RESUMEN
Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.
Asunto(s)
Linfadenopatía Inmunoblástica/metabolismo , Linfoma de Células T/metabolismo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Transducción de Señal , Proteína de Unión al GTP rhoA/metabolismo , Biomarcadores de Tumor , Línea Celular Tumoral , Citocinas/metabolismo , Análisis Mutacional de ADN , Humanos , Linfadenopatía Inmunoblástica/genética , Linfoma de Células T/genética , Mutación , Factores de Transcripción NFATC/metabolismo , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-vav/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Proteína de Unión al GTP rhoA/genéticaRESUMEN
Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses. Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/radioterapia , Adolescente , Adulto , Anciano de 80 o más Años , Quimioradioterapia , Estudios de Cohortes , Esquema de Medicación , Femenino , Humanos , Linfoma Extranodal de Células NK-T/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Adulto JovenRESUMEN
Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.
Asunto(s)
Biomarcadores de Tumor , Linfoma Extranodal de Células NK-T/genética , Mutación , Alelos , Sustitución de Aminoácidos , Linfocitos B/metabolismo , Linfocitos B/patología , ADN Metiltransferasa 3A , Reordenamiento Génico de Linfocito T , Predisposición Genética a la Enfermedad , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Inmunohistoquímica , Inmunofenotipificación , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/patología , Especificidad de Órganos/genética , Fenotipo , Análisis de Secuencia de ADN , Recombinación V(D)J , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoAsunto(s)
Linfoma de Células B Grandes Difuso/terapia , Neoplasias del Mediastino/terapia , Trasplante de Células Madre , Trasplante Autólogo , Adolescente , Adulto , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Neoplasias del Mediastino/tratamiento farmacológico , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenAsunto(s)
Busulfano/administración & dosificación , Enfermedades Hematológicas , Melfalán/administración & dosificación , Acondicionamiento Pretrasplante , Vidarabina/análogos & derivados , Adulto , Anciano , Trasplante de Células Madre de Sangre del Cordón Umbilical , Supervivencia sin Enfermedad , Femenino , Enfermedades Hematológicas/mortalidad , Enfermedades Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de Supervivencia , Vidarabina/administración & dosificación , Irradiación Corporal TotalRESUMEN
BACKGROUND: Pneumonia caused by Stenotrophomonas maltophilia is rare, but can be lethal in severely immunocompromised patients. However, its clinical course remains unclear. PATIENTS AND METHODS: Patients with pneumonia caused by S. maltophilia in Toranomon Hospital (890 beds, Tokyo, Japan) were reviewed retrospectively between April 2006 and March 2010. RESULTS: During the study period, 10 cases of S. maltophilia pneumonia were identified. Seven patients had acute myeloid leukemia, 2 had myelodysplastic syndrome, and 1 had malignant lymphoma. All patients developed symptoms after allogeneic hematopoietic stem cell transplantation (HSCT). Five patients received first cord blood transplantation (CBT), 4 patients received second CBT, and 1 patient received first peripheral blood stem cell transplantation (PBSCT). The overall incidence of S. maltophilia pneumonia among 508 patients who received HSCT during the period was 2.0%. The incidence was 0% (0/95) in patients after bone marrow transplantation, 0.8% (1/133) after PBSCT, and 3.2% (9/279) after CBT. Pneumonia developed a median of 13.5 days (range, 6-40) after transplantation. At onset, the median white blood cell count was 10/µL (range, 10-1900), and the median neutrophil count was 0/µL (range, 0-1720). In all patients, S. maltophilia bacteremia developed with bloody sputum or hemoptysis. The 28-day mortality rate was 100%; the median survival after onset of pneumonia was 2 days (range, 1-10). CONCLUSIONS: Hemorrhagic S. maltophilia pneumonia rapidly progresses and is fatal in patients with hematologic malignancy. Attention should be particularly paid to the neutropenic phase early after HSCT or prolonged neutropenia due to engraftment failure. A prompt trimethoprim-sulfamethoxazole-based multidrug combination regimen should be considered to rescue suspected cases of S. maltophilia pneumonia in these severely immunosuppressed patients.
