A systems biology approach to understand gut microbiota and host metabolism in morbid obesity: design of the BARIA Longitudinal Cohort Study.

INTRODUCTION: Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. METHODS: The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years. RESULTS: Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra-individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference. CONCLUSION: The BARIA study can add more understanding in how gut-microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity-associated disease epidemic.

Gastric bypass and abdominal pain: think of Petersen hernia.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most commonly performed bariatric surgical procedures. A laparoscopic gastric bypass is associated with specific complications: internal herniation is one of these. CASE REPORT: A 47-year-old woman had undergone a laparoscopic Roux-en-Y gastric bypass (LRYGB) 18 months before presentation at our emergency department with mild abdominal complaints. Physical examination showed signs of an ileus in the absence of an acute abdomen. Laboratory investigations revealed no abnormalities (CRP 2.0 mg/L, white blood count 6.3 x 109/L). During admission, there was clinical deterioration on the third day. Emergency laparotomy was performed. An internal herniation through Petersen's space was found that strangulated and perforated the small bowel. A resection with primary anastomosis and closure of the defects was performed. CONCLUSION: Diagnosing an internal herniation through Petersen's space is difficult due to the nonspecific clinical presentation. The interpretation of the CT scan poses another diagnostic challenge. This sign is present in 74% of the cases with this herniation. A missed diagnosis of internal herniation may cause potentially serious complications. A patient with a gastric bypass who experiences intermittent abdominal complaints should undergo laparoscopy to rule out internal herniation.

The effects of laparoscopic Roux-en-Y gastric bypass and one-anastomosis gastric bypass on glycemic control and remission of type 2 diabetes mellitus: study protocol for a multi-center randomized controlled trial (the DIABAR-trial).

BACKGROUND: Metabolic surgery induces rapid remission of type 2 diabetes mellitus (T2DM). There is a paucity of high level evidence comparing the efficacy of the laparoscopic Roux-en-Y gastric bypass (RYGB) and the laparoscopic one-anastomosis gastric bypass (OAGB) in glycemic control. Also, the mechanisms that drive the conversion of T2DM in severe obese subjects to euglycemia are poorly understood. METHODS: The DIABAR-trial is an open, multi-center, randomized controlled clinical trial with 10 years follow-up which will be performed in 220 severely obese patients, diagnosed with T2DM and treated with glucose-lowering agents. Patients will be randomized in a 1:1 ratio to undergo RYGB or OAGB. The primary outcome is glycemic control at 12 months follow-up. Secondary outcome measures are diverse and include weight loss, surgical complications, psychologic status and quality of life, dietary behavior, gastrointestinal symptoms, repetitive bloodwork to identify changes over time, glucose tolerance and insulin sensitivity as measured by mixed meal tests, remission of T2DM, presence of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in liver biopsy, oral and fecal microbiome, cardiovascular performance, composition of bile acids, and the tendency to develop gallstones. DISCUSSION: The DIABAR-trial is one of the few randomized controlled trials primarily aimed to evaluate the glycemic response after the RYGB and OAGB in severe obese patients diagnosed with T2DM. Secondary aims of the trial are to contribute to a deeper understanding of the mechanisms that drive the remission of T2DM in severe obese patients by identification of microbial, immunological, and metabolic markers for metabolic response and to compare complications and side effects of RYGB and OAGB. TRIAL REGISTRATION: ClinicalTrials.gov NCT03330756 ; date first registered: October 13, 2017.

Molecular alterations associated with liver metastases development in colorectal cancer patients.

BACKGROUND: Understanding the molecular biology of colorectal cancer (CRC) provides opportunities for effective personalised patient management. We evaluated whether chromosomal aberrations, mutations in the PI(3)K signalling pathway and the CpG-island methylator phenotype (CIMP) in primary colorectal tumours can predict liver metastases. METHODS: Formalin-fixed paraffin-embedded material from primary colorectal tumours of three different groups were investigated: patients with CRC without metastases (M0, n=39), patients who were treated with hyperthermal intraperitoneal chemotherapy for CRC metastases confined to the peritoneum (PM, n=46) and those who had isolated hepatic perfusion for CRC metastases confined to the liver (LM, n=48). RESULTS: All samples were analysed for DNA copy number changes, PIK3CA, KRAS, BRAF mutations, CIMP and microsatellite instability. The primary CRCs of the LM group had significantly higher frequency of amplified chromosome 20q (P=0.003), significantly fewer mutations in the PI(3)K signalling pathway (P=0.003) and fewer CIMP high tumours (P=0.05). There was a strong inverse correlation between 20q and the PI(3)K pathway mutations. CONCLUSION: The development of CRC liver metastases is associated with amplification of chromosome 20q and not driven by mutations in the PI(3)K signalling pathway.

