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Dupuis J.,Henri Mondor University Hospital | Morschhauser F.,Claude Huriez University Hospital | Ghesquieres H.,Leon Berard Cancer Center | Tilly H.,Henri Becquerel Cancer Center | And 14 more authors.
The Lancet Haematology | Year: 2015

BACKGROUND: Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease. METHODS: We enrolled patients aged 18-80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 40 mg/m2 on days 1-5) in association with varying doses of romidepsin. The starting dose was 10 mg/m2 intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526. FINDINGS: Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m2 had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m2 of romidepsin, an additional three at 10 mg/m2 (one dose-limiting toxicity), and six patients at 12 mg/m2 (three dose-limiting toxicities). We chose romidepsin 12 mg/m2 as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3-4 neutropenia, and 29 (78%) had grade 3-4 thrombocytopenia. INTERPRETATION: Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial. FUNDING: Celgene. © 2015 Elsevier Ltd. All rights reserved.


PubMed | University of Lille Nord de France, Hopital Jeanne de Flandre, Oscar Lambret Cancer Center, Claude Huriez University Hospital and Clinical Research Unit
Type: | Journal: Critical reviews in oncology/hematology | Year: 2016

Few reports describe how adverse events (AEs) are reported in cancer surgery trials.We systematically reviewed 179 consecutive study reports issued between January 1, 1990 and November 15, 2014, which investigated surgery in oesophago-gastric (OG) or gynecologic (GY) cancer patients. Based on the reviewed reports, we assessed how AEs were reported according to CONSORT statement.Morbidity assessment was the primary objective of 56 studies (31.3%). Postoperative AEs were described in 161 studies (90%). Definition of AEs and grading scale (NCI-CTC AE, Dindo-Clavien scale, etc ) were given in 27.3% and 16.8% of studies, respectively. AEs were reported by event and grade in 8.3% of studies. Definition of expectedness, seriousness, causality and safety population were present in 0.5%, 1.1%, 7.8%, and 7.2% of the studies, respectively. Reporting of AEs did not improve over time nor better in high-impact factor journals.The reporting of AEs in cancer trials investigating surgery needs to be improved.


PubMed | Brest University Hospital Center, University of Lyon, Claude Huriez University Hospital, Haut Leveque University Hospital and 3 more.
Type: Journal Article | Journal: The British journal of surgery | Year: 2016

The benefit of neoadjuvant chemotherapy (NCT) for early-stage oesophageal cancer is unknown. The aim of this study was to assess whether NCT improves the outcome of patients with stage I or II disease.Data were collected from 30 European centres from 2000 to 2010. Patients who received NCT for stage I or II oesophageal cancer were compared with patients who underwent primary surgery with regard to postoperative morbidity, mortality, and overall and disease-free survival. Propensity score matching was used to adjust for differences in baseline characteristics.Of 1173 patients recruited (181 NCT, 992 primary surgery), 651 (555 per cent) had clinical stage I disease and 522 (445 per cent) had stage II disease. Comparisons of the NCT and primary surgery groups in the matched population (181 patients in each group) revealed in-hospital mortality rates of 44 and 55 per cent respectively (P=0660), R0 resection rates of 917 and 867 per cent (P=0338), 5-year overall survival rates of 477 and 386 per cent (hazard ratio (HR) 068, 95 per cent c.i. 049 to 093; P=0016), and 5-year disease-free survival rates of 449 and 361 per cent (HR 068, 050 to 093; P=0017).NCT was associated with better overall and disease-free survival in patients with stage I or II oesophageal cancer, without increasing postoperative morbidity.


Bouvet E.,Purpan University Hospital | Borel C.,Purpan University Hospital | Oberic L.,Purpan University Hospital | Compaci G.,Purpan University Hospital | And 4 more authors.
Haematologica | Year: 2013

Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabine-cyclophosphamide-rituximab relative dose intensity may have an impact on outcome has not yet been investigated. We retrospectively assessed relative dose intensity in 106 communitybased patients included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide- rituximab as first-line treatment outside clinical trials. Dose reductions were observed in 51.4% of patients, mainly decided by the individual physician and not based on recommendations (52.7%), while there were fewer reports of toxicity or dose reduction because of impaired renal function. Progression-free survival was significantly reduced in patients who had a reduction in dose intensity of more than 20% in fludarabinecyclophosphamide and/or rituximab. Multivariate analysis showed dose of rituximab had a significant impact on minimal residual disease and progression-free survival. Although prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. This study shows that, in routine clinical practice, there is low adherence to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule, and that the decision to modify dosage was mostly taken by the individual physician and was based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interferes with progression-free survival. ©2013 Ferrata Storti Foundation.


