ABSTRACT
BACKGROUND: In France, advance directives are favourably perceived by most of the population, although the drafting rate is low. This ambivalence is challenging because advance directives are meant to promote the autonomy and freedom of choice of patients. The purpose of this study was to analyse the content of advance directives written by patients suffering from malignant haemopathies to better understand how patients put them into practice. These could be relevant as early as the initial diagnosis of haematological malignancies because of the uncertain course of the disease. METHODS: This was a multicentre, qualitative, descriptive study. The advance directives written by patients with malignant haemopathies treated in one of the six French hospital departments were included in the study from 01/06/2008 to 15/04/2016. A thematic analysis of the advance directives was performed by two researchers: a senior haematologist and a research assistant. RESULTS: The median age of the patients was 69. Most were women (sex ratio: 0.59), living as a couple (57%), with lymphoid pathologies (66%), who were still alive two years after the instructions were written (63%) and had nominated a health care proxy (88.6%). Free texts (62.9%) were richer in content than pre-defined forms. The advance directives were used in three ways: for a purely legal purpose, to focus on medical treatments or actions, or to communicate a message to the family. Three main themes emerged: (1) refusal of medical treatment (100%), in which patients express refusal of life-sustaining care (97.1%). The actual treatments or the moment when they should be limited or stopped were not always mentioned in detail. (2) A desire for effective pain relief to avoid suffering (57.1%) and (3) messages for their family (34.3%), such as funeral arrangements (17.1%) and messages of love or trust (14.3%). CONCLUSIONS: Patients who write advance directives are not necessarily at the end of their lives. Their content mainly conveys treatment wishes, although patients also use them to pass on personal messages to their close family. This emerging role of advance directives to communicate messages within the family should be valued, even if it is not their original purpose.
Subject(s)
Advance Directives/psychology , Choice Behavior , Family/psychology , Adolescent , Adult , Advance Directives/legislation & jurisprudence , Advance Directives/trends , Aged , Aged, 80 and over , Communication , Female , France , Hematology/methods , Humans , Male , Middle Aged , Qualitative Research , Retrospective StudiesABSTRACT
B-cell chronic lymphocytic leukemia (B-CLL) cells are resistant to apoptosis, and consequently accumulate to the detriment of normal B cells and patient immunity. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors drives cell transformation, and thus plays a critical role in malignancies. In this study, we identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed in B-CLL cells, whereas expression of its natural ligand, neurotensin (NTS), was minimal in both B-CLL cells and patient plasma. Surprisingly, NTSR2 remained in a constitutively active phosphorylated state, caused not by a mutation-induced gain-of-function but rather by an interaction with the oncogenic tyrosine kinase receptor TrkB. Functional and biochemical characterization revealed that the NTSR2-TrkB interaction acts as a conditional oncogenic driver requiring the TrkB ligand brain-derived neurotrophic factor (BDNF), which unlike NTS is highly expressed in B-CLL cells. Together, NTSR2, TrkB and BDNF induce autocrine and/or paracrine survival pathways that are independent of mutation status and indolent or progressive disease course. The NTSR2-TrkB interaction activates survival signaling pathways, including the Src and AKT kinase pathways, as well as expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. When NTSR2 was downregulated, TrkB failed to protect B-CLL cells from a drastic decrease in viability via typical apoptotic cell death, reflected by DNA fragmentation and Annexin V presentation. Together, our findings demonstrate that the NTSR2-TrkB interaction plays a crucial role in B-CLL cell survival, suggesting that inhibition of NTSR2 represents a promising targeted strategy for treating B-CLL malignancy.
Subject(s)
Apoptosis , Biomarkers, Tumor/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Membrane Glycoproteins/metabolism , Receptor, trkB/metabolism , Receptors, Neurotensin/metabolism , Biomarkers, Tumor/genetics , Brain-Derived Neurotrophic Factor/genetics , Cell Proliferation , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Membrane Glycoproteins/genetics , Receptor, trkB/genetics , Receptors, Neurotensin/genetics , Tumor Cells, CulturedABSTRACT
After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.
