Hospital M.-A.,University Paris Diderot |
Prebet T.,Institute Paoli Calmettes |
Bertoli S.,Center Hospitalier University Purpan |
Thomas X.,Hopital Edouard Herriot |
And 15 more authors.
Blood | Year: 2014
Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) ratewas 88%. With amedian follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality. © 2014 by The American Society of Hematology.
Fenaux P.,Service Route |
Giagounidis A.,St Johannes Hospital |
Selleslag D.,AZ St. Jan Bruges AV |
Beyne-Rauzy O.,Center Hospitalier University Purpan |
And 20 more authors.
Blood | Year: 2011
This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/ Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621. © 2011 by The American Society of Hematology.
PubMed | University of Limoges, University Paris - Sud, Center Hospitalier University Purpan, Gilead Sciences and 2 more.
Type: Clinical Trial, Phase II | Journal: The Lancet. Infectious diseases | Year: 2016
Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5.We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10,000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079.From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83-99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76-100) of the 21 patients who were treatment naive and 19 (95%, 75-100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse events were asthenia (16 [39%] patients), headache (11 [27%] patients), and fatigue (four [10%] patients). One patient had a serious adverse event, worsening depression, which we judged to be unrelated to study treatment.The oral regimen of ledipasvir-sofosbuvir is an effective and well-tolerated treatment for patients with HCV genotype 5 infection who are treatment naive or treatment experienced.Gilead Sciences.
Oschlies I.,University of Kiel |
Lisfeld J.,Justus Liebig University |
Lamant L.,Center Hospitalier University Purpan |
Nakazawa A.,National Center for Child Health and Development |
And 14 more authors.
Haematologica | Year: 2013
Anaplastic large cell lymphomas are peripheral T-cell lymphomas that are characterized by a proliferation of large anaplastic blasts expressing CD30. In children, systemic anaplastic large cell lymphomas often present at advanced clinical stage and harbor translocations involving the anaplastic lymphoma kinase (ALK) gene leading to the expression of chimeric anaplastic lymphoma kinase (ALK)-fusion proteins. Primary cutaneous anaplastic large cell lymphoma is regarded as an ALK-negative variant confined to the skin and is part of the spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. Thirty-three of 487 pediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial (1999 to 2006) presented with a skin limited CD30-positive lymphoproliferative disorder. In 23 of the 33 patients, material for international histopathological review was available, and the cases were studied for histopathological, immunophenotypical and clinical features as well as for breaks within the ALK gene. Five of 23 cases and one additional case (identified after closure of the trial) expressed ALKprotein. Complete staging excluded any other organ involvement in all children. Expression of ALK proteins was demonstrated by immunohistochemistry in all cases and the presence of breaks of the ALK gene was genetically confirmed in 5 evaluable cases. The histopathological and clinical picture of these skin-restricted ALK-positive lymphomas was indistinguishable from that of cutaneous anaplastic large cell lymphoma. Five children presented with a single skin lesion that was completely resected in 4 and incompletely resected in one. Three of these patients received no further therapy, 2 additional local radiotherapy, and one chemotherapy. All children remain in complete remission with a median follow up of seven years (range 1-8 years). We present 6 pediatric cases of ALK-positive primary cutaneous anaplastic large cell lymphomas. After thorough exclusion of systemic involvement, therapy confined to local measures seems to be sufficient to induce cure. ©2013 Ferrata Storti Foundation.
Desjobert C.,University Paul Sabatier |
Renalier M.-H.,French National Center for Scientific Research |
Renalier M.-H.,University Paul Sabatier |
Bergalet J.,University Paul Sabatier |
And 12 more authors.
