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1.
Lancet Haematol ; 6(8): e429-e437, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296423

RESUMO

BACKGROUND: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. METHODS: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual. FINDINGS: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. INTERPRETATION: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. FUNDING: Lymphoma Academic Research Organisation, and Celgene and Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
2.
J Allergy Clin Immunol Pract ; 7(7): 2387-2395.e3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30954641

RESUMO

BACKGROUND: Patients with mast cell diseases may suffer from various distressing symptoms, which can be insufficiently controlled with available therapies, severely affecting their quality of life. There is a need for new and safe treatment options for these patients. OBJECTIVES: We aimed to evaluate safety and efficacy of omalizumab administration in patients with a symptomatic mast cell disorder. METHODS: We included 55 patients with a mast cell disorder associated with debilitating symptoms who received omalizumab treatment between January 2015 and December 2017, after a multidisciplinary team meeting at the French National Reference Center for Mastocytosis. RESULTS: A complete response was achieved for 1 patient (1.8%), a major response for 30 patients (54.5%), and a partial response for 12 patients (21.8%), resulting in an overall best response rate of 78.2% (43 of 55 patients). The response was persistent at least 3 months in 33 of 43 responding patients (76.7%). At the last follow-up, the final overall response rate was 58.2% (32 of 55 patients). Median time to first response was 2 months and median time to best response was 6 months. Omalizumab was dramatically effective on all superficial and general vasomotor symptoms and on most gastrointestinal or urinary symptoms, and partially effective on most neuropsychiatric symptoms. Safety profile was acceptable, except for one severe adverse event (edema of the larynx and dyspnea after the first injection of omalizumab). Side effects were reported in 16 patients (29%), mainly of low to mild intensity, yet causing interruption of treatment in 5 patients (9%). CONCLUSION: Omalizumab seems to be a useful therapeutic option to control mast cell-mediator symptoms and displays a favorable safety profile.

4.
Am J Transplant ; 18(9): 2250-2260, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29397036

RESUMO

The diagnostic criteria for antibody-mediated rejection (ABMR) after small bowel transplantation (SBT) are not clearly defined, although the presence of donor-specific antibodies (DSAs) has been reported to be deleterious for graft survival. We aimed to determine the incidence and prognostic value of DSAs and C4d in pediatric SBT and to identify the histopathologic features associated with C4d positivity. We studied all intestinal biopsies (IBx) obtained in the first year posttransplantation (N = 345) in a prospective cohort of 23 children. DSAs and their capacity to fix C1q were identified by using Luminex technology. Eighteen patients (78%) had DSAs, and 9 had the capacity to fix C1q. Seventy-eight IBx (22.6%) were C4d positive. The independent determinants of C4d positivity were capillaritis grades 2 and 3 (odds ratio [OR] 4.02, P = .047 and OR 5.17, P = .003, respectively), mucosal erosion/ulceration (OR 2.8, P = .019), lamina propria inflammation grades 1 and 2/3 (OR 1.95, P = .043 and OR 3.1, P = .016, respectively), and chorion edema (OR 2.16, P = .028). Complement-fixing DSAs and repeated C4d-positive IBx were associated with poor outcome (P = .021 and P = .001, respectively). Our results support that capillaritis should be considered as a feature of ABMR in SBT and identify C1q-fixing DSAs and repeated C4d positivity as potential markers of poor outcome.

6.
N Engl J Med ; 377(13): 1250-1260, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28953447

RESUMO

BACKGROUND: Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response. METHODS: In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization. RESULTS: After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04). CONCLUSIONS: Rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival among patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis. (Funded by Roche and Amgen; LyMa ClinicalTrials.gov number, NCT00921414 .).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Fatores Imunológicos/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Citarabina/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Transplante Autólogo
7.
Pediatr Transplant ; 21(5)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28510265

RESUMO

In immunocompromised patients, the NoV infection is prolonged and severe. We retrospectively studied the severity of the NoV infection in children after an ITx, the treatment, and the long-term evolution. Norovirus PCR in stools was positive for 19 children in 21 separate episodes. The infection was symptomatic in 18 cases. At diagnosis, the median weight loss was 5% (0-11) and the creatinine clearance was 75 mL/min/1.73 m2 (19-142). On 14 digestive biopsies, the pathological findings were non-specific with a constant mononuclear infiltration, showing signs of rejection in one case. Fifteen children in 17 cases were hospitalized for a median duration of 41 days (0-119) with IV infusions for 33 days (0-120). The viral shedding lasted 78 days (20-360). Nine children with severe or prolonged diarrhea received intravenous IGs and four of them additional NTZ. On follow-up, five other children developed a rejection 12 months (1-33) after NoV infection. Four uncontrolled rejections led to graft removal. Children mostly needed hospital admission and IV rehydration, but the symptoms upon presentation were moderate. Symptoms and shedding durations are prolonged as expected. The treatment efficacy cannot be assessed. The rejection induction by the NoV cannot be excluded.