Subject(s)
Blood Transfusion , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Erythropoietin/therapeutic use , Myelodysplastic Syndromes/drug therapy , Thalidomide/analogs & derivatives , Aged , Anemia/prevention & control , Angiogenesis Inhibitors/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Lenalidomide , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Neoplasm Staging , Prognosis , Prospective Studies , Risk Factors , Thalidomide/therapeutic useABSTRACT
INTRODUCTION: Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70 years of age with non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: In the setting of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70 years of age who received AHSCT. RESULTS: The median age at AHSCT was 72.3 years [70-80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5×109/L neutrophils and 20 × 10(9)/L platelets were of 12 [9-76] days and 12 [0-143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. CONCLUSION: In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70 years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Non-Hodgkin/therapy , Societies, Medical , Aged , Aged, 80 and over , Bone Marrow Transplantation , Cell- and Tissue-Based Therapy , Disease-Free Survival , Female , Follow-Up Studies , France/epidemiology , Humans , Incidence , Lymphoma, Non-Hodgkin/epidemiology , Male , Prevalence , Retrospective Studies , Survival Rate/trendsABSTRACT
BACKGROUND: Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value. OBJECTIVES: To assess the predictive value of cTnI in patients with TTP for death or refractoriness. PATIENTS/METHODS: The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission. RESULTS: Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 µg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 µg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01). CONCLUSIONS: A CTnI level of > 0.25 µg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.
Subject(s)
Heart Diseases/blood , Heart Diseases/etiology , Purpura, Thrombotic Thrombocytopenic/blood , Purpura, Thrombotic Thrombocytopenic/complications , Troponin I/blood , ADAM Proteins/deficiency , ADAM Proteins/genetics , ADAMTS13 Protein , Adult , Aged , Biomarkers/blood , Chi-Square Distribution , Electrocardiography , Female , France , Heart Diseases/diagnosis , Heart Diseases/mortality , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Predictive Value of Tests , Prognosis , Prospective Studies , Purpura, Thrombotic Thrombocytopenic/diagnosis , Purpura, Thrombotic Thrombocytopenic/genetics , Purpura, Thrombotic Thrombocytopenic/mortality , Registries , Risk Factors , Time Factors , Up-RegulationABSTRACT
BACKGROUND: Autologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting. PATIENTS AND METHODS: Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients. RESULTS: Median overall survival (OS) after relapse of the whole study group was 19 months. A long (>12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis. Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation. CONCLUSIONS: MCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.
Subject(s)
Lymphoma, Mantle-Cell/mortality , Stem Cell Transplantation , Adult , Aged , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Mantle-Cell/pathology , Lymphoma, Mantle-Cell/therapy , Male , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local , Prognosis , Proportional Hazards Models , Retrospective Studies , Salvage Therapy , Transplantation, Autologous , Treatment Failure , Treatment OutcomeABSTRACT
In this study, we determined the respective roles of RelA and RelB NF-κB subunits in Epstein-Barr virus (EBV)-transformed B cells. Using different EBV-immortalized B-cell models, we showed that only RelA activation increased both survival and cell growth. RelB activity was induced secondarily to RelA activation and repressed RelA DNA binding by trapping the p50 subunit. Reciprocally, RelA activation repressed RelB activity by increasing expression of its inhibitor p100. To search for such reciprocal inhibition at the transcriptional level, we studied gene expression profiles of our RelA and RelB regulatable cellular models. Ten RelA-induced genes and one RelB-regulated gene, ARNTL2, were repressed by RelB and RelA, respectively. Apart from this gene, RelB signature was included in that of RelA Functional groups of RelA-regulated genes were for control of energy metabolism, genetic instability, protection against apoptosis, cell cycle and immune response. Additional functions coregulated by RelA and/or RelB were autophagy and plasma cell differentiation. Altogether, these results demonstrate a cross-inhibition between RelA and RelB and suggest that, in fine, RelB was subordinated to RelA. In the view of future drug development, RelA appeared to be pivotal in both classical and alternative activation pathways, at least in EBV-transformed B cells.
Subject(s)
Cell Transformation, Viral , Herpesvirus 4, Human/pathogenicity , Lymphoma, B-Cell/etiology , Transcription Factor RelA/physiology , Transcription Factor RelB/physiology , Cell Line , Humans , NF-kappa B/physiology , Transcription Factor RelA/antagonists & inhibitors , Transcription Factor RelA/genetics , Transcription Factor RelB/antagonists & inhibitors , Transcription Factor RelB/genetics , TranscriptomeABSTRACT
To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.
Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Mutation/genetics , Myeloid Differentiation Factor 88/genetics , Waldenstrom Macroglobulinemia/genetics , Flow Cytometry , Gene Rearrangement , Humans , Immunoglobulin Heavy Chains/immunology , Immunoglobulin M/metabolism , Immunoglobulin Variable Region/immunology , Lymph Nodes/immunology , Lymph Nodes/pathology , Lymphoma, B-Cell, Marginal Zone/classification , Lymphoma, B-Cell, Marginal Zone/immunology , Prognosis , Splenic Neoplasms/genetics , Splenic Neoplasms/immunology , Waldenstrom Macroglobulinemia/immunologyABSTRACT
BACKGROUND: The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. PATIENTS AND METHODS: Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. RESULTS: A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). CONCLUSION: In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoma, Large B-Cell, Diffuse/drug therapy , Adolescent , Adult , Aged , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/administration & dosage , Bleomycin/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Neoplasm Staging , Prednisone/administration & dosage , Prednisone/adverse effects , Rituximab , Treatment Outcome , Vindesine/administration & dosage , Vindesine/adverse effectsABSTRACT
Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.
