PubMed | Institute Paoli Calmettes, Assistance Publique Hopitaux de Paris, Hopitaux Universitaires Of Geneva, Lille University Hospital Center and 4 more.
Type: | Journal: Orphanet journal of rare diseases | Year: 2016
Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered.We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015.Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a -granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation.Platelet dysfunction suggestive of defective -granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.
Bennouna J.,Institute Of Cancerologie Of Louest |
Sastre J.,Hospital Clinico San Carlos |
Arnold D.,University of Hamburg |
Osterlund P.,University of Helsinki |
And 13 more authors.
The Lancet Oncology | Year: 2013
Background: Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment. Methods: In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102. Findings: Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [<1%]), gastrointestinal perforation (seven [2%] vs three [<1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group. Interpretation: Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers. Funding: F Hoffmann-La Roche. © 2013 Elsevier Ltd.
Conroy T.,University of Lorraine |
Desseigne F.,Center Leon Berard |
Ychou M.,Center Val dAurelle |
Bouche O.,Center Hospitalier University Robert Debre |
And 17 more authors.
New England Journal of Medicine | Year: 2011
BACKGROUND: Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. RESULTS: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). CONCLUSIONS: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.) Copyright © 2011 Massachusetts Medical Society.
PubMed | Service de Reanimation Medicale, Center Hospitalier, University of Angers, Departement dAnesthesie et Reanimation and 14 more.
Type: Clinical Trial | Journal: Intensive care medicine | Year: 2016
Over the last two decades, noninvasive ventilation (NIV) has been proposed in various causes of acute respiratory failure (ARF) but some indications are debated. Current trends in NIV use are unknown.Comparison of three multicenter prospective audits including all patients receiving mechanical ventilation and conducted in 1997, 2002, and 2011 in francophone countries.Among the 4132 patients enrolled, 2094 (51%) required ventilatory support for ARF and 2038 (49 %) for non-respiratory conditions. Overall NIV use was markedly increased in 2010/11 compared to 1997 and 2002 (37% of mechanically ventilated patients vs. 16% and 28%, P < 0.05). In 2010/11, the use of first-line NIV for ARF had reached a plateau (24% vs. 16% and 23%, P < 0.05) whereas pre-ICU and post-extubation NIV had substantially increased (11% vs. 4% and 11% vs. 7%, respectively, P < 0.05). First-line NIV remained stable in acute-on-chronic RF, continued to increase in cardiogenic pulmonary edema, but decreased in de novo ARF (16% in 2010/11 vs. 23% in 2002, P < 0.05). The NIV success rate increased from 56% in 2002 to 70% in 2010/11 and remained the lowest in de novo ARF. NIV failure in de novo ARF was associated with increased mortality in 2002 but not in 2010/11. Mortality decreased over time, and overall, NIV use was associated with a lower mortality.Increases in NIV use and success rate, an overall decrease in mortality, and a decrease of the adverse impact NIV failure has in de novo ARF suggest better patient selection and greater proficiency of staff in administering NIV.Clinicaltrials.gov Identifier NCT01449331.
Cazenave H.,Service de Dermatologie |
Maubec E.,Service de Dermatologie |
Mohamdi H.,French Institute of Health and Medical Research |
Mohamdi H.,University Paris Diderot |
And 6 more authors.
British Journal of Dermatology | Year: 2013
Background Genital and anorectal mucosal melanomas (GAMMs) are rare compared with cutaneous melanoma (CM). Many epidemiological and genetic studies have been carried out on CM. In contrast, the genetic and environmental risk factors for GAMM have been poorly documented up to now. Objectives To compare the distribution of pigmentation and naevus phenotypes, sun exposure and family history of melanoma between patients with GAMM and CM. Methods We compared two series of patients, 81 with GAMM and 293 with CM. Results Patients with GAMM and CM did not show significant differences for phenotypic risk factors. However, patients with GAMM tended to display red hair (11% vs. 5·5%, P = 0·08) and a poor tanning ability (22% vs. 13·3%, P = 0·06) at a higher frequency than patients with CM. A family history of melanoma was significantly more frequent with GAMM than with CM (18% vs. 7·5%, P = 0·005). Apart from the GAMM index case, affected relatives had CM except in one family. The frequency of multiple primary melanomas (MPMs) was similar in the GAMM and CM series (6% vs. 5·3%, P = 0·43). All patients with GAMM and MPM had only one GAMM primary, while the other primary was cutaneous. No CDKN2A germline mutation was detected in patients with GAMM. Conclusions This study shows that GAMM and CM may occur in the same patient, and GAMM may develop in a familial setting. The association of both GAMM and CM in patients and families suggests shared genetic factors by these two types of melanoma. What's already known about this topic? Genital and anorectal mucosal melanomas (GAMMs) are rare. Their genetic and environmental risk factors have been poorly documented. What does this study add? Patients with GAMM or cutaneous melanoma (CM) did not show significant differences for phenotypic risk factors. GAMM and CM may develop in the same patient. There is a noticeable frequency of family history of CM in patients with GAMM, and our findings suggest common genetic determinants to both types of melanomas. © 2013 British Association of Dermatologists.
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.
Wood C.,Center Hospitalier University Robert Debre |
von Baeyer C.L.,University of Saskatchewan |
Falinower S.,A4 SAS Agency |
Moyse D.,Statistician |
And 2 more authors.
