Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

L’objectif de ce travail était la recherche de biomarqueurs moléculaires prédictifs de la tolérance et de l’efficacité des chimio– thérapies utilisées dans le colorectal (CCR) métastatique. Nous avons effectué le génotypage de 20 polymorphismes présents au sein de 9 gènes connus ou suspectés d’être impliqués dans la voie du 5FU, de l’oxaliplatine, ou de l’irinotécan, à partir de l’ADN extrait du sang de 346 patients traités dans le cadre d’un essai de phase III. Cet essai comparait une chimiothérapie séquentielle par 5FU (schéma LV5FU2) suivie d’une association 5FU plus oxali– platine (schéma FOLFOX) à une chimiothérapie combinée de type FOLFOX d’emblée en première ligne de traitement. Nous avons trouvé un risque de toxicité hématologique sévère sous FOLFOX significativement augmenté chez les patients porteurs de l’allèle ERCC2-K751QC. La présence de l’allèle TS-5’UTR3RG du gène de la thymidylate synthase était associée à un taux de réponse significativement plus élevé sous LV5FU2. Le taux de réponse au FOLFOX en 2e ligne était significativement supérieur chez les patients porteurs de l’allèle ERCC1-IVS3+74G, et chez ceux ayant au moins un allèle de GSTT1 présent. L’analyse prédictive a montré un effet dépendant du traitement de certains polymorphismes. En effet, une survie sans progression significativement allongée par l’ajout de l’oxaliplatine en 1re ligne a été observée uniquement chez les patients ayant un génotype TS-5’UTR2R/2R ou 2R/3R, suggérant l’absence de bénéfice d’une bithérapie par FOLFOX d’emblée en première ligne chez les patients TS-5’UTR3R/3R. Ces résultats montrent que l’étude des polymorphismes constitutionnels permettent de prédire non seulement la toxicité mais aussi l’efficacité des chimiothérapies antitumorales du cancer colorectal, et ainsi (sous réserve d’une validation sur une population indépendante) d’orienter la stratégie thérapeutique à l’échelle de l’individu

Are the interactions between neurodegenerative proteins and polymeric surfaces related to the hydrophilic and hydrophobic balance ?

In pres

Are the interactions between recombinant prion protein and polymeric surfaces related to the hydrophilic and hydrophobic balance ?

peer reviewedIn pres

Impact of single‐nucleotide polymorphisms in DNA repair pathway genes on response to chemoradiotherapy in rectal cancer patients: Results from ACCORD‐12/PRODIGE‐2 phase III trial

International audienceWe examined whether 66 germline single-nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD-12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose-intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (pinteraction = 0.05) and XPA rs3176683 (pinteraction = 0.008), suggesting a predictive effect for response to oxaliplatin-based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40-38.23], pinteraction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32-0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34-0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease-free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT

Design and Evaluation of Personalized Services to Foster Active Aging: The Experience of Technology Pre-Validation in Italian Pilots

Assistive devices could promote independent living and support the active and healthy aging of an older population; however, several factors can badly influence the long-term use of new technologies. In this context, this paper presents a two-step methodology called “pre-validation” that aims to identify the factors that can bias the use of new services, thus minimizing the risk of an unsuccessful longer trial. The proposed pre-validation methodology is composed of two main phases that aim to assess the usability and the reliability of the technology assessed in a laboratory environment and the usability, acceptability, user experience, and reliability of the technology in real environments. The tested services include the socialization scenario, in which older adults are better connected to the community via technological solutions (i.e., socialization applications), and the monitoring scenario, which allows for the introduction of timely interventions (technologies involved include environmental monitoring sensors, a telepresence robot, wearable sensors, and a personalized dashboard). The obtained results underline an acceptable usability level (average System Usability Scale score > 65) for the tested technologies (i.e., socialization applications and a telepresence robot). Phase Two also underlines the good acceptability, user experience, and usability of the tested services. The statistical analysis underlines a correlation between the stress related to the use of technology, digital skills, and intention of use, among other factors. Qualitative feedback also remarks on a correlation between older adults with low digital skills and an anxiety about using technology. Positive correlation indexes were highlighted between the trust and usability scores. Eventually, future long-term trials with assistive technology should rely on motivated caregivers, be founded on a strong recruitment process, and should reassure older adults—especially the ones with low digital literacy—about the use of technology by proposing personalized training and mentoring, if necessary, to increase the trust

Adipose Tissue Properties in Tumor-Bearing Breasts

International audienceThe tissue stroma plays a major role in tumors' natural history. Most programs for tumor progression are not activated as cell-autonomous processes but under the conditions of cross-talks between tumor and stroma. Adipose tissue is a major component of breast stroma. This study compares adipose tissues in tumor-bearing breasts to those in tumor-free breasts with the intention of defining a signature that could translate into markers of cancer risk. In tumor-bearing breasts, we sampled adipose tissues adjacent to, or distant from the tumor. Parameters studied included: adipocytes size and density, immune cell infiltration, vascularization, secretome and gene expression. Adipose tissues from tumor-bearing breasts, whether adjacent to or distant from the tumor, do not differ from each other by any of these parameters. By contrast, adipose tissues from tumor-bearing breasts have the capacity to secrete twice as much interleukin 8 (IL-8) than those from tumor-free breasts and differentially express a set of 137 genes of which a significant fraction belongs to inflammation, integrin and wnt signaling pathways. These observations show that adipose tissues from tumor-bearing breasts have a distinct physiological status from those from tumor-free breasts. We propose that this constitutive status contributes as a non-cell autonomous process to determine permissiveness for tumor growth