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Hu M.I.,University of Houston | Glezerman I.G.,Sloan Kettering Cancer Center | Leboulleux S.,Institute Gustave Roussy | Insogna K.,Yale University | And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Hypercalcemia of malignancy (HCM) in patients with advanced cancer is often caused by excessive osteoclast-mediated bone resorption. Patients may not respond to or may relapse after iv bisphosphonate therapy. CopyrightObjective: We investigated whether denosumab, a potent inhibitor of osteoclast-mediated bone resorption, reduces serum calcium in patients with bisphosphonate-refractory HCM. Design, Setting, and Participants: In this single-arm international study, participants had serum calcium levels corrected for albumin (CSC) >12.5 mg/dL (3.1 mmol/L) despite bisphosphonates given >7 and ≤30 days before screening.Intervention: Patients received 120 mg sc denosumab on days 1, 8, 15, and 29 and then every 4 weeks.Main Outcome Measures: The primary endpoint was the proportion of patients with CSC ≤11.5 mg/dL (2.9 mmol/L) (response) by day 10. Secondary endpoints included response by visit, duration of response, and the proportion of patients with a complete response (CSC ≤10.8 mg/dL [2.7 mmol/L]) by day 10 and during the study.Results: Patients (N = 33) had solid tumors or hematologic malignancies. By day 10, 21 patients (64%) reachedCSC≤11.5 mg/dL,and12 patients (33%) reachedCSC≤10.8 mg/dL. During the study, 23 patients (70%) reached CSC ≤11.5 mg/dL, and 21 patients (64%) reached CSC ≤10.8 mg/dL. Estimated median response duration was 104 days. The most common serious adverse events were hypercalcemia worsening (5 patients, 15%) and dyspnea (3 patients, 9%).Conclusions: In patients with HCM despite recent iv bisphosphonate treatment, denosumab lowered serum calcium in64%of patients within 10 days, inducing durable responses.Denosumabmay offer a new treatment option for HCM. © 2014 by the Endocrine Society. Source


Patent
French Institute of Health, Medical Research, Institute Regional Du Cancer Of Montpellier Val Daurelle, Montpellier University and Oribase Pharma | Date: 2012-06-22

The present invention relates to anti-Axl antibodies and uses thereof in diagnostic and therapeutic methods. More particularly, the present invention relates to a monoclonal antibody having specificity for Axl comprising an heavy chain variable region comprising SEQ ID NO:2 in the H-CDR1 region, SEQ ID NO:3 in the H-CDR2 region and SEQ ID NO:4 in the H-CDR3 region; and a light chain variable region comprising SEQ ID NO: 6 in the L-CDR1 region, SEQ ID NO:7 in the L-CDR2 region and SEQ ID NO:8 in the L-CDR3 region. Said monoclonal antibody binds to the extracellular domain of Axl via, SEQ ID NO:9 and SEQ ID NO: 10.


Parisot S.,Ecole Centrale Paris | Parisot S.,French Institute for Research in Computer Science and Automation | Parisot S.,Intrasense SAS | Parisot S.,Imperial College London | And 15 more authors.
PLoS ONE | Year: 2016

Diffuse WHO grade II gliomas are diffusively infiltrative brain tumors characterized by an unavoidable anaplastic transformation. Their management is strongly dependent on their location in the brain due to interactions with functional regions and potential differences in molecular biology. In this paper, we present the construction of a probabilistic atlas mapping the preferential locations of diffuse WHO grade II gliomas in the brain. This is carried out through a sparse graph whose nodes correspond to clusters of tumors clustered together based on their spatial proximity. The interest of such an atlas is illustrated via two applications. The first one correlates tumor location with the patient's age via a statistical analysis, highlighting the interest of the atlas for studying the origins and behavior of the tumors. The second exploits the fact that the tumors have preferential locations for automatic segmentation. Through a coupled decomposed Markov Random Field model, the atlas guides the segmentation process, and characterizes which preferential location the tumor belongs to and consequently which behavior it could be associated to. Leave-one-out cross validation experiments on a large database highlight the robustness of the graph, and yield promising segmentation results. © 2016 Parisot et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Patent
French Institute of Health, Medical Research, French National Center for Scientific Research, Aix - Marseille University, Montpellier University, Institute Regional Du Cancer Of Montpellier Val Daurelle and Institute Paoli Calmettes | Date: 2015-09-16

The invention concerns antibody formats comprising VHsequence of Camelidae, such as llamas; antibodies of various formats have anti-CEA or anti-CD16 VH sequences thereof; vectors expressing the antibody formats, and methods for producing the same.


Conroy T.,Institut Universitaire de France | Galais M.-P.,Center Francois Baclesse | Raoul J.-L.,Center Eugene Marquis | Bouche O.,Center Hospitalier University Robert Debre | And 13 more authors.
The Lancet Oncology | Year: 2014

Background: Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer. Methods: We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I-IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0-2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m2 per day for 4 days and cisplatin 75 mg/m2 on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094. Findings: 134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9-36·4). Median progression-free survival was 9·7 months (95% CI 8·1-14·5) in the FOLFOX group and 9·4 months (8·1-10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70-1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil-cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin-fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group. Interpretation: Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery. Funding: UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer. © 2014 Elsevier Ltd. Source

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