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1.
Eur J Haematol ; 2020 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-32003046

RESUMEN

OBJECTIVE: Myelodysplastic syndromes (MDS), caused by various genetic mutations in hematopoietic stem cells, are associated with highly variable outcomes. Poly (ADP-ribose) polymerase-1 (PARP1) plays an important role in DNA damage repair and contributes to the progression of several types of cancer. Here, we investigated the impact of PARP1 V762A polymorphism on the susceptibility to and prognosis of MDS. METHODS: Samples collected from 105 MDS patients and 202 race-matched healthy controls were subjected to polymerase chain reaction-restriction fragment length polymorphism for genotyping. RESULTS: The allele and genotype frequencies of PARP1 V762A did not differ between MDS patients and the control group. However, MDS patients with the PARP1 V762A non-AA genotype, which is associated with high gene activity, had shorter overall survival rates (P = 0.01) than those with the AA genotype. Multivariate analysis of overall survival also revealed PARP1 V762A non-AA genotype as a poor prognostic factor (P = 0.02). When patients were analyzed according to treatment history, the PARP1 V762A non-AA genotype was only associated with poor survival in patients who had received treatment (P = 0.02). CONCLUSION: PARP1 V762A polymorphism may be an independent prognostic factor for MDS, and a predictive biomarker for MDS treatment.

2.
Intern Med ; 2020 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-31956206

RESUMEN

A 69-year-old man with palpitations and decreased blood pressure was referred. Echocardiography showed a mass in the right atrium and cardiac septum. The serum IgG4 level was 1450 mg/dl. A biopsy of the cardiac mass showed fibrosis with inflammatory cells and increased IgG4-positive plasma cells and lymphocytes. Flow cytometry and polymerase chain reaction of the immunoglobulin heavy chain did not demonstrate monoclonality. He was diagnosed with IgG4-related disease (IgG4-RD). IgG4-RD with a cardiac mass is rare and it is difficult to distinguish it from malignant lymphoma by a pathological examination alone. We therefore performed a biopsy and analyzed the clonality in order to make an accurate diagnosis of IgG4-RD.

3.
Br J Haematol ; 184(4): 570-577, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30417943

RESUMEN

The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.


Asunto(s)
Cromosomas Humanos Par 21/genética , Linfoma Folicular/genética , Linfoma Folicular/microbiología , Trisomía , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Folicular/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Factores de Riesgo , Rituximab/administración & dosificación , Tasa de Supervivencia
4.
Int J Hematol ; 109(1): 91-97, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30203253

RESUMEN

90Y-ibritumomab tiuxetan (90Y-IT) is widely used, but the factors responsible for its optimal treatment effects are unknown. We enrolled 34 patients with relapsed indolent lymphoma treated with 90Y-IT monotherapy at Gunma University Hospital between 2003 and 2014 in the present study. Clinical data including computed tomography and 18-Fluoro-deoxyglucose positron emission tomography were retrospectively analyzed. The overall response rate and complete response rate were 91% and 82%, respectively. The median progression-free survival (PFS) and overall survival were 32 months and not reached, respectively. In univariate analysis, tumor long-axis diameter ≤ 2.5 cm, maximum standardized uptake value (SUVmax) ≤ 6.5, localized disease, normal levels of serum soluble interleukin-2 receptor, and the number of involved nodal sites ≤ 3 immediately prior to 90Y-IT were associated with median PFS greater than 6 years. However, in multivariate analysis, only tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5 affected PFS [hazard ratio (HR) 0.130, P = 0.0021 and HR 0.283, P = 0.0311, respectively]. Patients with only one prior regimen needed less granulocyte colony-stimulating factor and platelet transfusion. Thus, 90Y-IT treatment should be considered for patients with indolent lymphoma in first relapse who have tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfoma no Hodgkin/radioterapia , Diagnóstico por Imagen , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Tomografía Computarizada por Rayos X , Radioisótopos de Itrio/uso terapéutico
5.
Int J Hematol ; 108(3): 246-253, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29737460

RESUMEN

Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35-12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.


Asunto(s)
ADN Glicosilasas/genética , Reparación del ADN/genética , Reparación del ADN/fisiología , Estudios de Asociación Genética , Genotipo , Leucemia Mieloide Aguda/genética , Mutación , Polimorfismo Genético , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Daño del ADN , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Especies Reactivas de Oxígeno , Recurrencia , Riesgo , Tasa de Supervivencia , Adulto Joven
6.
J Clin Exp Hematop ; 58(1): 10-16, 2018 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-29415976

RESUMEN

Recent studies have revealed the clinical and biological features of stage I follicular lymphoma (FL), but information about patients with stage I FL who underwent total resection after tissue biopsy is limited. Among 305 FL patients diagnosed between 2001 and 2013, clinical stage I disease was observed in 36 patients. Of these, 18 patients underwent total resection after diagnostic tissue biopsy. We used 18F-fluorodeoxyglucose positron emission CT for staging assessment in 13 of 18 patients (72.2%). The median age was 56.5 years. Six patients (33.3%) were male. The soluble interleukin-2 receptor alpha concentration was significantly lower than in patients with residual disease. Among these 18 patients, 7 patients (38.9%) were treated with a "watch-and-wait" (WW) policy, 7 (38.9%) were treated with involved-field irradiation, and 4 (22.2%) received systemic chemotherapy. Patients with resected disease were treated with significantly different strategies from those with residual disease (p = 0.0026). Five patients experienced relapse during follow-up (median follow-up: 48.2 months). All relapses were distant from the primary site, irrespective of treatment strategy. Among all stage I patients, disease resection was not a significant factor for survival (p = 0.9294). Collectively, the choice of treatment strategy was significantly influenced by patient status. Resection status was not significantly associated with survival after several treatment strategies.