Multidisciplinary discussion and management of rectal cancer: a population-based study.

BACKGROUND: The purpose of the present study was to evaluate the value of discussing rectal cancer patients in a multidisciplinary team (MDT). METHODS: All treated rectal cancer patients (>T1M0) diagnosed in 2006-2008 were included. According to the national guidelines, neoadjuvant (chemo)radiotherapy should be given to all rectal cancer patients. Patients were scored as "discussed" (MDT+) only if documented proof was available. The primary endpoint was the number of positive circumferential resection margins (CRM ≤ 1 mm). RESULTS: Of the 275 patients included, 210 were analyzed (exclusions: (recto)sigmoid tumor, acute laparotomy, and inoperability). Neoadjuvant treatment was applied in 174 (83%) patients and followed by total mesorectal excision in 171 (81%) patients. Patients considered not to require downstaging, received short-course radiotherapy (SCRT) (n = 116) or no radiotherapy (no RT) (n = 36), whereas 58 more advanced patients received chemoradiotherapy (CRT). The MDT discussion took place in 116 cases (55%). In the MDT+ group an MRI was used more often (p = 0.001) and TNM staging was more complete (p < 0.001). The proportion of patients with advanced disease was higher in the MDT+ group (88% ≥T3/N+ versus 68%; p = 0.001). The overall CRM+ rate was 13% and did not differ between the MDT+ and the MDT- group (p = 0.392). In patients receiving SCRT or no RT, the CRM+ rate was 10%, whereas the rate was 20% for patients receiving CRT. CONCLUSIONS: Although no difference in CRM+ rate was found for those patients who were discussed and those who were not, our results demonstrate room for improvement, especially in the selection of patients for SCRT or no RT. We advocate standardized documentation of treatment decisions and pathology reports.

Long-term Emergency Department Visits and Readmissions After Laparoscopic Roux-en-Y Gastric Bypass: a Systematic Review.

PURPOSE: There is considerable evidence on short-term outcomes after laparoscopic Roux-en-Y gastric bypass (LRYGB), but data on long-term outcome is scarce, especially on postoperative emergency department (ED) visits and readmissions. We aim to systematically review evidence on the incidence, indications, and risk factors of ED visits and readmissions beyond 30 days after LRYGB. MATERIALS AND METHODS: A systematic search in PubMed, Scopus, Embase.com , Cochrane Library, and PsycINFO was performed. All studies reporting ED visits and readmissions > 30 days after LRYGB, with ≥ 50 patients, were included. PRISMA statement was used and the Newcastle-Ottawa Scale for quality assessment. RESULTS: Twenty articles were included. Six studies reported on ED visits (n = 2818) and 19 on readmissions (n = 276,543). The rate of patients with an ED visit within 90 days after surgery ranged from 3.9 to 32.6%. ED visits at 1, 2, and 3 years occurred in 25.6%, 30.0%, and 31.1% of patients. Readmissions within 90 days and at 1-year follow-up ranged from 4.1 to 20.5% and 4.75 to 16.6%, respectively. Readmission was 29% at 2 years and 23.9% at 4.2 years of follow-up. The most common reason for ED visits and readmissions was abdominal pain. CONCLUSION: Emergency department visits and readmissions have been reported in up to almost one in three patients on the long-term after LRYGB. Both are mainly indicated for abdominal pain. The report on indications and risk factors is very concise. A better understanding of ED visits and readmissions after LRYGB is warranted to improve long-term care, in particular for patients with abdominal pains.

Randomized clinical trial of an enhanced recovery after surgery programme versus conventional care in laparoscopic Roux-en-Y gastric bypass surgery.

Background: Enhanced recovery after surgery (ERAS) programmes have led to a decreased duration of hospital stay in several surgical fields, but have not been fully tested in patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) for obesity. This study aimed to investigate an ERAS programme versus standard care in these patients. Methods: Between January 2013 and July 2014, patients undergoing LRYGB were randomized to ERAS or conventional care. The primary outcome was functional hospital stay, defined as the time between end of surgery and when predefined discharge criteria (pain adequately controlled, fever and postoperative nausea and vomiting (PONV) absent, full liquid diet tolerated, mobilized and feeling fit for discharge) were met. Secondary outcomes were total length of hospital stay, 30-day complication and mortality rates, duration of surgery, time spent on the recovery ward and health-related quality of life. Results: A total 220 patients were randomized to ERAS (110 patients) or conventional (110) care. Patients in the ERAS group had shorter functional hospital stay (17·4 versus 20·5 h; P < 0·001), quicker pain control, tolerated liquid diet earlier, had earlier control of PONV, mobilized sooner and were comfortable with discharge sooner than those receiving conventional care. Total length of hospital stay, duration of surgery, time spent on the recovery ward, health-related quality of life, complication and readmission rates did not differ between the study groups. There were no deaths. Conclusion: Patients under ERAS care recovered faster after LRYGB surgery than those receiving conventional care, with no increase in readmission and postoperative morbidity rates. Registration number: NTR3853 (http://www.trialregister.nl/).

