Interaction analysis of subgroup effects in randomized trials: the essential methodological points.

Subgroup analysis aims to identify subgroups (usually defined by baseline/demographic characteristics), who would (or not) benefit from an intervention under specific conditions. Often performed post hoc (not pre-specified in the protocol), subgroup analyses are prone to elevated type I error due to multiple testing, inadequate power, and inappropriate statistical interpretation. Aside from the well-known Bonferroni correction, subgroup treatment interaction tests can provide useful information to support the hypothesis. Using data from a previously published randomized trial where a p value of 0.015 was found for the comparison between standard and Hemopatch® groups in (the subgroup of) 135 patients who had hand-sewn pancreatic stump closure we first sought to determine whether there was interaction between the number and proportion of the dependent event of interest (POPF) among the subgroup population (patients with hand-sewn stump closure and use of Hemopatch®), Next, we calculated the relative excess risk due to interaction (RERI) and the "attributable proportion" (AP). The p value of the interaction was p = 0.034, the RERI was - 0.77 (p = 0.0204) (the probability of POPF was 0.77 because of the interaction), the RERI was 13% (patients are 13% less likely to sustain POPF because of the interaction), and the AP was - 0.616 (61.6% of patients who did not develop POPF did so because of the interaction). Although no causality can be implied, Hemopatch® may potentially decrease the POPF after distal pancreatectomy when the stump is closed hand-sewn. The hypothesis generated by our subgroup analysis requires confirmation by a specific, randomized trial, including only patients undergoing hand-sewn closure of the pancreatic stump after distal pancreatectomy.Trial registration: INS-621000-0760.

Meta-analysis of randomized clinical trials comparing robotic versus laparoscopic surgery for mid-low rectal cancers.

INTRODUCTION: Robotic surgery (RS) is experiencing major development, particularly in the context of rectal cancer. The aim of this meta-analysis was to summarize data from the literature, focusing specifically on the safety and effectiveness of robotic surgery in mid-low rectal cancers, based on the hypothesis that that robotic surgery can find its most rational indication in this anatomical location. METHOD: The meta-analysis was conducted according to the PRISMA 2000 recommendations, including all randomized trials that compared robotic surgery versus laparoscopic surgery (LS) that were found in the Medline-PICO, Cochrane Database, Scopus and Google databases. Data were extracted independently by two reviewers. The risk of bias was analyzed according to the Cochrane Handbook method and the certainty of the evidence according to the GRADE method. The analysis was carried out with R software Version 4.2-3 using the Package for Meta-Analysis "meta" version 6.5-0. RESULTS: Eight randomized trials were included (with a total of 2342 patients), including four that focused specifically on mid-low rectal cancer (n=1,734 patients). No statistically significant difference was found for overall morbidity, intra-operative morbidity, anastomotic leakage, post-operative mortality, quality of mesorectal specimen, and resection margins. The main differences identified were a lower conversion rate for RS (RR=0.48 [0.24-0.95], p=0.04, I2=0%), and a longer operative time for RS (mean difference=39.11min [9.39-68.83], p<0.01, I2=96%). The other differences had no real clinical relevance, i.e., resumption of flatus passage (5hours earlier after RS), and lymph node dissection (one more lymph node for LS). CONCLUSION: This meta-analysis does not confirm the initial hypothesis and does not show a statistically significant or clinically relevant benefit of RS compared to LS for mid-low rectal cancer.

Probiotics/Synbiotics to Reduce Infectious Complications after Colorectal Surgery: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