Rossignol J.,Claude Huriez University Hospital | Michallet A.-S.,University of Lyon | Oberic L.,Purpan University Hospital | Picard M.,Purpan University Hospital | And 6 more authors.
Leukemia | Year: 2011

We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders (AIDs) in 48 chronic lymphocytic leukemia (CLL) patients. Overall, 81% of patients were relapsing for AID after previous treatment with corticosteroids, splenectomy, rituximab or alemtuzumab. Diagnosis of AID was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenia (AITP) in 9 (18.8%), Evan's syndrome in 8 (16.7%) and pure red cell aplasia (PRCA) in 5 patients (10.5%). Median time of autoimmune disorder (AID) onset from CLL diagnosis was 60 months (range: 0-240), and CLL was considered progressive in 40% of subjects upon AID diagnosis (complex AID). Median hemoglobin pre-treatment was 7.7 g/100 ml, and median platelet count 36.5 × 109 /l, returning to a median of 12.5 /100ml and 37.5 × 109 /l, respectively. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). Median duration of response for autoimmunity (DR-AI) was 24 months, but DR-AI was higher for patients presenting: (1) AID early during CLL course (3 years), or (2) both PRCA and AIHA. Median time to CLL progression in 48 patients was 16 months, but this time was statistically shorter for Evan's syndrome and AITP patients as compared with AIHA and PRCA patients. This study emphasizes the relevance of CLL-directed immune chemotherapy in the management of CLL-associated AID. © 2011 Macmillan Publishers Limited All rights.


Michallet A.-S.,University of Lyon | Michallet A.-S.,Center Hospitalier Lyon Sud | Rossignol J.,Claude Huriez University Hospital | Cazin B.,Claude Huriez University Hospital | Ysebaert L.,Purpan University Hospital
Leukemia and Lymphoma | Year: 2011

We report our experience on rituximab-cyclophosphamide-dexamethasone (RCD) combination therapy for the treatment of autoimmune disorders in 48 patients with chronic lymphocytic leukemia (CLL). The diagnosis of autoimmune disease (AID) was autoimmune hemolytic anemia (AIHA) in 26 (54%), autoimmune thrombocytopenic purpura (AITP) in nine (18.8%), Evans syndrome in eight (16.7%), and pure red cell anemia (PRCA) in five patients (10.5%). CLL was considered progressive in 0% of subjects upon AID diagnosis. Overall, an 89.5% response rate was obtained with this combination, irrespective of the AID type. Relapse occurred in 19 patients (39.6%). The median duration of autoimmunity was 24 months, but the duration of response of autoimmunity (DR-AI) was higher for patients presenting with: (1) AID early during the CLL course (<3 years), or (2) both and pure red cell aplasia (PRCA) in five patients (10.5%) and AIHA. © 2011 Informa UK, Ltd.


Komorowski M.,European Astronaut Center | Watkins S.D.,NASA | Lebuffe G.,Claude Huriez University Hospital | Clark J.B.,Baylor College of Medicine
Aviation Space and Environmental Medicine | Year: 2013

In spaceflight beyond low Earth ' s orbit, medical conditions requiring surgery are of a high level of concern because of their potential impact on crew health and mission success. Whereas surgical techniques have been thoroughly studied in spaceflight analogues, the research focusing on anesthesia is limited. To provide safe anesthesia during an exploration mission will be a highly challenging task. The research objective is thus to describe specific anesthesia procedures enabling treatment of pre-identified surgical conditions. Among the medical conditions considered by the NASA Human Research Program Exploration Medical Capability element, those potentially necessitating anesthesia techniques have been identified. The most appropriate procedure for each condition is thoroughly discussed. The substantial cost of training time necessary to implement regional anesthesia is pointed out. Within general anesthetics, ketamine combines the unique advantages of preservation of cardiovascular stability, the protective airway reflexes, and spontaneous ventilation. Ketamine side effects have for decades tempered enthusiasm for its use, but recent developments in mitigation means broadened its indications. The extensive experience gathered in remote environments, with minimal equipment and occasionally by insufficiently trained care providers, confirms its high degree of safety. Two ketamine-based anesthesia protocols are described with their corresponding indications. They have been designed taking into account the physiological changes occurring in microgravity and the specific constraints of exploration missions. This investigation could not only improve surgical care during long-duration spaceflights, but may find a number of terrestrial applications in isolated or austere environments. © by the Aerospace Medical Association, Alexandria, VA.


