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.

ESDE-MIE fellowship: a descriptive analysis of the first experiences.

Esophageal resection is a high-risk and technically demanding procedure, with a long proficiency-gain curve. The European Society Diseases of the Esophagus (ESDE)-Minimally Invasive Esophagectomy (MIE) training program was launched in 2018 for European surgeons willing to train and to begin a career undertaking MIE. The aim of this study was to evaluate the first experience of the ESDE-MIE fellowship and relate this to the initially predetermined core principles and objectives of the program. Between October 2021 and May 2022, the participating fellows, in collaboration with the ESDE Educational Committee, initiated a survey to assess the outcome and experience of these fellowships. Data from each individual fellowship were analysed and reported in a descriptive manner. Between 2018 and 2022, in total, five fellows have completed the ESDE-MIE fellowship program. Despite the COVID-19 outbreak just the year after its launch, predetermined clinical and research goals were achieved in all cases. Each of the fellows were able to assist in a median of 40 (IQR 27-69) MIE and/or Robot assisted (RA)MIE procedures, of a total median of 115 (IQR 83-123) attended Upper GI cases. After the fellowship, MIE has been fully adopted by the fellows who returned to their home institutions as Upper GI surgeons. The fellowship was concluded by the European Union of Medical Specialists (UEMS) Multidisciplinary Joint Committee (MJC) certification in Upper GI Surgery, which was successfully obtained by all who took part. Based on the experience of the first five fellows, the ESDE-MIE training fellowship meets with the expected needs even despite the COVID-19 outbreak in 2019. Furthermore, these fellows have returned home and integrated MIE into their independent surgical practice, affirming the ability of this program to train the next generation of MIE surgeons, even in the most challenging of circumstances.

Prevention and treatment of a positive proximal margin after gastrectomy for cardia cancer.

A tumour-positive proximal margin (PPM) after extended gastrectomy for oesophagogastric junction (OGJ) adenocarcinoma is observed in approximately 2-20% of patients. Although a PPM is an unfavourable prognostic factor, the clinical relevance remains unclear as it may reflect poor tumour biology. This narrative review analyses the most relevant literature on PPM after gastrectomy for OGJ cancers. Awareness of the risk factors and possible measures that can be taken to reduce the risk of PPM are important. In patients with a PPM, surgical and non-surgical treatments are available but the effectiveness remains unclear.

Post-esophagectomy tracheobronchoesophageal fistula: management and results of a tertiary referral center.

A tracheobronchoesophageal fistula (TBEF) is a rare but life-threatening complication after esophagectomy. The existing literature on TBEF management is limited and many previous recommendations are contradictory. We aimed to describe our series of TBEF after esophagectomy and compare it with other reported series. Patients who developed a TBEF after esophagectomy were identified retrospectively. Baseline and intraoperative characteristics, postoperative and TBEF details, treatments for TBEF, and main outcomes are described. A univariate analysis was performed to compare some of the analyzed variables with the overall sample. Finally, our results are compared with the previously described series. Altogether, 16 patients with TBEF (3.11%) were analyzed from 514 patients who received esophagectomies between January 2014 and February 2020. As a first treatment attempt, 14 (87.5%) were treated with surgery, one was treated conservatively, and one was treated endoscopically. Surgery both at a first or second treatment attempt achieved a survival rate of 62.5% and oral intake at discharge of 43.75%. Six patients died during their hospital stay (37.5%). The presence of an anastomotic leak showed a strong association with TBEF development (100% vs. 19.7%; OR 1.163, 95% CI 1.080-1.253, p = 0.000). In our experience, surgical treatment as the first approach for TBEF associated with anastomotic leak after esophagectomy obtained good results. However, there is an urgent need to elaborate treatment guidelines based on international consensus.

Risk Factors, Diagnosis and Management of Chyle Leak Following Esophagectomy for Cancers: An International Consensus Statement.

This Delphi exercise aimed to gather consensus surrounding risk factors, diagnosis, and management of chyle leaks after esophagectomy and to develop recommendations for clinical practice. Background: Chyle leaks following esophagectomy for malignancy are uncommon. Although they are associated with increased morbidity and mortality, diagnosis and management of these patients remain controversial and a challenge globally. Methods: This was a modified Delphi exercise was delivered to clinicians across the oesophagogastric anastomosis collaborative. A 5-staged iterative process was used to gather consensus on clinical practice, including a scoping systematic review (stage 1), 2 rounds of anonymous electronic voting (stages 2 and 3), data-based analysis (stage 4), and guideline and consensus development (stage 5). Stratified analyses were performed by surgeon specialty and surgeon volume. Results: In stage 1, the steering committee proposed areas of uncertainty across 5 domains: risk factors, intraoperative techniques, and postoperative management (ie, diagnosis, severity, and treatment). In stages 2 and 3, 275 and 250 respondents respectively participated in online voting. Consensus was achieved on intraoperative thoracic duct ligation, postoperative diagnosis by milky chest drain output and biochemical testing with triglycerides and chylomicrons, assessing severity with volume of chest drain over 24 hours and a step-up approach in the management of chyle leaks. Stratified analyses demonstrated consistent results. In stage 4, data from the Oesophagogastric Anastomosis Audit demonstrated that chyle leaks occurred in 5.4% (122/2247). Increasing chyle leak grades were associated with higher rates of pulmonary complications, return to theater, prolonged length of stay, and 90-day mortality. In stage 5, 41 surgeons developed a set of recommendations in the intraoperative techniques, diagnosis, and management of chyle leaks. Conclusions: Several areas of consensus were reached surrounding diagnosis and management of chyle leaks following esophagectomy for malignancy. Guidance in clinical practice through adaptation of recommendations from this consensus may help in the prevention of, timely diagnosis, and management of chyle leaks.