Assuntos
Infecções por Caliciviridae/diagnóstico , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Intestinos/transplante , Complicações Pós-Operatórias/diagnóstico , Índice de Gravidade de Doença , Infecções por Caliciviridae/imunologia , Infecções por Caliciviridae/terapia , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/virologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Resultado do Tratamento
8.
Hum Pathol ; 64: 128-136, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28414090

RESUMO

Previous immunohistochemical (IHC) studies showed controversial data about the prognostic value of tumor-infiltrating lymphocytes (TILs) in follicular lymphoma (FL). To clarify this issue, a large series of FL samples from rituximab-treated patients enrolled in the randomized PRIMA trial was examined. IHC was quantified using automated image analysis in 417, 287, 418, 406, 379, and 369 patients for CD3, CD4, CD8, PD1, ICOS, and FOXP3, respectively. RNAseq analysis was used to quantify TIL-related mRNA transcripts from 148 patients. When each IHC marker was used as a continuous variable in the whole cohort, high CD3 counts were associated with better progression-free survival (PFS) (P = .025). When an optimal IHC cut point was applied to the whole patient population, high CD3 counts and high PD1 counts were associated with better PFS (P = .011 and P = .044, respectively), whereas none of the other TIL markers had any significant correlation with outcome. When a stringent analysis was performed by dividing the whole cohort into a training set and a validation set, none of the TIL markers showed a prognostic significance in both groups. RNAseq analysis showed a significant correlation between high levels of CD3 and CD8 transcripts and better PFS (P = .001 and P = .037, respectively). No prognostic correlation was found as to the level of other immune gene transcripts. These results suggest that the IHC prognostic value of TILs is circumvented by rituximab treatment, although there is a trend for high numbers of CD3+ TILs to correlate with better PFS.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Linfócitos T/efeitos dos fármacos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Complexo CD3/análise , Complexo CD3/genética , Intervalo Livre de Doença , Humanos , Interpretação de Imagem Assistida por Computador , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Valor Preditivo dos Testes , RNA Mensageiro/genética , Análise de Sequência de RNA , Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento , Microambiente Tumoral
9.
Nat Commun ; 8: 13998, 2017 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-28084299

RESUMO

Monolayered epithelia are composed of tight cell assemblies that ensure polarized exchanges. EpCAM, an unconventional epithelial-specific cell adhesion molecule, is assumed to modulate epithelial morphogenesis in animal models, but little is known regarding its cellular functions. Inspired by the characterization of cellular defects in a rare EpCAM-related human intestinal disease, we find that the absence of EpCAM in enterocytes results in an aberrant apical domain. In the course of this pathological state, apical translocation towards tricellular contacts (TCs) occurs with striking tight junction belt displacement. These unusual cell organization and intestinal tissue defects are driven by the loss of actomyosin network homoeostasis and contractile activity clustering at TCs, yet is reversed by myosin-II inhibitor treatment. This study reveals that adequate distribution of cortical tension is crucial for individual cell organization, but also for epithelial monolayer maintenance. Our data suggest that EpCAM modulation protects against epithelial dysplasia and stabilizes human tissue architecture.


Assuntos
Células Epiteliais/química , Epitélio/química , Actomiosina/química , Actomiosina/genética , Actomiosina/metabolismo , Adolescente , Fenômenos Biomecânicos , Células CACO-2 , Polaridade Celular , Criança , Pré-Escolar , Diarreia Infantil/genética , Diarreia Infantil/metabolismo , Enterócitos/química , Enterócitos/metabolismo , Molécula de Adesão da Célula Epitelial/química , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio/metabolismo , Feminino , Humanos , Lactente , Síndromes de Malabsorção/genética , Síndromes de Malabsorção/metabolismo , Masculino , Junções Íntimas/química , Junções Íntimas/genética , Junções Íntimas/metabolismo
10.
Lancet ; 389(10069): 612-620, 2017 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-28069279

RESUMO

BACKGROUND: Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. FINDINGS: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). INTERPRETATION: These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. FUNDING: AB Science (Paris, France).


