs 0; Brazilian cohort: median [IQR], 1 [1-3] vs 1 [0-1]) (all P < .001). Clinical obesity was associated with increased 30-day major postoperative complications (Clavien-Dindo grade ≥3) compared with preclinical obesity in the French cohort (4.0% vs 1.1%; P = .04). Conclusions and Relevance:This international, multicenter cross-sectional study found that the majority of MBS candidates met criteria for clinical obesity, while a substantial minority were classified as having preclinical obesity. Despite similar BMI distributions, patients with clinical obesity may have a greater disease burden, higher operative risk, and higher estimated cardiovascular risk, supporting its potential value as a clinically meaningful framework for surgical practice.

OBJECTIVE:To evaluate the evolution of postoperative mortality and morbidity associated with bariatric surgery over a 15-year period using a nationwide database. BACKGROUND:Bariatric surgery is a cornerstone in obesity management, demonstrating significant benefits in weight loss and comorbidity resolution. However, despite its proven efficacy, it remains underutilized, with only a small fraction of eligible patients undergoing surgery. Advances in surgical techniques and perioperative care have improved safety, yet long-term trends in mortality and morbidity require further evaluation. METHODS:This retrospective cohort study utilized data from the SNDS (Système National des Données de Santé), France's national health care database, covering all bariatric procedures performed between 2009 and 2023. Patients aged 18 to 65 years with a primary diagnosis of obesity were included. Outcomes assessed included 90-day and 180-day mortality, severe complications (Clavien-Dindo IV), reoperations, hospital readmissions, and postoperative medication use. RESULTS:Among 486,161 first-time bariatric procedures, sleeve gastrectomy and gastric bypass dominated. The overall 90-day mortality rate was 0.1%, varying significantly by procedure ( P < 0.001), with adjustable gastric banding exhibiting the lowest rate. Mortality decreased by 40% over time, but sleeve gastrectomy and gastric bypass showed a plateau effect since 2018. Reoperations declined (4.9%-4.5%), and intensive care unit admissions for severe complications fell by 58%. Medication analysis revealed reduced analgesic (-29.4%), antidepressant (-15.7%), and anxiolytic (-12.7%) use, while laxative consumption increased (+86.4%). CONCLUSIONS:Bariatric surgery has become safer over time, with declining mortality and complication rates. However, the stagnation of improvements in recent years highlights the need for further optimization strategies. These findings support the continued integration of surgery within a multimodal obesity treatment paradigm.

Persistent primary hyperparathyroidism is defined as the persistence or recurrence of hypercalcemia within 6 months of parathyroid surgery. Recurrent primary hyperparathyroidism is defined as the recurrence of primary hyperparathyroidism more than 6 months after an initially curative parathyroidectomy. In these situations, it is essential to rule out differential diagnoses, and in particular secondary hyperparathyroidism and familial hypocalciuric hypercalcemia. Failure to remove the pathological parathyroid gland or glands during initial surgery for primary hyperparathyroidism is the most common situation in non-expert centers. In other situations, genetically determined multi-glandular primary hyperparathyroidism must be screened for. More rarely, a second sporadic adenoma is identified, or, exceptionally, a parathyroid carcinoma or parathyromatosis. Effective morphological evaluation, combining a morphological and functional imaging, is essential prior to any new parathyroid surgery. The indications for surgery must be discussed in a multidisciplinary team, assessing the risk/benefit ratio, since the risk of surgical complications is higher. Revision surgery should be performed using a suitable approach, after laryngoscopy, in an expert center, ideally with intraoperative PTH measurement and recurrent nerve neuromonitoring.

BACKGROUND:Since 2007, single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) has been proposed as an alternative to Roux-en-Y gastric bypass (RYGB) in the treatment of obesity. We conducted a multicentre randomised trial, with the hypothesis that SADI-S could be more effective than RYGB at 2-year follow-up. METHODS:This multicentre, open-label, individually randomised superiority trial was conducted in France; patients were recruited from 22 bariatric institutions, mostly public academic hospitals. Key inclusion criteria were patients with a BMI ≥40 kg/m2 or ≥35 kg/m2 with obesity-related comorbidities (type 2 diabetes, hypertension, dyslipidaemia, sleep apnoea, or osteoarthrosis), and a candidate for SADI-S or RYGB gastric bypass as a primary surgery or after a sleeve gastrectomy. Main key exclusions included previous bariatric surgery (other than sleeve gastrectomy), inflammatory bowel disease, type 1 diabetes, and untreated Helicobacter pylori infection. Participants were randomly assigned (1:1) to SADI-S or RYGB, stratified by centre, failure of sleeve gastrectomy, and presence of type 2 diabetes. The primary endpoint was percentage excess weight loss (%EWL) at 2 years (%EWL=[(weight at 2 years - initial weight)/(initial weight - ideal weight)] × 100). The study is registered with ClinicalTrials.gov, NCT03610256 and is completed. FINDINGS:Between Nov 8, 2018, and Sept 29, 2021, a total of 381 patients were randomly assigned (intention-to-treat population) and included in the primary analysis (SADI-S: 190, RYGB: 191). Mean age was 44·4 years (SD 10·64), mean BMI was 46·2 kg/m2 (6·40), 265 (70%) were female, and 79 (21%) had a primary sleeve gastrectomy. 43 (12%) of 370 participants were lost to follow-up. At 2 years, the mean %EWL was statistically significantly higher in the SADI-S group compared with the RYGB group (-76·0% [SD 26·7] vs -68·1% [28·7], confirming the superiority of SADI-S (mean difference -6·72% [95% CI -12·64 to -0·80], p=0·026). The primary outcome was missing for 78 (20%) of 381 participants, with 46 (59%) of 78 participants in the SADI-S group and 32 (41%) of 78 in the RYGB group, p=0·09. The number of serious adverse events related to the surgical technique in the safety population, including all operated patients, was 40 in the SADI-S group including three anastomotic leaks and eight severe diarrhoea compared with 35 in the RYGB group including five internal hernia and five severe abdominal pain cases of which two required diagnostic laparoscopy. INTERPRETATION:SADI-S showed superior weight loss compared with RYGB at 2 years, with a similar safety profile. FUNDING:French Ministry of Health (Direction Générale de l'offre de Soin - DGOS).

