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Chatre L.,Institute Pasteur Paris | Chatre L.,French National Center for Scientific Research | Biard D.S.F.,French Atomic Energy Commission | Sarasin A.,University Paris - Sud | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

UV-sensitive syndrome (UVSS) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UVsS or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UVSS cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option. © 2015, National Academy of Sciences. All rights reserved.

Pailler E.,Institute Of Cancerologie Gustave Roussy
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

The diagnostic test for ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine-needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs). The presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter-adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib. All ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK-rearranged CTCs harbored a unique (3'5') split pattern, and heterogeneous patterns (3'5', only 3') of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib. ALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.

Crocetti L.,University of Pisa | De Baere T.,Institute Of Cancerologie Gustave Roussy | Lencioni R.,University of Pisa
CardioVascular and Interventional Radiology | Year: 2010

The development of image-guided percutaneous techniques for local tumour ablation has been one of the major advances in the treatment of liver malignancies. Among these methods, radiofrequency ablation (RFA) is currently established as the primary ablative modality at most institutions. RFA is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when liver transplantation or surgical resection are not suitable options [1, 2]. In addition, RFA is considered a viable alternate to surgery (1) for inoperable patients with limited hepatic metastatic disease, especially from colorectal cancer, and (2) for patients deemed ineligible for surgical resection because of extent and location of the disease or concurrent medical conditions [3]. These guidelines were written to be used in quality-improvement programs to assess RFA of HCC and liver metastases. The most important processes of care are (1) patient selection, (2) performing the procedure, and (3) monitoring the patient. The outcome measures or indicators for these processes are indications, success rates, and complication rates. © 2009 Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

Le Cesne A.,Institute Of Cancerologie Gustave Roussy
Expert Review of Anticancer Therapy | Year: 2013

Trabectedin (Yondelis® [PharmaMar S.A., Madrid, Spain]) is one of the most promising agents tested in the last two decades in patients with anthracycline/ifosfamide-resistant sarcomas and is the first agent highlighting the notion of prolonged tumor control in advanced soft tissue sarcoma. Indeed, the unusual pattern of tumor response to trabectedin has raised queries about the appropriateness of conventional radiological evaluation of efficacy according to Response Evaluation Criteria in Solid Tumors and has prompted the search for new end points for Phase II studies. The safety profile of trabectedin is unique and much more favorable than that of doxorubicin and ifosfamide especially as regards neutropenia and alopecia. Its efficacy in translocation-related sarcomas suggests a targeted approach to tumor control in these sarcoma subtypes. With numerous Phase II and III studies of trabectedin underway, it appears certain that the current standard-of-care paradigm in advanced soft tissue sarcoma is set for change. © 2013 2013 Expert Reviews Ltd.

Harel S.,Service dImmuno Hematologie | Ferme C.,Institute Of Cancerologie Gustave Roussy | Poirot C.,UF de Biologie de la Reproduction
Haematologica | Year: 2011

The risk of developing premature ovarian failure and azoospermia is a major concern in long-term survivors treated for Hodgkin's lymphoma. Alkylating chemotherapy containing procarbazine and/or cyclophosphamide causes prolonged azoospermia in 90-100% of men and premature ovarian failure in 5-25% of women under the age of 30. The risk of infertility increases with the cumulative dose of alkylating agents and the risk is high after salvage therapy including conditioning and autologous or allogeneic transplantation. The doxorubicin- bleomycin-vinblastine-dacarbazine regimen is associated with a lower risk of gonadal damage; the rate of infertility is less than 10%. The risk of premature ovarian failure is limited after the doxorubicin-bleomycin-vinblastine-dacarbazine regimen. However, age is an important factor; women over 30 years of age are at a much higher risk of ovarian failure. Semen cryopreservation should be routinely offered, especially before initial treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone or salvage therapy with high-dose chemotherapy and autologous transplantation. For women with a stable partner, in vitro fertilization for embryo cryopreservation is a routine procedure but can only be offered to a small number of patients and requires a delay in treatment initiation for at least four weeks. Cryopreservation of mature or immature oocytes remains experimental. Ovarian tissue cryopreservation is promising but has so far resulted in only a small number of pregnancies and births. This method, usually involving the removal of an entire ovary, is only proposed before treatment leading to a high risk of infertility. Analogs of LHRH were investigated in order to preserve fertility in women but are not recommended in the absence of studies demonstrating their effectiveness. The risk of secondary infertility should be discussed with patients from the time of the diagnosis and requires multidisciplinary collaboration between hematologists and Assisted Reproductive Techniques (ART) teams. ©2011 Ferrata Storti Foundation. This is an open-access paper.

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