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Irinotecan is an anticancer drug with a broad spectrum of activity, characterized by multistep and complex pharmacology. Regardless of its schedule of administration, neutropenia and delayed-type diarrhea are the most common side effects. The latter was the dose-limiting toxicity in phase I trials, and its prediction by pharmacogenetic (UGT1A1*28/*28) testing remains sub-optimal. Recent studies have highlighted the important role of the intestinal bacterial β-glucuronidase (BGUS) in the onset of irinotecan-induced diarrhea. Intestinal BGUS hydrolyses glucuronidated metabolites to their toxic form in intestines, resulting in intestinal damage. BGUS selective inhibitors that are currently in development may alleviate irinotecan-induced diarrhea, and may help to reduce its morbidity and enhance its activity. The discussion and description of irinotecan pharmacology may generate ideas that form the basis of clinical trials focusing on a personalized approach to treatment. In addition, we hypothesize that using BGUS activity as a predictive biomarker of irinotecan-induced diarrhea severity will help to select cancer patients for treatment with irinotecan chemotherapy (whether at full or adapted dose).

Background and objectives: The net treatment effect ( increment ) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on increment estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC).Study design: Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported. Results: In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and increment . This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than increment was, but correction proposed by Pe & acute;ron to account for censored observations showed quite robust results.Conclusions: The net treatment effect using Pe & acute;ron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes. This work was partially funded by a French governmental grant from the Programme Hospitalier pour la Recherche Clinique (PHRC). The funder had no involvement neither in the data collection, design, analysis nor interpretation of the data. We are strongly indebted to the F ́ed ́eration Francophone de Canc ́erologie Digestive (FFCD) Group, the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group and Sanofi for providing individual patients data to the GASTRIC collaboration. The trials’ sponsors were not involved in the design, the analysis and interpretation of this contribution. We thank the GASTRIC collaboration for giving access to their data collection

International audience; Skin aging is a complex biological process mixing intrinsic and extrinsic factors, such as sun exposure. At the molecular level, skin aging affects in particular the extracellular matrix proteins. Materials and Methods: Using Raman imaging, which is a nondestructive approach appropriate for studying biological samples, we analyzed how aging modifies the matrix proteins of the papillary and reticular dermis. Biopsies from the buttock and dorsal forearm of volunteers younger than 30 and older than 60 were analyzed in order to identify chronological and photoaging processes. Analyses were performed on skin section, and Raman spectra were acquired separately on the different dermal layers. Results: We observed differences in dermal matrix structure and hydration state with skin aging. Chronological aging alters in particular the collagen of the papillary dermis, while photoaging causes a decrease in collagen stability by altering proline and hydroxyproline residues in the reticular dermis. Moreover, chronological aging alters glycosaminoglycan content in both dermal compartments. Conclusion: Alterations of the papillary and reticular dermal matrix structures during photo-and chronological aging were clearly depicted by Raman spectroscopy.