Evolution of laparoscopic gastrectomy for cancer in the East and West.

Laparoscopic gastrectomy has evolved differently in Eastern and Western countries. Feasibility, safety and oncological outcomes of laparoscopic gastrectomy were addressed step-by-step by several randomized controlled trials from the East. Few phase III studies were published from the West that largely did not show a difference between the laparoscopic and open approach. Despite this, laparoscopic gastrectomy is seen as the standard for the surgical treatment of early and advanced gastric cancer in many European countries. Here, we review and comment on some important studies on laparoscopic gastrectomy for gastric cancer from Eastern and Western countries and also comment on current and future challenges.

Application of ERAS protocol in esophagectomy: a national survey among Italian centers performing esophageal surgery.

The application of enhanced recovery after surgery guidelines for esophageal surgery in different units remains unclear. This survey intended to investigate how such protocol is applied among Italian esophageal surgery units. A survey with 40 questions was mailed to Italian centers that performed at least 10 esophagectomies per year. It included questions about the type of hospital and unit and pre-, intra- and post-operative items. Difficulties encountered were investigated. Thirteen (65%) centers answered the survey, and all met the minimal safety requirements, e.g., the presence of intensive care units and 24-h on-call operative endoscopy and radiology facilities. Fifty percent of esophagectomies with a minimally invasive approach were performed in 84.6% of the centers. Regarding pre-operative items, the highest scores were for the application of nutritional support, dysphagia palliation and presence of a multidisciplinary tumor board, whereas the lowest score was for the use of immunonutrition. Regarding intra-operative items, hypothermia prevention and the use of goal-directed fluid therapy and volatile anesthesia were diffusely adopted, whereas the rate of using abdominal drains was high. Regarding post-operative items, nausea prevention, multimodal analgesia and early mobilization were applied frequently, whereas the use of nasogastric tubes and regular transfer to intensive care units was diffused. The primary barriers in enhanced recovery after surgery protocol application were resistance and a lack of paramedic personnel. This survey's results highlight the efforts undertaken by several centers to apply enhanced recovery after surgery philosophy and in this regard, demonstrate a good standing in Italy.

Perfusion speed of indocyanine green in the stomach before tubulization is an objective and useful parameter to evaluate gastric microcirculation during Ivor-Lewis esophagectomy.

BACKGROUND: Anastomotic leakage (AL) during Ivor-Lewis esophagectomy (ILE), owing to gastric conduit (GC) ischemia, is a serious complication. Measurement parameters during intraoperative ICG fluorescence angiography (ICG-FA) are unclear. We aimed to identify objective ICG-FA parameters associated with AL. STUDY DESIGN: Patients > 18 years with an indication for ILE were enrolled. ICG-FA was performed at the abdominal and thoracic stage, and data, such as time of fluorescence appearance, speed of ICG perfusion, quality of GC perfusion (good, poor, ischemic), blood pressure, baseline patient characteristics, GC dimensions, and other intraoperative parameters were collected. On postoperative day 4 to 6, Gastrografin swallow radiography was performed. AL development was classified based on the Clavien-Dindo and SISG severity classifications. Univariate analysis with a 95% confidence level (p < 0.05) was performed. Factors with p < 0.05 were included in the multivariate analysis. RESULTS: 100 patients were enrolled. During ICG-FA, evaluation of subjective perfusion was a very specific test (94.1%) with good negative predictive value (NPV 71.9%, p 0.034), but not powerful enough to detect patients at risk of leak (sensibility 21.8%, PPV 63.6%). The GC perfusion speed (cm/s) after gastric vascular isolation and before tubulization showed a significant association with AL (p < 0.003). Median arterial blood pressure in the thoracic stage (p < 0.001) or use of inotropic (p < 0.033) was associated with AL development. CONCLUSION: GC perfusion speed at ICG-FA is an objective parameter that could predict AL risk. Other results emphasize the importance of the microcirculation in the development of AL.

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.

Treatment of Epiphrenic Diverticulum: How I Do It.

Epiphrenic diverticulum is a rare esophageal disorder occurring as an outpouching of mucosa and submucosa through the muscular layers, within 10 cm above the cardia. As the majority of epiphrenic diverticula are asymptomatic, the real incidence varies because of a considerable number of cases detected incidentally during radiographic or endoscopic evaluation. Traditionally, the operation was performed through a left thoracotomy approach and the diverticulectomy was completed with esophago-cardial myotomy and a Belsey Mark IV fundoplication. Laparoscopy offers many advantages in the treatment such as the possibility of extension of the myotomy from the lower esophagus through the stomach and the concomitant antireflux procedure to avoid postoperative reflux. The abdominal approach is also more comfortable for the patients and, as there is no need for transthoracic drains, is more tolerated in terms of postoperative pain. In this article, we do review our technique with all the steps of the operation illustrated by intraoperative pictures.

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.