Transcriptional and epigenetic changes after dietary and surgical weight loss interventions in an animal model of obesity.

BACKGROUND: Identifying determinants that can predict response to weight loss interventions is imperative for optimizing therapeutic benefit. We aimed to identify changes in DNA methylation and mRNA expression of a subset of target genes following dietary and surgical interventions in high-fat-diet (HFD)-induced obese rats. METHODS: Forty-two adult Wistar Han male rats were divided into two groups: control rats (n = 7) and obese rats (n = 28), fed a HFD for 10 weeks (t10). Obese rats were randomly subdivided into five intervention groups (seven animals per group): (i) HFD; (ii) very-low-calorie diet (VLCD); (iii) sham surgery, and (iv) sleeve gastrectomy (SG). At week sixteen (t16), animals were sacrificed and tissue samples were collected to analyze changes in DNA methylation and mRNA expression of the selected genes. RESULTS: By type of intervention, the surgical procedures led to the greatest weight loss. Changes in methylation and/or expression of candidate genes occurred proportionally to the effectiveness of the weight loss interventions. Leptin expression, increased sixfold in the visceral fat of the obese rats, was partially normalized after all interventions. The expression of fatty acid synthase (FASN) and monocyte chemoattractant protein 1 (MCP-1) genes, which was reduced 0.5- and 0.15-fold, respectively, in the liver tissue of obese rats, were completely normalized after weight loss interventions, particularly after surgical interventions. The upregulation of FASN and MCP-1 gene expression was accompanied by a significant reduction in promoter methylation, up to 0.5-fold decrease in the case of the FASN (all intervention groups) and a 0.8-fold decrease in the case of the MCP-1 (SG group). CONCLUSIONS: Changes in tissue expression of specific genes involved in the pathophysiological mechanisms of obesity can be significantly attenuated following weight loss interventions, particularly surgery. Some of these genes are regulated by epigenetic mechanisms.

Analysis of the Management of Cholelithiasis in Bariatric Surgery Patients: a Single-Center Experience.

PURPOSE: Cholelithiasis is an issue in bariatric surgery patients. The incidence of cholelithiasis is increased in morbidly obese patients. After bariatric surgery, the management maybe sometimes challenging. There is no consensus about how to deal with cholelithiasis prior to bariatric surgery. MATERIALS AND METHODS: A retrospective review from our prospectively collected bariatric surgery database. Primary bariatric procedures from 2009 to 2020 were included. Prevalence of cholelithiasis and its management prior to bariatric surgery and the incidence and management of postoperative biliary events were analyzed. RESULTS: Over 1445 patients analyzed, preoperatively cholelithiasis was found in 153 (10.58%), and 68 out of them (44.44%) were symptomatic. Seventy-six patients had a concomitant cholecystectomy. In those cases, the bariatric procedure did not show increased operative time, length of stay, morbidity, or mortality compared to the rest of primary bariatric procedures. Twelve patients (15.58%) with previous cholelithiasis and no concomitant cholecystectomy presented any kind of biliary event and required cholecystectomy. De novo cholelithiasis rate requiring cholecystectomy was 3.86%. Postoperative biliary events both in de novo and persistent cholelithiasis population did not show any difference between the type of surgery, weight loss, and other characteristics. CONCLUSIONS: Cholelithiasis was present in 10.58% of our primary bariatric surgery population. Concomitant cholecystectomy was safe in our series. Non-surgical management of asymptomatic cholelithiasis did not lead to a higher risk of postoperative biliary events. The global postoperative cholecystectomy rate was equivalent to the general population.

Outcomes of Conversion from Sleeve Gastrectomy to Roux-en-Y Gastric Bypass Due to GERD-a Retrospective Analysis of 35 Patients.

