Michallet A.-S.,Center Hospitalier Lyon Sud
Current Opinion in Oncology | Year: 2014
PURPOSE OF REVIEW: Targeted inhibitors of B-cell receptor signaling have emerged as the most promising therapeutic options against non-Hodgkin's lymphoma. The inhibitor agents that target Bruton's tyrosine kinase (BTK) have elicited particularly high enthusiasm given the unprecedented positive responses observed in Phase I trials. The sheer amount of clinical data published since last year now requires reinterpretation in light of recently published findings on BTK. RECENT FINDINGS: Clinical trial data pertaining to various B-cell dyscrasia forms must be interpreted with great caution. The differing response rates reported with various BTK inhibitors for a range of lymphoma subtypes most likely mirror BTK's disease-specific pivotal role in the regulation of cell survival, migration, and proliferation pathways. It must also be stressed that activating or inhibitory somatic mutations affecting other critical components of targeted signaling cascades dramatically impact BTK inhibitor efficacy, and scientific evidence is mounting that warrants patient screening to identify those who, based on B-cell receptor activation modes, most likely benefit from BTK inhibitors. SUMMARY: Recent developments in BTK-based therapeutic strategies have undoubtedly changed the way we approach lymphoma therapy. As of yet, there is no cure for indolent lymphoma, and the future of BTK inhibitor therapy will undoubtedly include rational combinations to exploit synthetic lethality in distinct lymphoma subsets. Copyright © Lippincott Williams & Wilkins.
Combes A.,Lille 2 University of Health and Law |
Migaud H.,Lille 2 University of Health and Law |
Girard J.,Lille 2 University of Health and Law |
Duhamel A.,Lille 2 University of Health and Law |
Fessy M.H.,Center Hospitalier Lyon Sud
Clinical Orthopaedics and Related Research | Year: 2013
Background: Dual-mobility (DM) cups were introduced to minimize the risk of THA dislocation. The overall rate of dislocation of DM cups (including both large and small articulations) is controversial and ranges from 0% to 5% in previous studies. Questions/purposes: We therefore recorded (1) the dislocation rate, (2) loosening and osteolysis, and (3) subsequent related revisions with DM cups. Methods: Between 1998 and 2003, 2480 primary THAs with DM cups were undertaken in 2179 patients. The mean age was 69 years (range, 19-94 years). This group underwent specific clinical and radiographic evaluation at a minimum followup of 0.17 years (mean, 7 years; range, 0.17-11 years) to assess dislocation, reoperation, osteolysis, and cup fixation. Results: There were 22 dislocations (0.88%): 15 dislocations of large articulations (0.6%), with two (0.08%) recurring but only one requiring revision (0.04%), and seven intraprosthetic small articulation dislocations (0.28%), all needing revision surgery. At last followup, mean Harris hip score was 91 (range, 60-100); 2439 cups (98%) showed no signs of loosening; and 141 patients (145 hips) had osteolysis (6%). Osteolysis and cup loosening were more frequent in patients younger than 50 years at the time of surgery. The 10-year survivorship considering revision for any reason was 93% (95% CI, 91%-95%). Conclusions: DM cups had a low dislocation rate in primary THA, with a limited frequency of adverse effects. We recommend DM cups to minimize dislocation in populations at high risk for instability, but they should be avoided in younger, active patients at higher risk for osteolysis. Level of Evidence: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. © 2013 The Association of Bone and Joint Surgeons®.
Rognant N.,Center Hospitalier Lyon Sud
World Journal of Hepatology | Year: 2015
Acute kidney injury (AKI) is a frequent clinical event in patients with liver disease, compounding their prognosis. Furthermore, it is likely that the occurrence of AKI has a detrimental impact on the subsequent renal function and the long-term survival of these patients. Recently, some authors advocated the use of new diagnostic criteria for detecting acute kidney injury in patients with cirrhosis. These criteria are based on the rapidity and extent of the creatinine increase comparing to the basal creatinine and also on the kinetics of diuresis decrease. Although their validity in this population requires further studies to be clearly established, these new criteria could have two advantages: (1) to allow earlier diagnosis of AKI and, thus, hepatorenal syndrome for which earlier intervention could improve patients' survival; and (2) to promote more intensive monitoring of renal function in these patients with high risk of AKI. Finally, recent practice guidelines about the prevention and treatment of general AKI have been published which should be useful in optimising the management of AKI in cirrhotic patients. © The Author(s) 2015. Published by Baishideng Publishing Group Inc.
