Incidental findings in a series of 2500 gene panel tests for a genetic predisposition to cancer: Results and impact on patients.

With next generation sequencing, physicians are faced with more complex and uncertain data, particularly incidental findings (IF). Guidelines for the return of IF have been published by learned societies. However, little is known about how patients are affected by these results in a context of oncogenetic testing. Over 4 years, 2500 patients with an indication for genetic testing underwent a gene cancer panel. If an IF was detected, patients were contacted by a physician/genetic counsellor and invited to take part in a semi-structured interview to assess their understanding of the result, the change in medical care, the psychological impact, and the transmission of results to the family. Fourteen patients (0.56%) were delivered an IF in a cancer predisposition gene (RAD51C, PMS2, SDHC, RET, BRCA2, CHEK2, CDKN2A, CDH1, SUFU). Two patients did not collect the results and another two died before the return of results. Within the 10 patients recontacted, most of them reported surprise at the delivery of IF, but not anxiety. The majority felt they had chosen to obtain the result and enough information to understand it. They all initiated the recommended follow-up and did not regret the procedure. Information regarding the IF was transmitted to their offspring but siblings or second-degree relatives were not consistently informed. No major adverse psychological events were found in our experience. IF will be inherent to the development of sequencing, even for restricted gene panels, so it is important to increase our knowledge on the impact of such results in different contexts.

Human hepatic cell uptake of resveratrol: involvement of both passive diffusion and carrier-mediated process.

This work reports significant advances on the transport in hepatic cells of resveratrol, a natural polyphenol with potent protective properties. First, we describe a new simple technique to qualitatively follow resveratrol cell uptake and intracellular distribution, based on resveratrol fluorescent properties. Second, the time-course study and the quantification of (3)H-labelled resveratrol uptake have been performed using human hepatic derived cells (HepG2 tumor cells) and hepatocytes. The temperature-dependence of the kinetics of uptake as well as the cis-inhibition experiments agree with the involvement of a carrier-mediated transport in addition to passive diffusion. The decrease of passive uptake resulting from resveratrol binding to serum proteins brings to light a mediated mechanism in physiological situation.

Long-term survival of immunocompetent rats with intraperitoneal colon carcinoma tumors using herpes simplex thymidine kinase/ganciclovir and IL-2 treatments.

We evaluated the gain in long-term survival of BDIX rats bearing DHDProB colon cancer developed in the peritoneal cavity after in vivo therapy with the tk gene and GCV. The sensitivity and the bystander effect of DHDProB cells stably transduced with the tk gene evaluated in vitro were low, as one tk+ cell killed two tk- cells. This correlated with the low ability of a fluorescent dye to diffuse through gap junctions. In vivo, more than 75% of tk-transduced cells were required and at least 100 mg/kg/day of GCV had to be injected no later than day 5 after tumor implantation to obtain a curative effect. A partial protection of the cured animals against rechallenge with the parental cells was also observed. Based on these results, a protocol of in vivo gene therapy was designed in which the tk/GCV treatment was combined with IL-2 gene expression. When the tk- and IL-2 encoding plasmids were injected twice i.p. with DOTAP and the animals treated with GCV, three of five rats were cured. This antitumoral activity resulted from the combined toxic effects of DNA/DOTAP and tk/GCV plus a potential immune response mediated by IL-2.