BACKGROUND: Sleeve gastrectomy (SG) has become one of the most performed bariatric procedures worldwide. Its main weaknesses are weight regain and gastroesophageal reflux disease (GERD). Conversion to Roux-en-Y gastric bypass (RYGB) is considered the gold standard to manage GERD and related symptoms. METHODS: Retrospective evaluation from a prospective bariatric surgery database of all our institution's patients converted from SG to RYGB due to GERD between January 2010 and December 2018. Clinical characteristics and workups before SG and before and after RYGB were analyzed. RESULTS: During the study period, 35 patients needed a conversion to RYGB, due to GERD or GERD-related symptoms. Mean age was 48.6 years, 85.7% were women, and mean BMI was 31.4 kg/m2. The interval between SG and RYGB was in a range 7 to 70 months (mean 33 months). All conversions were completed laparoscopically, associating a hiatoplasty in 45.7% of cases. A complete remission of symptoms was observed in 74% of patients, some improvement in 20%, and no relief in 6%. There were 3 cases of hiatal hernia persistence and 2 of recidivism. Only 1 patient presented pathological pHmetry, while moderate esophagitis was demonstrated in 2 patients. CONCLUSIONS: Conversion to RYGB was effective in almost all patients. Pathological acid exposure and hiatal hernias seem to be the main findings prior to conversion, justifying an exhaustive examination and aggressive approach to the hiatus. Due to the insufficient correlation between symptoms and findings on morphological and functional tests, actively searching for signs of GERD is advisable.

Seeking an Initial-Weight-Independent Metric in a Mediterranean Cohort of Gastric Bypass Patients: the %AWL Revisited.

BACKGROUND: Most relative weight-loss metrics follow the formula "Weight loss(%) = 100 · (Initial BMI - Final BMI) / (Initial BMI-a)," where a is the reference point that defines the metric. The percentage of total weight loss (%TWL, a = 0) and percentage of excess weight loss (%EWL, a = 25) are influenced by a patient's initial weight. Recently, the percentage of alterable weight loss metric (%AWL, a = 13) has been reported to produce initial-weight-independent outcomes. OBJECTIVES: This study aimed to replicate the methodology used for %AWL determination in a Mediterranean cohort of bariatric patients. SETTINGS: Multicenter study in 10 large hospitals in Spain. METHODS: Two large prospective databases were retrospectively searched for all primary laparoscopic gastric bypass patients with 2 years of follow-up. Outcomes at nadir were expressed and analyzed with 26 different metrics (a from 0 to 25), looking for the metric whose outcomes produced (1) the lowest coefficient of variation, (2) no differences between initially lighter and heavier patients, and (3) no correlation with patients' initial BMI. RESULTS: A cohort of 1793 patients was stratified into 4 gender-age groups: younger women (YW, n = 733), older women (OW, n = 674), younger men (YM, n = 197), and older men (OM, n = 189). The calculations suggested an optimal reference point of 18 kg/m2, defining a new metric (percentage of Mediterranean alterable weight loss, %MAWL). When %TWL, %EWL, %AWL, and %MAWL were tested on the whole sample, only %MAWL produced initial-weight-independent results. CONCLUSIONS: In our Mediterranean cohort of patients, a reference point of 18 (and not 13) yielded initial-weight-independent outcomes.

Effects of negative-pressure therapy with and without ropivacaine instillation in the early evolution of severe peritonitis in pigs.

PURPOSE: The abdomen is the second most common source of sepsis and secondary peritonitis, which likely lead to death. In the present study, we hypothesized that instillation of local anesthetics into the peritoneum might mitigate the systemic inflammatory response syndrome (SIRS) in the open abdomen when combined with negative-pressure therapy (NPT) to treat severe peritonitis. METHODS: We performed a study in 21 pigs applying a model of sepsis based on ischemia/reperfusion and fecal spread into the peritoneum. The pigs were randomized into three groups, and treated for 6 h as follows: Group A: temporary abdominal closure with ABTHERA™ Open Abdomen Negative-Pressure Therapy; Group B: temporary abdominal closure with ABTHERA™ Open Abdomen Negative-Pressure Therapy plus abdominal instillation with physiological saline solution (PSS); and Group C: temporary abdominal closure with ABTHERA™ Open Abdomen Negative-Pressure Therapy plus peritoneal instillation with a solution of ropivacaine in PPS. RESULTS: A comparison between the three groups revealed no statistically significant difference for any of the parameters registered (p > 0.05), i.e., intra-abdominal pressure, blood pressure, heart rate, O2 saturation, diuresis, body temperature, and blood levels of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and c-reactive protein (CRP). In addition, histological studies of the liver, ileum, kidney and lung showed no difference between groups. CONCLUSIONS: The use of abdominal instillation (with or without ropivacaine) did not change the effect of 6 h of NPT after sepsis in animals with open abdomen. The absence of adverse effects suggests that longer treatments should be tested.