Subject(s)
Biomarkers, Tumor/genetics , Cytogenetic Analysis , DNA (Cytosine-5-)-Methyltransferases/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Mutation/genetics , Adolescent , Adult , DNA Methyltransferase 3A , DNA, Neoplasm/genetics , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/classification , Male , Middle Aged , Nucleophosmin , Polymerase Chain Reaction , Prognosis , Prospective Studies , Retrospective Studies , Risk Factors , Survival Rate , Young Adult , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
We evaluated the prognostic value of serum ferritin (SF) level at diagnosis in 318 newly diagnosed IPSS low and int 1 (lower) risk MDS patients included in the French MDS registry, who did not require RBC transfusions and had baseline SF level determination. Increased baseline SF level (>300 ng/ml) was correlated with male gender, more pronounced anaemia, and diagnosis of RARS but had no negative impact on progression to AML or survival.
Subject(s)
Blood Transfusion , Ferritins/metabolism , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/blood , Prognosis , Risk Factors , Survival RateSubject(s)
Megakaryocytes/pathology , Primary Myelofibrosis/pathology , Suppressor of Cytokine Signaling Proteins/physiology , Thrombopoietin/physiology , Cell Proliferation , DNA Methylation , Humans , Promoter Regions, Genetic , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/geneticsABSTRACT
BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome. PATIENTS AND METHODS: We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV. RESULTS: All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed. CONCLUSION: These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparaginase/administration & dosage , Leukemia/drug therapy , Lymphoma, Extranodal NK-T-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Drug Resistance, Neoplasm/drug effects , Female , Humans , Leukemia/pathology , Lymphoma, Extranodal NK-T-Cell/pathology , Male , Middle Aged , Recurrence , Retrospective Studies , Treatment Outcome , Western WorldABSTRACT
MPL (or thrombopoietin receptor, TPO-R) 515 mutations have recently been described in 5-10% of primitive myelofibrosis (PMF) cases as decisive oncogenic events capable of triggering the disease. Here we report additional mutations located in exon 10 of MPL in PMF patients. We investigated whether these new mutations also lead to cell transformation. MPL exon 10 was systematically sequenced in 100 PMF patients. Seven different mutations were found in eight patients. We introduced each MPL mutant in Ba/F3 cells to determine whether they correspond to gain-of-function mutations. Only MPL W515 mutations induced (1) Ba/F3 proliferation independently of growth factors, (2) tumorigenesis in nude mice, (3) spontaneous activation of JAK/STAT, RAS/MAPK and PI3K transduction pathways and (4) increased S phase of cell cycle. Similar to all other myeloproliferative disorder oncogenic events identified to date, these results demonstrate that only the detected MPL W515 mutations trigger spontaneous MPL activation leading to a G(1)/S transition activation. The other mutations are devoid of significant transforming activity but may synergize with JAK2 V617F or other not yet characterized molecular events.
Subject(s)
G1 Phase , Mutation , Primary Myelofibrosis/genetics , Receptors, Thrombopoietin/genetics , S Phase , Animals , Apoptosis , Cell Proliferation , Mice , Mice, Nude , Primary Myelofibrosis/pathology , Signal TransductionABSTRACT
Upper limb lymphangitis often complicates varied wounds on the hand or forearm and improvement is obtained in a few days with adapted antibiotic therapy. A 28-year-old woman presented since few years episodes of lymphangitis of the arm associated with vesicles on an erythematous base, on the palmar face of the first phalanx of the index finger, spontaneous relief within 10 days, without antibiotic therapy. Herpetic origin was confirmed on viral culture. No primary infection neither recurrence was noted. Because of the recurrences, a prophylactic treatment with valaciclovir was instituted. There was no reported recurrence at two years follow-up. Upper limb lymphangitis rarely complicates herpetic whitlow in immunocompetent patient. Clinicians should be aware of viral lymphangitis, which is often overlooked and associated with diagnostic errors and treatment delay.
Subject(s)
Herpes Simplex/diagnosis , Lymphangitis/virology , Simplexvirus/isolation & purification , Upper Extremity/virology , Acyclovir/analogs & derivatives , Acyclovir/therapeutic use , Adult , Antiviral Agents/therapeutic use , Female , Humans , Prodrugs/therapeutic use , Recurrence , Valacyclovir , Valine/analogs & derivatives , Valine/therapeutic useABSTRACT
Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.