Asunto(s)
Neoplasias Hematológicas/complicaciones , Hemorragia/etiología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/mortalidad , Stenotrophomonas maltophilia/aislamiento & purificación , Adulto , Antibacterianos/uso terapéutico , Sangre/microbiología , Medios de Cultivo , Progresión de la Enfermedad , Femenino , Infecciones por Bacterias Gramnegativas/complicaciones , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Huésped Inmunocomprometido , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/tratamiento farmacológico , Factores de Tiempo , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
The purpose of this study was to elucidate the effect of solute miscibility in frozen solutions on their micro- and macroscopic structural integrity during freeze-drying. Thermal analysis of frozen solutions containing poly(vinylpyrrolidone) (PVP) and dextran showed single or multiple thermal transitions (T'g: glass transition temperature of maximally freeze-concentrated solutes) depending on their composition, which indicated varied miscibility of the concentrated noncrystalline polymers. Freeze-drying of the miscible solute systems (e.g., PVP 10,000 and dextran 1060, single T'g induced physical collapse during primary drying above the transition temperatures T'g). Phase-separating PVP 29,000 and dextran 35,000 mixtures (two T'g s) maintained their cylindrical structure following freeze-drying below both of the T'g s (<-24 °C). Primary drying of the dextran-rich systems at temperatures between the two T'g s (-20 to -14 °C) resulted in microscopically disordered "microcollapsed" cake-structure solids. Freeze-drying microscopy (FDM) analysis of the microcollapsing polymer system showed locally disordered solid region at temperatures between the collapse onset (T(c1)) and severe structural change (T(c2)). The rigid dextran-rich matrix phase should allow microscopic structural change of the higher fluidity PVP-rich phase without loss of the macroscopic cake structure at the temperature range. The results indicated the relevance of physical characterization and process control for appropriate freeze-drying of multicomponent formulations.
Asunto(s)
Dextranos/química , Liofilización , Povidona/química , Rastreo Diferencial de Calorimetría , Congelación , Solubilidad , Soluciones/química , Temperatura de TransiciónAsunto(s)
Antígenos CD/inmunología , Trasplante de Médula Ósea , Linfoma Cutáneo de Células T/inmunología , Micosis Fungoide/inmunología , Recurrencia Local de Neoplasia , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Micosis Fungoide/patología , Fenotipo , Insuficiencia del TratamientoRESUMEN
BACKGROUND: A growing number of studies demonstrate the utility of (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in the management of malignant lymphoma. The results of FDG-PET, however, have not been studied extensively for T-cell and natural killer (NK)-cell neoplasms. PATIENTS AND METHODS: We retrospectively evaluated pretreatment FDG-PET scans in 41 patients with T/NK-cell neoplasms diagnosed according to the World Health Organization (WHO) classification. Histological subtypes frequently included were peripheral T-cell lymphoma, unspecified (PTCLu, n = 11), extranodal NK/T-cell lymphoma, nasal type (ENKL, n = 8), primary cutaneous anaplastic large cell lymphoma (C-ALCL, n = 5), and angioimmunoblastic T-cell lymphoma (AILT, n = 4). RESULTS: FDG-PET detected a lymphoma lesion in at least one site in 36 out of 41 patients. The positive rate was equally high in most histological subtypes except for cutaneous lymphomas: PTCLu 91%, ENKL 100%, C-ALCL 60%, AILT 100%. All the patients without an FDG-avid lesion had lesions restricted to skin. Among patients who had cutaneous lesions, only 50% had FDG-avid cutaneous lesions, all of which were tumorous. The positive rate of FDG-PET for bone marrow involvement was only 20%. CONCLUSION: T/NK-cell neoplasms incorporated in this study were generally FDG-avid except for cutaneous lesions and bone marrow involvement.