Assuntos
Mastocitose Sistêmica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Astenia/induzido quimicamente , Diarreia/induzido quimicamente , Método Duplo-Cego , Exantema/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Urticária/induzido quimicamente , Adulto Jovem
11.
Genes Chromosomes Cancer ; 56(3): 221-230, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27750397

RESUMO

Plasma-cell post-transplantation lymphoproliferative disorder (PC-PTLD) is a rare monomorphic PTLD entity divided into plasma cell myeloma (PCM) and plasmacytoma-like lesion (PLL) PTLD. To date, there are no exhaustive published cytogenetic data on PC-PTLD. We report array-based comparative genomic hybridization (aCGH) of 10 cases of PCM and PLL-PTLD. Patients had received kidney (n = 6), heart (n = 2), lung (n = 1) or bone marrow (n = 1) transplantation. There were six men and median age at time of PTLD was 56.5 years (3-74). We identified two different cytological features, plasmacytic and plasmablastic, among six PLL and three PCM PTLD. Eight cases were associated with EBV. First line treatment was heterogeneous: rituximab alone (n = 5), CHOP-like (n = 3) and multiple myeloma-like (n = 1). One patient died before any treatment. After a median follow-up of 19.5 months (0-150), five patients died (four from PTLD) and five were alive without evidence of disease. By aCGH, 5/10 demonstrated a complex profile. The most frequent abnormalities were +7q (5/10), +16q (5/10), +17q (5/10), +17p (4/10), +5q (4/10), t7 (4/10), t9 (3/10), del1p (3/10). No del17p13 (TP53) were observed. Del1p32.3 (CDKN2C) was observed in 2 cases. On univariate prognostic analysis, a complex aCGH was associated with a shorter OS. Thus, cytogenetic abnormalities seem to be closely related to those reported in multiple myeloma or diffuse large B cell lymphoma. Complex aCGH constitutes an unfavorable prognostic marker and aCGH should be integrated in the evaluation of patients with PLL/PCM-PTLD. © 2016 Wiley Periodicals, Inc.


Assuntos
Biomarcadores Tumorais/genética , Hibridização Genômica Comparativa/métodos , Transtornos Linfoproliferativos/diagnóstico , Transplante de Órgãos/efeitos adversos , Plasmócitos/patologia , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
12.
PLoS One ; 11(10): e0162965, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27749916

RESUMO

Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders and B-cell non-Hodgkin lymphomas (B-NHLs). Evaluation of the efficacy and safety profiles of different antiviral therapies in HCV patients with B-NHL is warranted. METHODS: First, we evaluated the sustained virologic response (SVR) and safety of Peg-interferon-alpha (Peg-IFN) + ribavirin +/- first protease inhibitors (PI1s) therapy in 61 HCV patients with B-NHL enrolled in a nationwide observational survey compared with 94 matched HCV-infected controls without B-NHL. In a second series, interferon-free regimens using a newly optimal combination therapy with direct-acting antiviral drugs (DAAs) were evaluated in 10 patients with HCV and B-NHL. RESULTS: The main lymphoma type was diffuse large B-cell lymphoma (38%) followed by marginal zone lymphoma (31%). In the multivariate analysis, patients with B-NHL treated by Peg-IFN-based therapy exhibited a greater SVR rate compared with controls, 50.8% vs 30.8%, respectively, p<0.01, odds ratio (OR) = 11.2 [2.3, 52.8]. B-NHL response was better (p = 0.02) in patients with SVR (69%) than in patients without SVR (31%). Premature discontinuation of Peg-IFN-based therapy was significantly more frequent in the B-NHL group (19.6%) compared with the control group (6.3%), p<0.02. Overall, survival was significantly enhanced in the controls than in the B-NHL group (hazard ratio = 34.4 [3.9, 304.2], p< 0.01). Using DAAs, SVR was achieved in 9/10 patients (90%). DAAs were both well tolerated and markedly efficient. CONCLUSIONS: The virologic response of HCV-associated B-NHL is high. Our study provides a comprehensive evaluation of different strategies for the antiviral treatment of B-NHL associated with HCV infection.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Linfoma de Células B/complicações , Idoso , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/mortalidade , Hepatite C/virologia , Humanos , Interferon-alfa/uso terapêutico , Linfoma de Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma Difuso de Grandes Células B/complicações , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Polietilenoglicóis/uso terapêutico , Modelos de Riscos Proporcionais , Inibidores de Proteases/uso terapêutico , RNA Viral/sangue , RNA Viral/metabolismo , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento
13.
Medicine (Baltimore) ; 95(41): e5047, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27741115