Sensitivity and Specificity of 50% Excess Weight Loss (50%EWL) and Twelve Other Bariatric Criteria for Weight Loss Success.

BACKGROUND: Criteria for bariatric weight loss success are numerous. Most of them are arbitrary. None of them is evidence-based. Our objective was to determine their sensitivity and specificity. METHODS: Thirteen common bariatric weight loss criteria were compared to a benchmark reflecting the gold standard in bariatric surgery. We used an elaborate baseline BMI-independent weight loss percentile chart, based on retrospective data after laparoscopic Roux-en-Y gastric bypass (LRYGB), performed between 2007 and 2017. Percentile curves p31.6 (patients' expectation), p25 (interquartile range), p15.9 (1 standard deviation (SD) below median), and p10.9 (surgeons' goal) were used as possible cutoff for success to determine true or false positive and negative results beyond 1 year. RESULTS: We operated 4497 primary LRYGB patients, with mean follow-up 22 (± 1 SD 19; range 0-109) months, 3031 patients with last result ≥ 1 year, 518 ≥ 5 years. For all four cutoff percentile curves for success, specificities were low (2-72%) for criteria < 35 body mass index (BMI), ≥ 25percentage excess BMI loss (%EBMIL), ≥ 50%EBMIL, ≥ 15 percentage total weight loss (%TWL), ≥ 20%TWL, ≥ 25 percentage excess weight loss (%EWL), and high (83-96%) for < 30 BMI. No criterion had > 80% specificity and sensitivity for a cutoff above p15.9. For p15.9, they were both > 80% for criteria ≥ 10 BMI reduction and ≥ 50%EWL, both > 90% for ≥ 25%TWL and ≥ 35 percentage alterable weight loss (%AWL). All criteria had high sensitivities for all cutoff percentile curves (87-100%), except < 30 BMI (65-78%). CONCLUSIONS: For the first time, common bariatric criteria for weight loss success were systematically validated. Most criteria recognized success very well (high sensitivities), but ≥ 15%TWL, ≥ 20%TWL, < 35BMI, ≥ 25%EWL, ≥ 25%EBMIL, and ≥ 50%EBMIL left too many poor responders unnoticed (low specificities). Bariatric weight loss success is best assessed by comparing results to percentile curve 1 SD below median (p15.9) in a bariatric baseline BMI-independent weight loss percentile chart. Criteria ≥ 35%AWL and ≥ 25%TWL came close to that curve, both with > 90% sensitivity and specificity. Among others, criterion ≥ 50%EBMIL did not.

Validating the alterable weight loss (AWL) metric with 2-year weight loss outcome of 500 patients after gastric bypass.

BACKGROUND: Percentage alterable weight loss (AWL) is the only known weight loss metric independent of the initial body mass index (BMI), a unique feature ideal for use in weight loss research. AWL was not yet validated. The aim of the study is to validate the AWL metric and to confirm advantages over the excess weight loss (EWL) metric. METHODS: AWL is tested with 2-year weight loss results of all primary laparoscopic Roux-en-Y gastric bypass patients operated in our hospital. Nadir results of patients with higher and lower initial BMI are compared (Mann-Whitney; p < 0.05) using outcome metrics BMI, percentage weight loss (WL), EWL, and AWL, for the whole group, for each gender, and for <40 and ≥40 years separately. RESULTS: Five-hundred patients (401 female) out of 508 (98.4 %) had 2-year follow-up. Of all four metrics, only AWL rendered results not significantly influenced by initial BMI. The AWL outcome is initial BMI independent for both genders and age-groups. Results also confirm that women and younger patients had significantly higher AWL outcome. CONCLUSION: The recently developed AWL metric, defined as 100% × (initialBMI - BMI) / (initialBMI - 13), is now validated. In contrast to the well-known outcome metrics BMI, EWL, and WL, the AWL metric is independent of the initial BMI. It should replace the misleading EWL metric for comparing weight loss results in bariatric research and for expressing the effectiveness of bariatric procedures. This effectiveness does not act on the total body mass, or on the excess part, but on the alterable part, defined as BMI minus 13 kg/m(2) for all adult patients, female, male, young, and old.