PubMed | Saint Antoine Hospital, University of Lyon, Claude Huriez University Hospital, Gustave Roussy Institute Villejuif and 4 more.
Type: Journal Article | Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association | Year: 2016

The prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, and the utility of perioperative chemotherapy for such a tumor has been questioned . This study was performed to assess the impact of the SRC type on survival following resection of gastric adenocarcinoma, and to assess whether the prognostic factors (including perioperative chemotherapy) for non-SRC adenocarcinoma differed from those for SRC adenocarcinoma.1799 cases of adenocarcinoma that were consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors, and a modified D2 for upper tumors. SRC adenocarcinoma was diagnosed based on the presence of isolated carcinoma cells containing mucin.A total gastrectomy was performed in 979 (54.4%) patients. SRC adenocarcinoma was diagnosed in 899 (50%) patients. Patients with an SRC tumor were more frequently female, younger, and malnourished, had lower ASA scores, and had larger tumors than non-SRC patients. Median survival in patients with non-SRC carcinoma was 51months, as compared to 26months in patients with SRC carcinoma (p<0.001). At multivariate analysis, SRC type remained an independent adverse prognostic factor (HR=1.182). Factors that were prognostic in the SRC subgroup but not in the non-SRC subgroup were age >60years, linitis, and involvement of adjacent organs. In contrast to non-SRC tumors, pre- and postoperative chemotherapy did not significantly impact on survival following resection of SRC adenocarcinoma.In comparison to non-SRC adenocarcinoma, the SRC type has a worse prognosis, different prognostic factors, and is only poorly sensitive to perioperative chemotherapy. Non-SRC and SRC adenocarcinomas should be considered different entities in future therapeutic trials.


Colombat P.,University of Tours | Brousse N.,Necker University hospital | Salles G.,University of Lyon | Morschhauser F.,Claude Huriez University hospital | And 12 more authors.
Annals of Oncology | Year: 2012

Background: The purpose of this study was to report long-term results of rituximab induction monotherapy in patients with low-tumor-burden follicular lymphoma (LTBFL). Patients and methods: Of 49 first-line LTBFL patients who received weekly doses of rituximab (375 mg/m. 2), 46 have been followed with a long-term analysis of clinical and molecular responses. Results: Best clinical response (at any staging within a year following treatment) was 80%, 24 (52%) patients had complete or unconfirmed complete response, 13 (28%) had partial response and 9 (20%) had stable or progressive disease. Of 31 patients having a positive bcl2-JH rearrangement, 15 (48%) became negative following treatment. After 83.9 months of follow-up (95% confidence interval 6.4-92.8 months), the median progression-free survival is 23.5 months and overall survival (OS) is 91.7%. Five patients died (one progression, one myelodysplasia, one diffuse large B-cell lymphoma and two solid tumors). Seven patients (15%) are progression-free including five who are bcl2 informative. No unexpected long-term adverse event has been observed. Conclusion: A significant proportion of patients remain progression-free 7 years after a single 4-dose rituximab treatment in first-line LTBFL. The 7-year overall survivalOS is very high in this selected population of patients. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Brest University Hospital Center, University of Lyon, Claude Huriez University Hospital, University of Lausanne and 2 more.
Type: Journal Article | Journal: The Annals of thoracic surgery | Year: 2016

Major oncologic surgery is associated with a high incidence of venous thromboembolic events (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE). However, the incidence and risk factors for symptomatic VTE during curative treatment for patients with esophageal cancer are poorly documented.Data were collected from 30 European centers from 2000 to 2010. The incidence of in-hospital VTE was assessed in 2,944 patients with esophageal cancer having surgery with curative intent, and 50 clinically relevant parameters were assessed as potential risk factors for VTE. Patients received low molecular weight heparin prophylaxis during hospital stay and for 4 weeks after surgery.Eighty-four patients (2.9%) developed a symptomatic VTE; all of them had a DVT and 44 were also diagnosed with a PE. In the VTE group there were 19postoperative deaths recorded, 5 of which (26.3%) weredirectly caused by PE at postoperative days 7, 10, 21, 45, and 48 despite VTE prophylaxis. In-hospital postoperative mortality was significantly higher in VTE patients (23% versus 7%, p < 0.001) and mean hospital stay was also longer in this group (33 24 versus 25 21 days, p < 0.001). Multivariable analysis showed that highAmerican Society of Anesthesiologists (ASA) class (p= 0.008), pneumopathy (p= 0.002), or an acute respiratory distress syndrome (ARDS) (p= 0.015) were significantly associated with VTE.Patients with ASA class III or IV and those who present a postoperative pneumopathy or ARDS seem to be at higher risk for VTE. Thus, current VTE screening and thromboprophylaxis for these patients might be inadequate and needs further investigation.

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