RESUMO

INTRODUCTION: We report the case of a multicentric Castleman disease (MCD) with initial renal involvement. Although the renal involvement in this case was typical of MCD, it constitutes a rare presentation of the disease, and in our case the renal manifestations led to the haematological diagnosis. CLINICAL FINDINGS/PATIENT CONCERNS: The patient was admitted for fever, diarrhea, anasarca, lymphadenopathies and acute renal failure. Despite intravenous rehydration using saline and albumin, renal function worsened and the patient required dialysis. While diagnostic investigations were performed, right hemiplegia occurred. There was no anemia or thrombocytopenia. DIAGNOSES: Kidney biopsy was consistent with glomerular thrombotic microangiopathy (TMA). Lymph node histology was consistent with hyalin-vascular variant of Castleman disease. OUTCOMES: Given the renal and neurological manifestations of this MCD-associated TMA, the patient was treated with plasma exchange during one month, and six courses of rituximab, cyclophosphamide and dexamethasone. The evolution was favorable. CONCLUSION: Although rare, this diagnosis is worth knowing, as specific treatment has to be started as soon as possible and proved to be efficient in our case as well as in other reports in the literature.


Assuntos
Hiperplasia do Linfonodo Gigante/complicações , Glomérulos Renais/diagnóstico por imagem , Microangiopatias Trombóticas/etiologia , Biópsia , Hiperplasia do Linfonodo Gigante/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Microangiopatias Trombóticas/diagnóstico
14.
Oncotarget ; 7(40): 66299-66309, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27602777

RESUMO

Mast cell sarcoma (MCS) is a rare form of mastocytosis characterized by the presence of solid tumor(s) comprising malignant mast cells that harbor destructive infiltration capability and metastatic potential. Here, we present an extensive literature review and report on 23 cases of MCS, including 3 new cases from the French National Reference Center for Mastocytosis. From our analysis, it appears that MCS can occur at any age. It can manifest de novo or, to a lesser extent, may evolve from a previously established mastocytosis. Bone tumor is a frequent manifestation, and symptoms of mast cell activation are rare. Histological diagnosis can be difficult because MCS is frequently composed of highly atypical neoplastic mast cells and can thus mimic other tumors. Unexpectedly, the canonical KIT D816V mutation is found in only 21% of MCS; therefore, complete KIT gene sequencing is required. The prognosis of patients with MCS is poor, with a median survival time of less than 18 months, and progression to mast cell leukemia is not unusual. Because conventional chemotherapies usually fail, the role of targeted therapies and bone marrow transplantation warrants further investigation in such aggressive neoplasms.


Assuntos
Sarcoma de Mastócitos/patologia , Sarcoma de Mastócitos/terapia , Progressão da Doença , Humanos , Prognóstico
15.
Optom Vis Sci ; 93(11): 1440-1443, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27560850

RESUMO

PURPOSE: Mastocytosis is characterized by clonal mast cell proliferation with accumulation within various organs and uncontrolled activation with excessive mast cell mediator release. Ocular manifestations have rarely been published. We describe a 63-year-old man with bilateral exophthalmos that led to the diagnosis of systemic mastocytosis. CASE REPORT: A patient presented with bilateral eyelid edema with exophthalmos associated with binocular diplopia. Ophthalmologic examination showed bilateral axial, symmetrical, and painless exophthalmos with eyelid edema, and limitation in elevation of the right eye. Visual acuity was normal. Orbital magnetic resonance imaging showed increased volume of both the superior and medial recti muscles and right inferior oblique muscle, and histopathological examination of orbital fat and muscle biopsies revealed an infiltration by mast cells. Serum tryptase was elevated. The patient also complained of a long history of pruritis and diffuse skin erythema that could be elicited with just mild pressure (Darier's sign). A bone marrow biopsy confirmed the infiltration of abnormal mast cells with a D816V mutation in the KIT gene. Treatment with cladribine was initiated and resulted in resolution of both ocular and systemic signs and symptoms that persisted without relapse 18 months after discontinuation. Ocular mastocytosis is a rare condition, which was previously reported to involve the conjunctiva, cornea, uvea, eyelid, orbit, and choroid. Cases of ocular mastocytosis can be classified into two main groups: mast cells tumors (mastocytomas) and ocular manifestations associated with systemic mastocytosis. Histological examination of ocular samples is rarely performed, and there are no standard criteria for the diagnosis of ocular mastocytosis. Our case emphasizes cladribine could represent an alternative treatment. CONCLUSIONS: Our case is the first published case of exophthalmos and eyelid edema associated with systemic mastocytosis confirmed by pathologic examination of periocular biopsies that was treated effectively with cladribine.