Management of the staple line in laparoscopic sleeve gastrectomy: comparison of three different reinforcement techniques.

BACKGROUND: Nowadays, laparoscopic sleeve gastrectomy (LSG) is one of the most widely performed bariatric procedures. Different techniques have been described to reduce the rate of complications associated with the staple line, but no consensus has been reached. The aim of this study was to determine the incidence of surgical complications after LSG with three different approaches to the staple line. PATIENTS AND METHODS: A retrospective matched analysis was performed, comparing three groups of 100 patients each: partial oversewing of the staple line (PO group), complete oversewing of the staple line (CO group), and reinforcement with buttress material (BM group). Operative time, early surgical complications (superficial surgical site infection, leakage and hemorrhage), length of stay, weight evolution, and revisional surgery rates were analyzed. RESULTS: All three groups were comparable at baseline. All surgeries were performed laparoscopically. Operative time was significantly longer in the CO group (PO: 84.2 ± 22; CO: 104.7 ± 17; BM: 82.3 ± 22; PO vs CO, p = 0.021; BM vs CO, p = 0.011). There were no differences in length of stay, early surgical complications, and weight outcomes at 36 months between the groups. The need for a revisional surgery was significantly higher in the CO group compared to the PO group (PO: 3%; CO: 14%; BM: 9%; PO vs CO, p = 0.005). CONCLUSION: The CO group required a longer operative time. There were no differences in early surgical complications between the groups. The CO group had a higher need for revisional surgery than the PO group.

Effects of COVID-19 lockdown on a bariatric surgery waiting list cohort and its influence in surgical risk perception.

PURPOSE: The COVID-19 outbreak has forced a 2-month lockdown (LD) in Spain. We aimed to assess how that had affected our cohort of bariatric patients waiting for surgery. METHODS: A review of electronic records and a structured phone interview with each patient were conducted. Changes in severity of obesity were analyzed using the Obesity Surgery Score (OSS) and changes in health-related quality of life (HRQoL) using the validated EQ-5D questionnaire. Other miscellaneous questions about behavior modifications and surgical risk perception were also analyzed. RESULTS: All 51 patients fully answered the questionnaires. Mean age was 47 years and mean time on waiting list 91 days. Mean BMI increased during LD (42.7 vs 43.2; p < 0.001). Both OSS (2.84 vs 3; p = 0.011) and EQ-5D (69 vs 64; p < 0.001) mildly worsened during LD, mainly due to psychosocial issues. Twenty-seven patients (53%) thought that perioperative risks were higher under the current circumstances but they were as willing to undergo surgery as those who believed that the risks had not increased (74% vs 87%, p = 0.2). CONCLUSIONS: COVID-19 LD had a significant but mild effect on our cohort of bariatric surgery waiting list patients. Although perioperative risk perception had increased, patients were still willing to undergo their planned surgeries.

Abdominal Wall Hernia and Metabolic Bariatric Surgery.

The management of morbidly obese patients with a concomitant ventral hernia (VH) is a great challenge for surgeons. There is controversy over the optimal strategy to tackle both health problems, requiring an individualized approach. Obese patients have a higher recurrence rate after hernia repair, and bariatric surgery in the presence of a VH can be difficult. As morbid obesity is related with severe comorbidities, including increased cardiovascular and anesthetic risks, some advocate for a single-stage strategy. A primary hernia repair carried out during the bariatric surgery, however, may increase morbidity without definitively solving the problem. Biological meshes are expensive and also have a high recurrence rate. The laparoscopic placement of a synthetic mesh offers good results, but it is worrisome because bariatric surgery is a clean-contaminated procedure. Moreover, there is a great chance that a plastic surgery would be necessary after completing the weight-loss process, and the abdominal wall surgery could be performed at that point. There are many arguments, but the evidence is weak. We present an extensive review of the currently available literature on the management of VH in morbidly obese patients. We aim to provide objective information regarding the pros and cons of the different strategies that have been proposed, to facilitate the selection of the best approach to individual morbidly obese patients with abdominal wall hernias precising both of surgical repair.