Blood | Year: 2011
Although deregulated expression of specific microRNAs (miRNAs) has been described in solid cancers and leukemias, little evidence of miRNA deregulation has been reported in ALK-positive (ALK+) anaplastic large cell lymphomas (ALCL). These tumors overexpress the major antiapoptotic protein myeloid cell leukemia 1 (MCL-1), a situation that could compensate for the lack of BCL-2. We report that ALK+ ALCL cell lines and biopsy specimens (n = 20) express a low level of miR-29a and that this down-modulation requires an active NPM-ALK kinase. Murine models (transgenic mice and mouse embryonic fibroblast [MEF] cells), which allow conditional NPM-ALK fusion protein expression, showed an increase of miR-29a expression in the absence of NPMALK. Concordant results were observed after the abolition of NPM-ALK kinase activity (siALK or PF-2341066) in NPM-ALK+ ALCL cell lines. In addition, we showed that low expression of miR-29a, probably through methylation repression, plays an important regulatory role inMCL-1overexpression that could promote tumor cell survival by inhibiting apoptosis. Enforced miR-29a expression was found to modulate apoptosis through inhibition of MCL-1 expression in ALCL cell lines and in a xenografted model, with a concomitant tumor growth reduction. Thus, synthetic miR-29a represents a potential new tool to affect tumorigenesis in these lymphomas. © 2011 by The American Society of Hematology.
Puissegur M.P.,French Institute of Health and Medical Research |
Puissegur M.P.,Center Hospitalier University Purpan |
Eichner R.,French Institute of Health and Medical Research |
Eichner R.,University Paul Sabatier |
And 14 more authors.
Leukemia | Year: 2012
B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis. © 2012 Macmillan Publishers Limited.
Capuani C.,Center Hospitalier University Purpan |
Capuani C.,Toulouse University Hospital Center |
Meggetto F.,French Institute of Health and Medical Research |
Duga I.,Center Hospitalier University Purpan |
And 5 more authors.
Placenta | Year: 2013
Introduction: Chronic histiocytic intervillositis of unknown etiology (CIUE) is a rare placental lesion characterized by an intervillous mononuclear inflammatory infiltrate of maternal origin. Although the mechanism and origin of these lesions are currently not understood, they appear to be related to an immune conflict between mother and fetus cells. Aim: To clarify the inflammatory cell profile and evaluate the T regulatory lymphocyte (Treg) status in CIUE. Materials and methods: All cases of CIUE that occurred over an 8-year period were analyzed using immunohistochemistry. Results: The inflammatory profile of CIUE was characterized by a clearly predominant component of histiocytic cells (80% ± 6.9) associated with some T cells (24% ± 5.7). The ratio of CD4+ versus CD8+ T cells was close to 1. This profile differs from infectious disease and chronic histiocytic villitis, the main differential diagnoses of CIUE. As for normal pregnancies most regulatory T cells were localized in the decidua basalis. Nevertheless, their appearance was also noted in the intervillous space. In both the intervillous space and the deciduas the number of Tregs gradually increased from grade 1 to 3. Conclusion: We found that CIUE is associated with an increase in Treg lymphocytes in the decidua basalis and the intervillous space. Contrary to previously published data on human miscarriage, this result appears to be specific to CIUE and would support the hypothesis of an immunopathological disorder for CIUE. © 2012 Elsevier Ltd. All rights reserved.
Yuan L.L.,French Institute of Health and Medical Research |
Green A.S.,University of Paris Descartes |
Bertoli S.,French Institute of Health and Medical Research |
Bertoli S.,Center Hospitalier University Purpan |
And 9 more authors.
Leukemia | Year: 2014
Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN-/-cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3-and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies. © 2014 Macmillan Publishers Limited.
PubMed | French Institute of Health and Medical Research, Center Hospitalier University Purpan, BC Cancer Agency, Catholic University of the Sacred Heart and 2 more.
Type: Journal Article | Journal: Oncoimmunology | Year: 2016
Upregulation of T cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by
PubMed | University Paul Sabatier, Toulouse University Hospital Center and Center Hospitalier University Purpan
Type: Journal Article | Journal: Journal of forensic sciences | Year: 2016
Decision trees provide an alternative to multivariate discriminant analysis, which is still the most commonly used in anthropometric studies. Our study analyzed the metric characterization of a recent virtual sample of 113 coxal bones using decision trees for sex determination. From 17 osteometric type I landmarks, a dataset was built with five classic distances traditionally reported in the literature and six new distances selected using the two-step ratio method. A ten-fold cross-validation was performed, and a decision tree was established on two subsamples (training and test sets). The decision tree established on the training set included three nodes and its application to the test set correctly classified 92% of individuals. This percentage was similar to the data of the literature. The usefulness of decision trees has been demonstrated in numerous fields. They have been already used in sex determination, body mass prediction, and ancestry estimation. This study shows another use of decision trees enabling simple and accurate sex determination.