AIM: The aims of this systematic review and meta-analysis were to assess to what extent probiotics/synbiotics reduce infectious complications after colorectal surgery and whether probiotics or synbiotics should be considered as perioperative measures preventing or reducing infectious complications after CRS and should be included in enhanced recovery programmes (ERP). Secondary aims were to answer practical questions precisely on the best formulation and the type and timing of probiotics or synbiotics in CRS. METHOD: This systematic review and quantitative meta-analysis were conducted in accordance with PRISMA 2020 guidelines. Inclusion criteria were randomised trials comparing perioperative probiotics/synbiotics with a placebo or standard care in elective colorectal surgery. Exclusion criteria were non-randomised trials. Overall infectious complications and surgical site infections (SSIs including both deep abdominal infections and wound (skin or under the skin) infections) were the primary outcomes. Secondary outcomes were pulmonary and urinary infections, wound infections, and anastomotic leaks. The databases consulted were Medline, Cochrane Database of Systematic Reviews, Scopus, and Clinical Trials Register. Risk of bias was assessed according to the GRADE approach. The analysis calculated the random effects estimates risk ratio (RR) for each outcome. RESULTS: 21 trials were included; 15 evaluated probiotics, and 6 evaluated synbiotics. There were significantly fewer infectious complications (risk ratio (RR) 0.59 [0.47-0.75], I2 = 15%) and fewer SSI (RR 0.70 [0.52-0.95], I2 = 0%) in the probiotic or synbiotic group. There were also significantly fewer pulmonary infections (RR 0.35 [0.20-0.63]) and urinary infections RR 0.41 [0.19-0.87]) as opposed to anastomotic leaks (RR 0.83 [0.47-1.48]) and wound infections (RR 0.74 [0.53-1.03]). Sensitivity analyses showed no significant difference between probiotics and synbiotics in reducing postoperative infections (RR 0.55 [0.42-0.73] versus RR 0.69 [0.42-1.13], p = 0.46). CONCLUSIONS: Based on the finding of this study, probiotics/synbiotics reduce infectious complications after colorectal surgery. The effect size was more pronounced for pulmonary and urinary infections. From a practical aspect, some of the questions related to formulations and duration of probiotics or synbiotics need to be answered before including them definitively in enhanced recovery after colorectal surgery programmes.

Evaluation and acceptability of concept maps as a learning tool in medical studies.

BACKGROUND: the use of concept maps (CM) in medical studies has been largely reported in the literature. In our context, we used to promote case-based-teaching methods but students aren't used to construct CM. AIM: To evaluate the acceptability of using CM by the students and the reproducibility of 2 methods of scoring, a holistic and an analytic one, associated to a master map in order to assess them. METHODS: the authors supervised a 2-session-case-based-learning performed in a department of pathology. One case dealing with a real story about a colon cancer diagnosed in the musician Debussy (http://fr.wikipedia.org/wiki/Debussy) was adapted and presented to the students. At the end of the first session, the students were encouraged to construct collectively a concept map. At the end of the second session, the students were asked to fulfill a questionnaire about their acceptability of the learning process. Besides, two raters scored all the concept maps using 2 different scoring methods associated to a master map. The reproducibility of both scoring systems was evaluated using the kappa coefficient. RESULTS: 31 students were enrolled in this study with a mean age of 21 years. The raters evaluated 8 CM. The kappa coefficient reached a value of 1 in the holistic scoring and a value of 0.46 in the hierarchical scoring indicating respectively a very strong and a moderate agreement between evaluators. 15 students reported their satisfaction about the use of CM collectively. 10 students expressed their will to use CM individually, 17 students felt that using the CM collectively made them feel to belong to a group but without expressing their own knowledge and reflecting their progress. CONCLUSIONS: our study highlighted the acceptability of using concept maps in medical studies and the possibility of reaching valid and reproducible scoring methods especially when associating a master map.

Endogenous hyperinsulinism: diagnostic and therapeutic difficulties.

Endogenous hyperinsulinism is an abnormal clinical condition that involves excessive insulin secretion, related in 55% of cases to insulinoma. Other causes are possible such as islet cell hyperplasia, nesidioblastosis or antibodies to insulin or to the insulin receptor. Differentiation between these diseases may be difficult despite the use of several morphological examinations. We report six patients operated on for endogenous hyperinsulinism from 1st January 2000 to 31st December 2015. Endogenous hyperinsulinism was caused by insulinoma in three cases, endocrine cells hyperplasia in two cases and no pathological lesions were found in the last case. All patients typically presented with adrenergic and neuroglycopenic symptoms with a low blood glucose level concomitant with high insulin and C-peptide levels. Computed tomography showed insulinoma in one case out of two. MRI was carried out four times and succeeded to locate the lesion in the two cases of insulinoma. Endoscopic ultrasound showed one insulinoma and provided false positive findings three times out of four. Intra operative ultrasound succeeded to localize the insulinoma in two cases but was false positive in two cases. Procedures were one duodenopancreatectomy, two left splenopancreatectomy and two enucleations. For the sixth case, no lesion was radiologically objectified. Hence, a left blind pancreatectomy was practised but the pathological examination showed normal pancreatic tissue. Our work showed that even if morphological examinations are suggestive of insulinoma, other causes of endogenous hyperinsulinism must be considered and therefore invasive explorations should be carried out.