Is bariatric surgery resolving NAFLD via microbiota-mediated bile acid ratio reversal? A comprehensive review.

Despite the fact that there is still insufficient evidence to consider non-alcoholic fatty liver disease (NAFLD) as an stand-alone indication for bariatric surgery, many clinical and histopathological beneficial effects on both NAFLD and non-alcoholic steatohepatitis (NASH) have been shown. Although weight loss seems to be the obvious mechanism, weight-loss independent factors are also believed to be involved. Among them, changes in gut microbiota and bile acids (BA) composition may be playing an unappreciated role in the improvement of NAFLD. In this review we examine the mechanisms and interdependence of the gut microbiota and BA, and their influence on NAFLD pathogenesis and its reversal following bariatric surgery. According to the currently available evidence, gut microbiota has a major influence on BA composition. In fact, both BA and microbiome disturbances (dysbiosis) play a role in the etiopathogenesis of NAFLD and might be potential therapeutic targets. In addition, bariatric surgery can modify the intraluminal ileal environment in a way that causes significant repopulation of the gut microbiota and a reversal of the plasma primary/secondary BA ratio, which, in turn, induces weigh-independent metabolic improvements.

Laparoscopic sleeve gastrectomy induces molecular changes in peripheral white blood cells.

BACKGROUND & AIMS: Peripheral white blood cells (PWBC) may allow for the development of obesity biomarkers. We aimed to investigate the existence of gene expression and DNA methylation changes in PWBC after a very low calorie diet (VLCD) followed by a laparoscopic sleeve gastrectomy (LSG), and its correlation with surgical outcomes. METHODS: From July 2013 to June 2014, 35 consecutive bariatric patients and 33 healthy lean volunteers were recruited. Molecular data was obtained once on the control group and at 3 different times on the LSG group: 1) at baseline; 2) after 2 weeks of VLCD, right before LSG; and 3) 6 months after LSG. The expression of 12 genes in PWBC was analyzed by quantitative real-time polymerase chain reaction: ghrelin (GHRL), visfatin (NAMPT), insulin receptor substrate 1 (IRS1), fat mass and obesity-related gene (FTO), leptin (LEP), peroxisome proliferator-activated receptor gamma (PPARG), adiponectin (ADIPOQ), fatty acid synthase (FASN), melanocortin 4 receptor (MC4R), fas cell surface death receptor (FAS), tumor necrosis factor alpha (TNF) and chemokine (C-C motif) ligand 2 (CCL2). Moreover, DNA methylation of GHRL, NAMPT and FAS promoters was analyzed in PWBC by bisulfite pyrosequencing. RESULTS: Seven genes (GHRL, NAMPT, IRS1, FTO, FAS, TNF and CCL2) had detectable expression in PWBC. FTO expression at baseline was lower in patients than in controls (p = 0.042), equalizing after LSG. In patients, FAS expression decreased after VLCD (p = 0.01) and stayed low after LSG (p = 0.015). Also, CCL2 expression decreased 50% after LSG compared to pre-surgical levels (p = 0.016). All studied CpG sites in the GHRL gene promoter followed a consistent pattern of DNA methylation/demethylation. No direct correlation between these molecular changes and surgical outcomes was found at 1-year follow-up. CONCLUSIONS: FTO expression increased and FAS and CCL2 expression decreased in PWBC after LSG. Molecular changes did not correlate with surgical outcomes.

