A phase I clinical and pharmacological study evaluating vinflunine in combination with doxorubicin as first line treatment in metastatic breast cancer

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluatio

Gametogenesis in the Pacific Oyster Crassostrea gigas: A Microarrays-Based Analysis Identifies Sex and Stage Specific Genes

Background: The Pacific oyster Crassostrea gigas (Mollusca, Lophotrochozoa) is an alternative and irregular protandrous hermaphrodite: most individuals mature first as males and then change sex several times. Little is known about genetic and phenotypic basis of sex differentiation in oysters, and little more about the molecular pathways regulating reproduction. We have recently developed and validated a microarray containing 31,918 oligomers (Dheilly et al., 2011) representing the oyster transcriptome. The application of this microarray to the study of mollusk gametogenesis should provide a better understanding of the key factors involved in sex differentiation and the regulation of oyster reproduction. Methodology/Principal Findings: Gene expression was studied in gonads of oysters cultured over a yearly reproductive cycle. Principal component analysis and hierarchical clustering showed a significant divergence in gene expression patterns of males and females coinciding with the start of gonial mitosis. ANOVA analysis of the data revealed 2,482 genes differentially expressed during the course of males and/or females gametogenesis. The expression of 434 genes could be localized in either germ cells or somatic cells of the gonad by comparing the transcriptome of female gonads to the transcriptome of stripped oocytes and somatic tissues. Analysis of the annotated genes revealed conserved molecular mechanisms between mollusks and mammals: genes involved in chromatin condensation, DNA replication and repair, mitosis and meiosis regulation, transcription, translation and apoptosis were expressed in both male and female gonads. Most interestingly, early expressed male-specific genes included bindin and a dpy-30 homolog and female-specific genes included foxL2, nanos homolog 3, a pancreatic lipase related protein, cd63 and vitellogenin. Further functional analyses are now required in order to investigate their role in sex differentiation in oysters. Conclusions/Significance: This study allowed us to identify potential markers of early sex differentiation in the oyster C. gigas, an alternative hermaphrodite mollusk. We also provided new highly valuable information on genes specifically expressed by mature spermatozoids and mature oocytes

Francis turbine draft tube modelling for prediction of pressure fluctuations on prototype

The prediction of pressure fluctuations amplitudes on Francis turbine prototype is a challenge for hydro-equipment industry since it is subjected to guarantees to ensure smooth and reliable operation of the hydro units. The European FP7 research project Hyperbole aims to setup a methodology to transpose the pressure fluctuations measured on the reduced scale model to the prototype generating units. This paper presents this methodology which relies on an advanced modelling of the draft tube cavitation flow, and focuses on the transposition to the prototype of the draft tube model parameters identified on the reduced scale model. Different modelling assumptions of the draft tube are considered and their influence on the eigenmodes and the forced response of the system are presented

Experimental investigation of the mass flow gain factor in a draft tube with cavitation vortex rope

At off-design operating operations, cavitating flow is often observed in hydraulic machines. The presence of a cavitation vortex rope may induce draft tube surge and electrical power swings at part load and full load operations. The stability analysis of these operating conditions requires a numerical pipe model taking into account the complexity of the two-phase flow. Among the hydroacoustic parameters describing the cavitating draft tube flow in the numerical model, the mass flow gain factor, representing the mass excitation source expressed as the rate of change of the cavitation volume as a function of the discharge, remains difficult to model. This paper presents a quasi-static method to estimate the mass flow gain factor in the draft tube for a given cavitation vortex rope volume in the case of a reduced scale physical model of a ν = 0.27 Francis turbine. The methodology is based on an experimental identification of the natural frequency of the test rig hydraulic system for different Thoma numbers. With the identification of the natural frequency, it is possible to model the wave speed, the cavitation compliance and the volume of the cavitation vortex rope. By applying this new methodology for different discharge values, it becomes possible to identify the mass flow gain factor and improve the accuracy of the system stability analysis

Curative treatment can be an option for patients with metastatic squamous cell cancer of the head and neck

Clémence Guenne,1 Jérôme Fayette,2 Alain Cosmidis,1 Carine Fuchsmann,1 Sophie Tartas,3 Véronique Favrel,4 Philippe Céruse1 1Head and Neck Surgery Department, Lyon-I University, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; 2Medicine Department, Lyon-I University, Centre Léon Bérard, Lyon, France; 3Medical Oncology Department, Lyon-I University, Hospices Civils de Lyon, Lyon Sud Hospital, 4Radiotherapy Department, Lyon-I University, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France Background: No specific study has focused on patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) at diagnosis. Due to high response rates of induction chemotherapy in chemo-naïve patients with localized disease, their prognosis should be better than patients with recurrent disease.Methods: From January 1, 2008 to July 1, 2012, we retrospectively collected all patients’ records with SCCHN diagnosed as metastatic. Patients, disease, treatment and its results were analyzed. Survival was calculated using the Kaplan–Meier method.Results: Of the 749 new patients treated for SCCHN in our institution, 16 (2.1%) were metastatic at diagnosis, of whom five had cytological results to prove it. Six patients died before treatment or had palliative care and ten received initial chemotherapy and then surgery and/or radiotherapy according to the primary response. Four patients treated with first-line chemotherapy with docetaxel-5FU-cisplatin (TPF) showed a complete response of metastatic lesions allowing locoregional treatment. The overall survival at 1 year and 3 years was 50% and 24%, respectively. The median survival was 7 months (1–72 months). Seven patients (43.7%) had a higher survival at 12 months, including five (31.5%) who are still alive without recurrence with a mean follow-up of 30 months. There was a significant difference in overall survival (P<0.01) between patients who had chemotherapy with TPF versus other therapeutic protocols. The median survival of patients with lung metastases only was 15 months (1–72 months), significantly higher than that of patients with liver and/or bone localizations, which was 2 months (1–9 months).Conclusion: Patients with metastatic SCCHN treated by TPF followed by multimodal treatment could achieve long survival. Keywords: squamous cell carcinoma, head and neck, metastases, TPF, cetuxima