Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study

PrefHer revealed compelling and consistent patient preference for subcutaneous (s.c.) trastuzumab, regardless of delivery by single-use injection device or hand-held syringe. s.c. trastuzumab was well-tolerated and safety data, including immunogenicity, were consistent with previous reports. No new safety signals were identified compared with the known intravenous trastuzumab profile in early breast cance

Evaluation de l'association 5-fluoro-uracile-acide folinique-gemcitabine-oxaliplatine (folfu-gemox) chez des patients porteurs d'adénocarcinome de site primitif inconnu

Une polychimiothérapie comportant du 5-FU, de l'acide folinique, de la gemcitabine et de l'oxaliplatine (FOLFU-GEMOX) a été proposée à 16 patients Présentant un adénocarcinome de site primitif inconnu et suivi au CHU de Grenoble entre juin 1998 et juin 2003. Le taux de réponse objective est de 19% avec une durée médiane de réponse de 25 semaines. Le taux de réponse objective et de stabilisation est de 62%. La médiane de survie est de 11,5 mois. Comparé aux études de phase II actuelles, le taux de réponse objective est décevant mais la médiane de survie est plutôt satisfaisante. Par contre, la toxicité hématologique est marquée avec 56% des patients présentant une toxicité de grade 3-4, dont 37% de neutropénies grade 3-4. La toxicité globale du traitement est à l'origine de son arrêt prématuré chez 25% des patients. L'ensemble de ces résultats ne permet pas d'envisager des études plus approfondies sur le FOLFU-GEMOX, dans cette indication.FOLFU-GEMOX regimen (5-fluorouracil, folinic acid, gemcitabine, oxaliplatin) has been administrated to 16 patients with a diagnosis of adenocarcinoma of unknown primary site, since 1998 to 2003. Ten patients (62%) experienced an objective response or a stable disease. The median duration of OR+SD is 25 weeks. Median overall survival is 11.5 months. FOLFU-GEMOX is a toxic regimen with 56% of grade 3-4 hematologic toxicity (37% of grade 3-4 neutropenia) and 30% of grade 3-4 stomatitis. Four patients (25%) have stopped their treatment because of toxicity. Therefore, to our mind, FOLFU-GEMOX is not an effective treatment of adenocarcinoma of unknown primary site.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Monitoring Monoclonal Antibody Delivery in Oncology: The Example of Bevacizumab

Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/227 mg/L following the first dose administered, and 213+/2105 mg/L after the last (6 th) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therap

Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562 cells.

International audienceAs mitochondria play a key role in the commitment to cell death, we have investigated the mitochondrial consequences of resistance to doxorubicin (DOX) in K562 cells. We found that the permeability transition pore (PTP) inhibitor cyclosporine A (CsA) failed to inhibit PTP opening in the resistant clone. Moreover, the Ca2+ loading capacity in the resistant clone was identical to that observed in the parent cells in the presence of CsA, suggesting that the PTP was already inhibited in a CsA-like manner in the resistant cells. In agreement with this proposal, the mitochondrial target of CsA cyclophilin D (CyD) decreased by half in the resistant cells. The levels of adenine nucleotide translocator, voltage anion-dependent channel, Bax, Bcl-2, Bcl-xL, AIF and Smac/Diablo, were similar in both cell lines, whereas cytochrome c content was divided by three in the resistant cells. Since P-glycoprotein inhibition did not restore DOX toxicity in the resistant cells, while DOX-induced cell death in the parent cells was prevented by either PTP inhibition or siRNA-induced decrease in cytochrome c content, we conclude that the inhibition of PTP opening and the decrease in cytochrome c content participate in the mechanism that makes K562 cells resistant to DOX

Rotenone inhibits the mitochondrial permeability transition-induced cell death in U937 and KB cells.

International audienceThe permeability transition pore (PTP) is a mitochondrial inner membrane Ca(2+)-sensitive channel that plays a key role in different models of cell death. Because functional links between the PTP and the respiratory chain complex I have been reported, we have investigated the effects of rotenone on PTP regulation in U937 and KB cells. We show that rotenone was more potent than cyclosporin A at inhibiting Ca(2+)-induced PTP opening in digitonin-permeabilized cells energized with succinate. Consistent with PTP regulation by electron flux through complex I, the effect of rotenone persisted after oxidation of pyridine nucleotides by duroquinone. tert-butyl hydroperoxide induced PTP opening in intact cells (as shown by mitochondrial permeabilization to calcein and cobalt), as well as cytochrome c release and cell death. All these events were prevented by rotenone or cyclosporin A. These data demonstrate that respiratory chain complex I plays a key role in PTP regulation in vivo and confirm the importance of PTP opening in the commitment to cell death

Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers

Abstract Background In breast cancer, as in all cancers, genetic and epigenetic deregulations can result in out-of-context expressions of a set of normally silent tissue-specific genes. The activation of some of these genes in various cancers empowers tumours cells with new properties and drives enhanced proliferation and metastatic activity, leading to a poor survival prognosis. Results In this work, we undertook an unprecedented systematic and unbiased analysis of out-of-context activations of a specific set of tissue-specific genes from testis, placenta and embryonic stem cells, not expressed in normal breast tissue as a source of novel prognostic biomarkers. To this end, we combined a strict machine learning framework of transcriptomic data analysis, and successfully created a new robust tool, validated in several independent datasets, which is able to identify patients with a high risk of relapse. This unbiased approach allowed us to identify a panel of five biomarkers, DNMT3B, EXO1, MCM10, CENPF and CENPE, that are robustly and significantly associated with disease-free survival prognosis in breast cancer. Based on these findings, we created a new Gene Expression Classifier (GEC) that stratifies patients. Additionally, thanks to the identified GEC, we were able to paint the specific molecular portraits of the particularly aggressive tumours, which show characteristics of male germ cells, with a particular metabolic gene signature, associated with an enrichment in pro-metastatic and pro-proliferation gene expression. Conclusions The GEC classifier is able to reliably identify patients with a high risk of relapse at early stages of the disease. We especially recommend to use the GEC tool for patients with the luminal-A molecular subtype of breast cancer, generally considered of a favourable disease-free survival prognosis, to detect the fraction of patients undergoing a high risk of relapse

Patient characteristics.

<p>Serum bevacizumab concentrations were determined at the plateau (70 days; values labeled with an asterisk correspond to 56 days). M: Male; F: Female.</p

Evolution of blood bevacizumab concentrations over the first 3 months of treatment.

<p>Points represent the mean bevacizumab concentrations for the 17 patients (+/− SD).The dotted line corresponds to the theoretical bevacizumab concentration in a 70-kg patient, with treatment by 7 repeat administrations of 10 mg/kg every other week. The theoretical value was calculated using the bevacizumab half-life reported by Roche-Genentech (20 days).</p

Additional file 2 of Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers

Additional file 2: Table S1. List of genes with predominant expression in testis, placenta and/or embryonic stem cells. Table S2. Frequencies of ectopic activations of the tissue-specific genes. Table S3. Results of the validation step in the biomarker discovery pipeline. Table S4. Datasets of normal tissues and breast cancers with corresponding sample sizes. Table S5. List of normal tissues and the corresponding sample sizes