Asunto(s)
Médula Ósea/patología , Fluorodesoxiglucosa F18 , Células Asesinas Naturales/patología , Linfoma Anaplásico Cutáneo Primario de Células Grandes/diagnóstico por imagen , Linfoma de Células T/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Late-onset neutropenia (LON) has been reported following rituximab-containing chemotherapy. Its incidence and risk factors, however, have not been extensively studied. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 107 patients treated with rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphomas and identified cases with LON as defined by the neutrophil count of Asunto(s)
Anticuerpos Monoclonales/efectos adversos
, Antígenos CD20/metabolismo
, Antineoplásicos/efectos adversos
, Linfoma de Células B/tratamiento farmacológico
, Neutropenia/inducido químicamente
, Adulto
, Anciano
, Anciano de 80 o más Años
, Anticuerpos Monoclonales de Origen Murino
, Femenino
, Humanos
, Incidencia
, Linfoma de Células B/metabolismo
, Masculino
, Persona de Mediana Edad
, Estudios Retrospectivos
, Rituximab
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Inmunosupresores/efectos adversos , Mononucleosis Infecciosa/inducido químicamente , Metotrexato/efectos adversos , Anciano , Médula Ósea/patología , ADN Viral/análisis , Diagnóstico Diferencial , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Herpesvirus Humano 4/genética , Humanos , Inmunosupresores/administración & dosificación , Mononucleosis Infecciosa/diagnóstico , Mononucleosis Infecciosa/virología , Metotrexato/administración & dosificación , Reacción en Cadena de la Polimerasa , Tomografía Computarizada por Rayos XRESUMEN
Clinical impact of high-grade (HG) cytomegalovirus (CMV) antigenemia after hematopoietic stem cell transplantation has not been clarified. Therefore, in order to investigate the risk factors and outcome for HG-CMV antigenemia, we retrospectively analyzed the records of 154 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2002 at the University of Tokyo Hospital. Among 107 patients who developed positive CMV antigenemia at any level, 74 received risk-adapted preemptive therapy with ganciclovir (GCV), and 17 of these developed HG-antigenemia defined as > or = 50 positive cells per two slides. The use of systemic corticosteroids at > or = 0.5 mg/kg/day at the initiation of GCV was identified as an independent significant risk factor for HG-antigenemia. Seven of the 17 HG-antigenemia patients developed CMV disease, with a cumulative incidence of 49.5%, which was significantly higher than that in the low-grade antigenemia patients (4%, P<0.001). However, overall survival was almost equivalent in the two groups. In conclusion, the development of HG-antigenemia appeared to depend on the profound immune suppression of the recipient. Although CMV disease frequently developed in HG-antigenemia patients, antiviral therapy could prevent a fatal outcome.
Asunto(s)
Antígenos Virales/sangre , Infecciones por Citomegalovirus/sangre , Citomegalovirus , Neoplasias Hematológicas/sangre , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Antivirales/administración & dosificación , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/prevención & control , Femenino , Ganciclovir/administración & dosificación , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Trasplante HomólogoRESUMEN
Alemtuzumab is a humanized monoclonal antibody directed against human CD52 with a strong lympholytic effect. We have performed unmanipulated hematopoietic stem cell transplantation (HSCT) from 2- or 3-locus-mismatched family donors in 14 patients using in vivo alemtuzumab. All achieved complete donor cell engraftment and grade III-IV acute graft-versus-host disease was observed in only one patient. However, eight of the 14 patients developed grade II-IV cardiac complications according to Bearman's criteria. Next, we retrospectively analyzed the records of 142 adult patients who underwent allogeneic HSCT from 1995 to 2004 to evaluate whether the use of alemtuzumab was an independent risk factor for cardiac complications. Among several factors that increased the incidence of grade II-IV cardiac complications with at least borderline significance, a multivariate analysis identified the cumulative dose of anthracyclines (P=0.0016) and the use of alemtuzumab (P=0.0001) as independent significant risk factors. All of the cardiac complications in the alemtuzumab group were successfully treated with diuretics and/or catecholamines. Patient selection and close monitoring of cardiac function may be important in HLA-mismatched HSCT using in vivo alemtuzumab.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antineoplásicos/administración & dosificación , Catecolaminas/uso terapéutico , Diuréticos/uso terapéutico , Cardiopatías/tratamiento farmacológico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Adulto , Alemtuzumab , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/efectos adversos , Estudios de Casos y Controles , Evaluación de Medicamentos , Femenino , Supervivencia de Injerto/efectos de los fármacos , Enfermedad Injerto contra Huésped/etiología , Cardiopatías/etiología , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Trasplante HomólogoRESUMEN