To evaluate the evolution of postoperative mortality and morbidity associated with bariatric surgery over a 15-year period using a nationwide database. Bariatric surgery is a cornerstone in obesity management, demonstrating significant benefits in weight loss and comorbidity resolution. However, despite its proven efficacy, it remains underutilized, with only a small fraction of eligible patients undergoing surgery. Advances in surgical techniques and perioperative care have improved safety, yet long-term trends in mortality and morbidity require further evaluation. This retrospective cohort study utilized data from the SNDS (Système National des Données de Santé), France’s national health care database, covering all bariatric procedures performed between 2009 and 2023. Patients aged 18 to 65 years with a primary diagnosis of obesity were included. Outcomes assessed included 90-day and 180-day mortality, severe complications (Clavien-Dindo IV), reoperations, hospital readmissions, and postoperative medication use. Among 486,161 first-time bariatric procedures, sleeve gastrectomy and gastric bypass dominated. The overall 90-day mortality rate was 0.1%, varying significantly by procedure (P < 0.001), with adjustable gastric banding exhibiting the lowest rate. Mortality decreased by 40% over time, but sleeve gastrectomy and gastric bypass showed a plateau effect since 2018. Reoperations declined (4.9%–4.5%), and intensive care unit admissions for severe complications fell by 58%. Medication analysis revealed reduced analgesic (-29.4%), antidepressant (-15.7%), and anxiolytic (-12.7%) use, while laxative consumption increased (+86.4%). Bariatric surgery has become safer over time, with declining mortality and complication rates. However, the stagnation of improvements in recent years highlights the need for further optimization strategies. These findings support the continued integration of surgery within a multimodal obesity treatment paradigm.

OBJECTIVE:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player in liver metabolism and health. Hippurate, a host-microbial co-metabolite has been associated with human gut microbial gene richness and with metabolic health. However, its role on liver metabolism and homeostasis is poorly understood. METHODS:We characterised liver biospies from 318 patients with obesity using RNAseq and metabolomics in liver and plasma to derive associations among hepatic hippurate, hepatic gene expression and MASLD and phenotypes. To test a potential beneficial role for hippurate in hepatic insulin resistance, we profile the metabolome of (IHH) using ultra-high-performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-MS/MS), and characterised intracellular triglyceride accumulation and glucose internalisation after a 24 h insulin exposure. RESULTS:We first report significant associations among MASLD traits, plasma and hepatic hippurate. Further analysis of the hepatic transcriptome shows that liver and plasma hippurate are inversely associated with MASLD, implicating lipid metabolism and regulation of inflammatory responses pathways. Hippurate treatment inhibits lipid accumulation and rescues insulin resistance induced by 24-hour chronic insulin in IHH. Hippurate also improves hepatocyte metabolic profiles by increasing the abundance of metabolites involved in energy homeostasis that are depleted by chronic insulin treatment while decreasing those involved in inflammation. CONCLUSIONS:Altogether, our results further highlight hippurate as a mechanistic marker of metabolic health, by its ability to improve metabolic homeostasis as a postbiotic candidate.

IMPORTANCE:Metabolic flexibility, a key hallmark of cancer, reflects aberrant tumour changes associated with metabolites. The metabolic plasticity of pancreatic neuroendocrine tumours (pNETs) remains largely unexplored. Notably, the heterogeneity of pNETs complicates their diagnosis, prognosis, and therapeutic management. OBJECTIVE:Here, we compared the plasma metabolomic profiles of patients with pNET and non-cancerous individuals to understand metabolic dysregulation. DESIGN, SETTING, PARTICIPANTS, INTERVENTION AND MEASURE:Plasma metabolic profiles of 76 patients with pNETs and 38 non-cancerous individuals were analyzed using LC-MS/MS and FIA-MS/MS (Biocrates AbsoluteIDQ p180 kit). Statistical analyses, including univariate and multivariate methods, were performed along with the generation of receiver operating characteristic (ROC) curves for metabolomic signature identification. RESULTS:Compared with non-cancerous individuals, patients with pNET exhibited elevated levels of phosphoglyceride metabolites and reduced acylcarnitine levels, indicating an upregulation of fatty acid oxidation (FAO), which is crucial for the energy metabolism of pNET cells and one-carbon metabolism metabolites. Elevated glutamate levels and decreased lipid metabolite levels have been observed in patients with metastatic pNETs. Patients with the germline MEN1 mutations showed lower amino acid metabolites and FAO, with increased metabolites related to leucine catabolism and lipid metabolism, compared to non-MEN1 mutated patients. The highest area under the ROC curve was observed in patients with pNET harbouring MEN1 mutations. CONCLUSION AND RELEVANCE:This study highlights the distinct plasma metabolic signatures of pNETs, including the critical role of FAO and elevated glutamate levels in metastasis, supporting the energy and biosynthetic needs of rapidly proliferating tumour cells. Mapping of these dysregulated metabolites may facilitate the identification of new therapeutic targets for pNETs management.