Michallet A.-S.,Center Hospitalier Lyon Sud |
Lebras L.,Center Hospitalier Lyon Sud |
Coiffier B.,Center Hospitalier Lyon Sud
Current Opinion in Oncology | Year: 2012
Purpose of Review: In this article, we focused on the role of maintenance therapy in diffuse large B-cell lymphoma (DLBCL). Recent Findings: Treatment with maintenance rituximab after a response to induction therapy appears to be an effective approach to extending response duration. In randomized phase III trials, investigators have reported improved event-free and progression-free survival with maintenance rituximab in patients with newly diagnosed follicular lymphoma. Summary: Rituximab administered as induction or maintenance therapy in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly prolonged event-free survival. However, continued use of rituximab after R-CHOP failed to demonstrate benefit. The necessity of a subsequent dose-intense consolidation or maintenance strategy continues to be an issue. High-dose therapy followed by autologous stem cell transplantation is the treatment of choice for patients with relapsed DLBCL who are still responding to salvage therapy. Although rituximab is effective, its role in salvage therapy after autologous transplant remains unclear. Maintenance therapy with rituximab in patients with complete remission after autologous transplant may be a useful novel approach capable of eradicating minimal residual disease. However, there are currently no data confirming this hypothesis. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Karlin L.,Center Hospitalier Lyon Sud |
Coiffier B.,Center Hospitalier Lyon Sud
Seminars in Hematology | Year: 2014
Peripheral T-cell lymphomas (PTCLs) are the most common sub-entity of mature T-cell lymphomas, and apart from particular presentations, share a poor prognosis with frequent short-term, agressive, and chemorefractory relapses. Because of the rarity and also the heterogeneity of the disease, we lack randomized clinical trials. However, to date, neither intensification of frontline chemotherapy or autologous transplant has led to any improvement of survival, and the standard CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) regimen remains the most employed as induction therapy. In the past few years, new chemotherapeutic agents, with the capability to encompass the resistance to conventional chemotherapy, such as pralatrexate or bendamustine, have been evaluated. Furthermore, identification of cell surface molecular markers (CD52, CD30, CCR4) has led to the development of new monoclonal antibodies. Similarly, the better comprehension of physiopathological mechanisms and detection of deregulated intracellular pathways encouraged the use of novel therapies such as histone deacetylase inhibitors or immunomodulatory drugs. Some of these compounds have been approved for relapse, and are currently evaluated upfront in ongoing clinical trials. Despite these efforts, the global prognosis still remains much inferior to those of B-cell lymphomas, highlighting the necessity of multicenter clinical trials. © 2014 Elsevier Inc.
Traverse-Glehen A.,Center Hospitalier Lyon Sud
Discovery medicine | Year: 2012
Among splenic lymphomas with circulating cells presenting cytoplasmic projections, a homogeneous clinico-pathological entity has been recently individualized as Splenic Diffuse Red Pulp Lymphomas (SDRPL) and introduced in the provisional "unclassifiable splenic lymphoma" category of the current updated WHO classification until more is known. SDRPL presents characteristic circulating basophilic villous lymphocytes and diffuse infiltration of the splenic red pulp, distinct from Splenic Marginal Zone Lymphoma (SMZL) and Hairy Cell Leukemia (HCL), but reminiscent of HCL-Variant (HCL-V). Series of SDRPL remain sparse in the literature and controversies exist about the relationship with other splenic lymphomas. Distinction of these disorders at diagnosis can be difficult, but an adequate diagnosis is important due to differences in patient management and clinical outcome. Especially, BRAF mutations have been detected in almost all patients with HCL that may have implications for pathogenesis, diagnosis, and targeted therapy. This review will report literature data and discuss the differential diagnosis, particularly with HCL-V.