Assuntos
Diplopia/diagnóstico , Edema/diagnóstico , Exoftalmia/diagnóstico , Doenças Palpebrais/diagnóstico , Mastocitose Sistêmica/diagnóstico , Administração Oral , Diplopia/tratamento farmacológico , Edema/tratamento farmacológico , Exoftalmia/tratamento farmacológico , Doenças Palpebrais/tratamento farmacológico , Glucocorticoides/administração & dosagem , Humanos , Infusões Intravenosas , Masculino , Mastocitose Sistêmica/tratamento farmacológico , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Acuidade Visual
17.
PLoS One ; 11(6): e0156384, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27257992

RESUMO

Hepatitis C Virus (HCV) infection is associated with the B-cell non-Hodgkin lymphomas (NHL), preferentially marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL). While chronic antigenic stimulation is a main determinant of lymphomagenesis in marginal zone lymphomas (MZL), a putative role of HCV infection of B-cells is supported by in vitro studies. We performed a pathological study within the "ANRS HC-13 LymphoC" observational study focusing on in situ expression of the oncogenic HCV non structural 3 (NS3) protein. Lympho-C study enrolled 116 HCV-positive patients with B-NHL of which 86 histological samples were collected for centralized review. Main histological subtypes were DLBCL (36%) and MZL (34%). Almost half of DLBCL (12/26) were transformed from underlying small B-cell lymphomas. NS3 immunostaining was found positive in 17 of 37 tested samples (46%). There was a striking association between NS3 detection and presence of high grade lymphoma features: 12 out of 14 DLBCL were NS3+ compared to only 4 out of 14 MZL (p = 0.006). Moreover, 2 among the 4 NS3+ MZL were enriched in large cells. Remarkably, this study supports a new mechanism of transformation with a direct oncogenic role of HCV proteins in the occurrence of high-grade B lymphomas.


Assuntos
Hepacivirus/metabolismo , Hepatite C/complicações , Hepatite C/virologia , Linfoma de Células B/etiologia , Linfoma de Células B/virologia , Proteínas não Estruturais Virais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/metabolismo , Linfócitos B/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas não Estruturais Virais/genética
18.
J Clin Oncol ; 34(22): 2575-82, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27298402

RESUMO

PURPOSE: To study the outcome of histologic transformation (HT) in a large prospective cohort of patients with follicular lymphoma (FL) who previously responded to immunochemotherapy. PATIENTS AND METHODS: After a median 6-year follow-up of 1,018 randomly assigned patients from the PRIMA trial, disease progression was observed in 463 patients, 194 of whom had histologic documentation. RESULTS: Forty patients had histology consistent with HT, and 154 had untransformed FL (median time to recurrence, 9.6 v 22.8 months, respectively; P = .018). Thirty-seven percent of biopsies performed during the first year of follow-up showed HT corresponding to 58% of all HTs. Altered performance status, anemia, high lactate dehydrogenase level, "B" symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis were identified as HT risk factors. Response (complete v partial) to immunochemotherapy or rituximab maintenance had no impact on the risk of HT. After salvage treatment, patients with HT had less frequent complete response (50.3% v 67.4%; P = .03) and more disease progression (28.2% v 9.6%; P < .001) than patients without HT. Estimated overall survival for the patients with HT was poorer (median, 3.8 v 6.4 years; hazard ratio, 3.9; 95% CI, 2.2 to 6.9). Autologous stem cell transplantation improved the outcomes of patients with HT (median overall survival, not reached v 1.7 years) but not of patients with persistent FL histology. CONCLUSION: HT in patients with FL who previously responded to immunochemotherapy is an early event associated with a poor outcome that may deserve intensive salvage with autologous stem cell transplantation. These data emphasize the necessity for biopsy at the first recurrence of FL.


Assuntos
Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Linfoma Folicular/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Prospectivos , Fatores de Risco , Terapia de Salvação , Transplante de Células-Tronco , Resultado do Tratamento
19.
Clin Cancer Res ; 22(12): 2919-28, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-26819451

RESUMO

PURPOSE: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. EXPERIMENTAL DESIGN: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20(+)de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays. RESULTS: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell-like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses. CONCLUSIONS: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919-28. ©2016 AACRSee related commentary by Lim and Elenitoba-Johnson, p. 2829.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Anticorpos Monoclonais Murinos/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/patologia , Proteínas de Ciclo Celular/genética , Ciclofosfamida/uso terapêutico , Proteínas de Ligação a DNA/genética , Doxorrubicina/uso terapêutico , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Carioferinas/genética , Proteínas Oncogênicas/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Prednisona/uso terapêutico , Estudos Prospectivos , Receptores Citoplasmáticos e Nucleares/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Vincristina/uso terapêutico , Sequenciamento Completo do Exoma
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