Morphofunctional Changes After Sleeve Gastrectomy and Very Low Calorie Diet in an Animal Model of Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is found in 70% of obese people. The evidence available to date suggests that bariatric surgery could be an effective treatment by reducing weight and also by improving metabolic complications in the long term. This work aimed to compare, in a diet-induced NAFLD animal model, the effect of both sleeve gastrectomy (SG) and very-low calorie diet (VLCD). METHODS: Thirty-five Wistar rats were divided into control rats (n = 7) and obese rats fed a high-fat diet (HFD). After 10 weeks, the obese rats were subdivided into four groups: HFD (n = 7), VLCD (n = 7), and rats submitted to either a sham operation (n = 7) or SG (n = 7). Both liver tissue and blood samples were processed to evaluate steatosis and NASH changes in histology (Oil Red, Sirius Red and H&E); presence of endothelial damage (CD31, Moesin/p-Moesin, Akt/p-Akt, eNOS/p-eNOS), oxidative stress (iNOS) and fibrosis (αSMA, Col1, PDGF, VEGF) proteins in liver tissue; and inflammatory (IL6, IL10, MCP-1, IL17α, TNFα), liver biochemical function, and hormonal (leptin, ghrelin, visfatin and insulin) alterations in plasma. RESULTS: Both VLCD and SG improved histology, but only SG induced a significant weight loss, improved endothelial damage, and a decreased cardiovascular risk by reducing insulin resistance (IR), leptin, total cholesterol, and triglyceride levels. There were no relevant variations in the inflammatory and fibrosis markers. CONCLUSION: Our study suggests a slight superiority of SG over VLCD by improving not only the histology but also the IR and cardiovascular risk markers related to NAFLD.

Subtotal colectomy versus left hemicolectomy for the elective treatment of splenic flexure colonic neoplasia.

BACKGROUND: Optimal elective surgical treatment for splenic flexure neoplasm (SFN) is unclear. Subtotal colectomy (STC) and left hemicolectomy (LHC) are the two more common strategies used. METHODS: Observational multicentric study comparing postoperative morbidity, mortality and long-term survival on patients with SFN electively operated by STC versus LHC between 2003 and 2014. RESULTS: After revision of the databases, 144 patients were included (STC group, n = 68; LHC group, n = 76). No differences were found on epidemiological and surgical data. A higher global morbidity (58%vs37%, p = 0.014), surgical morbidity (50%vs33%, p = 0.037), postoperative ileus (37%vs20%, p = 0.023) and harvested lymph nodes (26vs18, p = 0.0001) were found on the STC group. No significant differences in complications according to severity, reoperation rate, hospital stay, mortality, recurrence or long-term survival were found between groups. CONCLUSIONS: A higher surgical morbidity was found on the STC group, mainly due to mild postoperative ileus. No differences on long-term oncological results were found.

Long-term results of pancreaticoduodenectomy with superior mesenteric and portal vein resection for ductal adenocarcinoma in the head of the pancreas.

INTRODUCTION: The benefit of pancreaticoduodenectomy (PD) with superior mesenteric-portal vein resection (PVR) for pancreatic adenocarcinoma (PA) is still controversial in terms of morbidity, mortality and survival. We conducted a retrospective study to analyze outcomes of PD with PVR in a Spanish tertiary centre. METHODS: Between 2002 and 2012, 10 patients underwent PVR (PVR+ group) and 68 standard PD (PVR- group). Morbidity, mortality, overall survival (OS) and disease-free survival (DFS) were compared between PVR+ and PVR- group. Prognostic factors were identified by a Cox regression model. RESULTS: Postoperative mortality was 5% (4/78), all patients in PVR- group. Morbidity was higher in the PVR- group compared to PVR+ (63 vs. 30%, P=.004). OS at 3 and 5 years was 43 and 43% in PVR+ group, 35 and 29% in PVR- group (P=.07). DFS at 3 and 5 years DFS were 28 and 15% in PVR+ group, 25 and 20% in PVR- group (P=.84). Median survival was 23.1 months in PVR- group, and 22.8 months in PVR+ group (P=.73). Factors related with OS were absence of adjuvant treatment (OR 2.9, 95%IC: 1.39-6.14, P=.003), R1 resection (OR 2.3, 95%IC: 1.2-4.43, P=.006), preoperative CA 19.9 level ≥ 170 UI/mL (OR 2.3, 95%IC: 1.22-4.32, P=.01). DFS risk factors were R1 resection (OR 2.6, 95%IC: 1.41-4.95, P=.002); moderate or poor tumor differentiation grade (OR 2.7, 95%IC: 1.23-6.17, P=.01); N1 lymph node status (OR 1.8, 95%IC: 1.02-3.19, P=.04); CA 19.9 level ≥ 170 UI/mL (OR 2.4, 95%IC: 1.30-4.54, P=.005). CONCLUSIONS: PVR for PA can be performed safely. Patients with PVR have a comparable survival to patients undergoing standard PD if disease-free margins can be obtained.