BMC Pediatrics | Year: 2011
Background: Assessment of pain in children is an important aspect of pain management and can be performed by observational methods or by self-assessment. The Faces Pain Scale-Revised (FPS-R) is a self-report tool which has strong positive correlations with other well established self-report pain intensity measures. It has been recommended for measuring pain intensity in school-aged children (4 years and older). The objective of this study is to compare the concordance and the preference for two versions, electronic and paper, of the FPS-R, and to determine whether an electronic version of the FPS-R can be used by children aged 4 and older.Methods: The study is an observational, multicenter, randomized, cross-over, controlled, open trial. Medical and surgical patients in two pediatric hospitals (N = 202, age 4-12 years, mean age 8.3 years, 58% male) provided self-reports of their present pain using the FPS-R on a personal digital assistant (PDA) and on a paper version. Paper and electronic versions of the FPS-R were administered by a nurse in a randomized order: half the patients were given the PDA version first and the other half the paper version first. The time between the administrations was planned to be less than 30 minutes but not simultaneous. Two hundred and thirty-seven patients were enrolled; 35 were excluded from analysis because of misunderstanding of instructions or abnormal time between the two assessments.Results: Final population for analysis comprised 202 children. The overall weighted Kappa was 0.846 (95%CI: 0.795; 0.896) and the Spearman correlation between scores on the two versions was rs= 0.911 (p < 0.0001). The mean difference of pain scores was less than 0.1 out of 10, which was neither statistically nor clinically significant; 83.2% of children chose the same face on both versions of the FPS-R. Preference was not modified by order, sex, age, hospitalization unit (medical or surgical units), or previous analgesics. The PDA was preferred by 87.4% of the children who expressed a preference.Conclusion: The electronic version of the FPS-R can be recommended for use with children aged 4 to 12, either in clinical trials or in hospitals to monitor pain intensity. © 2011 Wood et al; licensee BioMed Central Ltd.
Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study
PubMed | Institute Mutualiste Montsouris, Hopital Tenon, Cliniques Universitaires Saint Luc, Institute Sainte Catherine and 9 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017
LBA4003 Background: CRT in patients with LAPC controlled after induction CT could be superior to continuing CT (Huguet, JCO 2007). The role of erlotinib is unknown. We aimed to define the role of 1) CRT after disease control with gemcitabine, 2) erlotinib in LAPC.LAPC PS 0-2 patients were first randomized to gemcitabine alone or plus erlotinib 100 mg/d for 4 months (R1, stratification: center, PS). Patients with controlled disease were then randomized to 2 additional months of CT (Arm 1) or CRT (Arm 2) 54 Gy and capecitabine 1600 mg/moverall survival (OS) in R2 patients. Secondary objectives: role of erlotinib on OS (R1), tolerance, predictive markers, and circulating tumor cells. Taking into account a 30% progression rate between R1 and R2, and 5% lost to follow-up, 722 patients were required to observe 392 deaths to show a median OS increase from 9 to 12 m (HR=0.75) in the CRT arm (2 sided =5% and =20%) with planned interim analyses using alpha spending function and OBrien Fleming boundaries (to reject H0 or H1). Kaplan-Meier, log rank and univariate Cox tests were used.From 442 pts included for R1, 269 pts reached R2 (arm1:136; arm 2:133). Main baseline characteristics in arms 1/2: female 44%/56%, mean age 63/62, head tumor 65%/62%, PS 0 56%/48%. After a median follow-up of 36 m, 221 deaths had occurred allowing the planned interim analysis (information fraction 56.4%). OS in R2 pts was 16.5 m [15.5-18.5] and 15.3 m [13.9-17.3] in arms 1 and 2, respectively (HR=1.03 [0.79-1.34], p=0.83). IDMC has confirmed that the futility boundary for the hypothesis of CRT superiority was crossed and considered this as the final analysis of the study.Administering CRT is not superior to continuing CT in patients with controlled LAPC after 4 months of CT.NCT00634725.
Panel P.,Center Hospitalier Of Versailles |
Bajka M.,University of Zürich |
Le Tohic A.,Center Hospitalier Of Versailles |
El Ghoneimi A.,Center Hospitalier University Robert Debre |
And 2 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2012
Study objective: To assess face and construct validity of a new virtual reality (VR) training simulator for hysteroscopic placement of tubal sterilization implants. Design Nonrandomized, controlled trial comparing responses and performance of novices and experts on the simulator. Design classification: Canadian task force II-1. Setting: Forty-six gynecologists were personally invited or recruited at the 33rd Conference of the French National College of Gynecologists and Obstetricians (CNGOF) from December 9 to 12, 2009, grouped as 20 experts and 26 novices. They all performed the defined sequence of virtual procedures on the simulator (case 1 for familiarization, case 4 for study assessment) and finally completed the study questionnaire. Measurements and main results: Responses to realism, educational potential, and general opinion were excellent, proving face validity. Significant differences between novices and experts were assessed for 7 of the 15 metrics analyzed, proving construct validity. Conclusions: We established face and construct validity for EssureSim™, an educational VR simulator for hysteroscopic tubal sterilization implant placement. The next steps are to investigate convergent and predictive validity to affirm the real capacity of transferring the skills learned on the training simulator to the patient in the operating room. © Springer Science+Business Media, LLC 2012.