Thomas X.,Center Hospitalier Lyon Sud |
Thomas X.,French Institute of Health and Medical Research
Expert Opinion on Drug Discovery | Year: 2012
Introduction: DNA methylation is an epigenetic change mediated by DNA methyltranferases (DNMTs), which are promising epigenetic targets for the treatment of acute myeloid leukemia (AML). This is evidenced by the two DNMT inhibitors (azacitidine and decitabine) approved by the Food and Drug Administration of the United States for the treatment of high-risk myelodysplastic syndromes and the first clinical data available in AML. Areas covered: This paper reviews data from the international literature regarding the design, sites of impact and pharmacodynamic characteristics of DNMT inhibitors, and their first clinical experiences in AML. Expert opinion: The strongest advances in epigenetic therapy have been in the treatment of AML. There are now an increasing number of DNMT inhibitors. These agents may be potentially administered at different times of leukemia therapy: before or instead of chemotherapy, as maintenance therapy, prior to allogeneic stem cell transplant (SCT) or after relapse following SCT. © 2012 Informa UK, Ltd.
Coiffier L.K.B.,Center Hospitalier Lyon Sud
OncoTargets and Therapy | Year: 2013
Abstract: Prognosis of diffuse large B-cell lymphoma (DLBCL) has considerably improved during the last decade, mainly due to the addition of rituximab to chemotherapy. However, a significant proportion of patients still experience primary refractory disease or short-term relapses, conferring poor survival. Thus, achieving first-line complete remission is of major importance, especially in young and fit patients. Current strategies are based on the age-adapted International Prognostic Index, which separates patients into three prognostic subgroups (lowrisk, intermediate-risk, and high-risk). However, it is based only on clinical variables, and we have learned from daily practice that there remains a marked heterogeneity within each subgroup. Recently, biological prognostic factors have emerged, and should now be part of initial evaluation to guide treatment. Among those, so-called double-hit DLBCL with deregulation of both MYC and BCL2 genes usually follows a particularly aggressive course and should be treated more intensively. But for many other patients, the indication of high-dose therapy rather than immunochemotherapy alone remains controversial. In these cases, the interest of an early 18 F fluoro-2-deoxy-d-glucose positron emission tomography evaluation-based strategy is now being assessed in ongoing clinical trials. Moreover, other strategies to improve response and survival consist in adding novel agents to standard chemotherapy. In this field, newly developed anti-CD20 monoclonal antibodies and immunomodulatory drugs could be of particular interest during induction therapy to optimize the quality of response, but also in maintenance treatment, in order to decrease the risk of relapse. Only well-conducted clinical trials will be able to resolve all these issues. Therefore, physicians should be encouraged, as far as possible, to propose them to their patients. © 2013 Karlin and Coiffier.
Coiffier B.,Center Hospitalier Lyon Sud
Clinical Lymphoma, Myeloma and Leukemia | Year: 2013
Most patients with mantle cell lymphoma (MCL) relapse within a few years of treatment. Conventional agents provide little benefit, thus identification of new therapies is critical to improve patient outcomes. Temsirolimus, an inhibitor of mammalian target of rapamycin, is an effective, well-tolerated option authorized in Europe for treatment of patients with relapsed/refractory MCL. Intravenous temsirolimus has been extensively studied in MCL and has consistently demonstrated single-agent antitumor activity. In the pivotal phase III trial, treatment with temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly (175/75 mg) resulted in significant improvements in progression-free survival (P =.0009) and objective response rate (P =.002) vs. investigator's choice of therapy. Hematologic toxicities (thrombocytopenia, neutropenia) were the principal grade 3/4 adverse events associated with temsirolimus 175/75 mg. Other toxicities included increases in serum cholesterol and triglycerides, hyperglycemia, fatigue, and dyspnea. Overall, the safety profile of temsirolimus is acceptable in this setting, and most toxicities are manageable with dose modification or medical intervention. Clinical studies of temsirolimus in relapsed or refractory MCL patients aim to clarify the optimal treatment schedule and to assess rational combinations with other therapeutic agents, such as rituximab or chemotherapy. Practical considerations are discussed for the clinical use of temsirolimus in patients with MCL. © 2013 Elsevier Inc. All rights reserved.
Sobh M.,Center Hospitalier Lyon Sud
Leukemia | Year: 2016
We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18–78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.Leukemia advance online publication, 20 May 2016; doi:10.1038/leu.2016.101. © 2016 Macmillan Publishers Limited