The value of pre-transplant factors for predicting the development of cardiac complications after transplantation has been inconsistent among studies. We analyzed the impact of pre-transplant factors on the incidence of severe cardiac complications in 164 hematopoietic stem cell transplant recipients. We identified eight patients (4.8%) who experienced grade III or IV cardiac complications according to the Bearman criteria. Seven died of cardiac causes a median of 3 days after the onset of cardiac complications. On univariate analysis, both the cumulative dose of anthracyclines and the use of anthracyclines within 60 days before transplantation affected the incidence of severe cardiac complications (P=0.0091 and 0.011). The dissociation of heart rate and body temperature, which reflects "relative tachycardia", was also associated with a higher incidence of cardiac complications (P=0.024). None of the variables obtained by electrocardiography or echocardiography were useful for predicting cardiac complications after transplantation, although the statistical power might not be sufficient to detect the usefulness of ejection fraction. On a multivariate analysis, the cumulative dose of anthracyclines was the only independent significant risk factor for severe cardiac complications. We conclude that the cumulative dose of anthracyclines is the most potent predictor of cardiac complications and the administration of anthracyclines should be avoided within two months before transplantation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Taquicardia/diagnóstico , Adulto , Antraciclinas/uso terapéutico , Temperatura Corporal , Terapia Combinada , Ciclofosfamida/uso terapéutico , Ecocardiografía , Electrocardiografía , Femenino , Frecuencia Cardíaca , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Complicaciones Posoperatorias , Estudios Retrospectivos , Factores de Riesgo , Taquicardia/etiología , Acondicionamiento Pretrasplante , Trasplante Homólogo/métodos , Irradiación Corporal TotalRESUMEN
The effect of graft-versus-host disease (GVHD) on relapse incidence and survival has been analyzed in several studies, but previous studies included heterogeneous patients. Therefore, we analyzed the data of 2114 patients who received unmanipulated bone marrow graft from an HLA-identical sibling donor with a GVHD prophylaxis using cyclosporin A and methotrexate. Among the 1843 patients who survived without relapse at 60 days after transplantation, 435 (24%) developed grade II-IV acute GVHD. Among the 1566 patients who survived without relapse at 150 days after transplantation, 705 (47%) developed chronic GVHD. The incidence of relapse was significantly lower in patients who developed acute or chronic GVHD, but disease-free survival (DFS) was significantly inferior in patients who developed acute GVHD. A benefit of 'mild' GVHD was only seen in high-risk patients who developed grade I acute GVHD. The strongest association between GVHD and a decreased incidence of relapse was observed in patients with standard-risk acute myelogenous leukemia/myelodysplastic syndrome. In conclusion, the therapeutic window between decreased relapse and increased transplant-related mortality due to the development of GVHD appeared to be very narrow.
Asunto(s)
Trasplante de Médula Ósea , Ciclosporina/uso terapéutico , Enfermedad Injerto contra Huésped/complicaciones , Metotrexato/uso terapéutico , Adulto , Anciano , Trasplante de Médula Ósea/mortalidad , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
We retrospectively compared the incidence of acute graft-versus-host disease (GVHD) before and after September 1999, when we changed the mode of cyclosporine A (CsA) administration from twice-daily infusions (TD) (n=58) to continuous infusion (CIF) (n=71). The incidence of grade II-IV acute GVHD in the CIF group (56%) was significantly higher than that in the TD group (27%, P=0.00022). Multivariate analysis identified only two independent significant risk factors for the development of grade II-IV acute GVHD; CIF of CsA (relative risk 2.59, 95% CI 1.46-4.60, P=0.0011) and the presence of HLA mismatch (2.01, 95% CI 1.15-3.53, P=0.014). The incidence of relapse was significantly lower in the CIF group when adjusted for disease status before transplantation (0.41, 95% CI 0.18-0.95, P=0.038), which resulted in better disease-free survival in high-risk patients (43 vs 16% at 2 years, P=0.039), but not in standard-risk patients (72 vs 80%, P=0.45). CIF of CsA with a target level of 250-400 ng/ml may not be appropriate for GVHD prophylaxis in standard-risk patients.