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Passot G.,University of Lyon | Passot G.,The Surgical Center | Dupre A.,Center Leon Berard Lyon | Rivoire M.,Center Leon Berard Lyon | And 5 more authors.
Clinical and Translational Oncology | Year: 2012

Introduction: Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is currently the only potentially curative treatment for peritoneal carcinomatosis (PC). Systemic administration of bevacizumab improves survival in patients with metastatic colorectal or ovarian cancer. Intraperitoneal administration of bevacizumab has been shown to be safe and effective in treating malignant ascites. The combination of CRS with intraperitoneal (IP) bevacizumab could maximize local control and survival from PC, but the associated morbidity from this is unknown. The aim of this study was to evaluate the safety of the combination of CRS with IP bevacizumab and to determine the pharmacokinetics of the drug in a rabbit model. Methods: Twenty healthy rabbits underwent a standardized procedure of debulking surgery, including peritonectomy and gastrointestinal anastomosis and were randomized to receive IP bevacizumab (25 mg/kg) or placebo. Another group of three rabbits underwent an instillation of IP bevacizumab (25 mg/kg) without surgery. Results: One rabbit that received IP bevacizumab died with no complication associated with the use of bevacizumab at autopsy. There was no significant difference between IP bevacizumab and placebo in weight loss, length of surgery or morbidity. The plasma concentration of bevacizumab increased to a peak at 24 h post IP administration. Bevacizumab was not detected in the plasma of animals without surgery. Conclusion: This study suggests that IP bevacizumab does not increase morbidity and mortality of debulking surgery in an animal model. When surgery is performed, the pharmacokinetics of IP bevacizumab are modified in plasma. © 2012 Federación de Sociedades Españolas de Oncología (FESEO). Source

Fayet Y.,Jean Moulin University Lyon 3 | Fayet Y.,EA Sante Individu Societe | Chasles V.,Jean Moulin University Lyon 3 | Ducimetiere F.,EA Sante Individu Societe | And 12 more authors.
Bulletin du Cancer | Year: 2014

Rare cancer issues have not been much explored yet because of their low incidence. That is why epidemiological studies have difficulties in identifying indisputable etiological risk factors. An expert opinion, mainly concentrated in some establishments, is required for these cancers' management. However, on account of the potential remoteness of these therapeutic resources, the patients' way of care remains also unstudied. By means of a geographical analysis of a regional exhaustive cohort of sarcoma, diagnosed in 2006 and 2007 and followed during five years at least, we can make progress on these different issues. Gastro-Intestinal and Stromal Tumors (GIST) occur more frequently in privileged territories while liposarcomas arise in more deprived areas. The association between liposarcomas and areas deprivation is significant (P=0.05). Moreover, pre-operative biopsy and some clinical patient characteristics, age, grade or tumor localization, are associated with an increase in the distance covered by patients for the first-line treatment (p ≤ 0,001). In the scope of an interdisciplinary collaboration, the geographical approach develops some hypothesis for rare cancers research, which must be tested by other larger scale studies. ©John Libbey Eurotext. Source

El Abed R.,University of Sousse | Bourdon V.,Institute Paoli Calmettes | Voskoboinik I.,Peter MacCallum Cancer Center | Omri H.,Service dHematologie Clinique | And 19 more authors.
Hereditary Cancer in Clinical Practice | Year: 2011

Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein. © 2011 El Abed et al; licensee BioMed Central Ltd. Source

Angevin E.,Institute Of Cancerologie Gustave Roussy | Tabernero J.,Autonomous University of Barcelona | Elez E.,Autonomous University of Barcelona | Cohen S.J.,Fox Chase Cancer Center | And 18 more authors.
Clinical Cancer Research | Year: 2014

Purpose: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors. Experimental Design: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks. Results: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed. Conclusions: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks. © 2014 American Association for Cancer Research. Source

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