Asunto(s)
Glucosa-6-Fosfato/análogos & derivados , Linfoma Folicular , Tomografía de Emisión de Positrones , Anciano , Supervivencia sin Enfermedad , Femenino , Glucosa-6-Fosfato/administración & dosificación , Humanos , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/mortalidad , Linfoma Folicular/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasia Residual , Tasa de Supervivencia
7.
Br J Haematol ; 180(5): 705-714, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29359792

RESUMEN

Programmed death-1 (PD-1, PDCD1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CTLA4) play central roles in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PDCD1 and CTLA4 have been reported to be associated with susceptibility to some autoimmune diseases. However, the potential association between SNPs in these immune checkpoint genes and risk of chronic immune thrombocytopenia (cITP) remain controversial and obscure. The aims of this study were to clarify the influence of PDCD1 and CTLA4 SNPs on the risk of developing cITP and its clinical features. We obtained genomic DNA from 119 patients with cITP and 223 healthy controls; their genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients with cITP had a significantly higher frequency of the PDCD1 +7209 TT genotype compared with healthy controls. The CTLA4 -1577 GG genotype and CT60 GG genotype showed higher frequencies of platelet count <5 × 109 /l at diagnosis, minimum platelet count <5 × 109 /l, and bleeding symptoms. Moreover, the PDCD1 -606 AA genotype and +63379 TT genotype were significantly associated with a lower number of patients who achieved a complete response to prednisolone treatment. Our results suggest that the immune checkpoint polymorphisms may affect the susceptibility to the clinical features of cITP, and treatment response of the affected patients.


Asunto(s)
Antígeno CTLA-4/genética , Polimorfismo de Nucleótido Simple/genética , Receptor de Muerte Celular Programada 1/genética , Púrpura Trombocitopénica Idiopática/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Factores de Riesgo , Adulto Joven
8.
J Pediatr Hematol Oncol ; 40(3): e171-e175, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29200172

RESUMEN

We describe a rare case of chronic active Epstein-Barr virus (CAEBV) infection, with infiltration of the skeletal muscle. A 19-year-old woman with swollen cervical lymph nodes and a fever was referred to our hospital. Swelling of the trapezium muscle and elevation of creatinine kinase level were observed. Biopsy results of the brachialis muscle revealed infiltration of Epstein-Barr virus (EBV)-encoded RNA-positive CD8 T lymphocytes. The EBV virus load in the peripheral blood was high, and EBV monoclonality was determined by Southern blot analysis. Owing to the rarity of CAEBV with skeletal muscle infiltration, this case alerts physicians to the potential diagnostic pitfalls of CAEBV.


Asunto(s)
Linfocitos T CD8-positivos/virología , Infecciones por Virus de Epstein-Barr/patología , Músculo Esquelético/patología , Enfermedad Crónica , Femenino , Herpesvirus Humano 4 , Humanos , Miositis/patología , Miositis/virología , Adulto Joven
9.
Hematol Oncol ; 36(1): 196-201, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28786198

RESUMEN

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A -197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A -197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A -197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL-17 and IL-23R polymorphisms may affect severity, bone lesions, and extra-medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.


Asunto(s)
Interleucina-17/genética , Mieloma Múltiple/genética , Receptores de Interleucina/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Polimorfismo de Nucleótido Simple , Pronóstico , Análisis de Supervivencia
10.
Br J Haematol ; 179(3): 449-460, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28770558

RESUMEN

Extramedullary myeloma (EMM) occurs when myeloma develops outside the bone marrow; it often develops after chemotherapy and is associated with the acquisition of chemo-resistance and a fatal course. The mechanisms underlying extramedullary spread have not yet been fully elucidated. MALAT1 is a highly abundantly and ubiquitously expressed long non-coding RNA that plays important roles in cancer metastasis. The aims of this study were to clarify the association of MALAT1 with EMM and to elucidate the underlying mechanism of EMM formation under chemotherapeutic pressure. MALAT1 expression was significantly higher in multiple myeloma (MM) than in monoclonal gammopathy of undetermined significance. Furthermore, MALAT1 expression was markedly higher in EMM compared with that in corresponding intramedullary myeloma cells. A higher MALAT1 level was associated with shorter overall and progression-free survival. MALAT1 expression level was positively correlated with expression of HSP90AA1, HSP90AB1 and HSP90B1 but not with TP53 expression. MALAT1 was significantly upregulated by bortezomib and doxorubicin. Considering the known functions of MALAT1, our results suggest that it acts as a stress response gene that is upregulated by chemotherapy, thereby linking chemotherapy to EMM formation. Elucidating the biological implication of long non-coding RNA contributes to deeper understanding concerning the pathogenesis and investigation of novel therapeutic targets for MM.


Asunto(s)
Biomarcadores de Tumor/genética , Mieloma Múltiple/patología , ARN Largo no Codificante/genética , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Bortezomib/farmacología , Progresión de la Enfermedad , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/metabolismo , Mieloma Múltiple/genética , Pronóstico , ARN Largo no Codificante/biosíntesis , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Estrés Fisiológico/genética , Análisis de Supervivencia , Células Tumorales Cultivadas
11.
Cancer Sci ; 108(8): 1556-1564, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28544233

RESUMEN

B-cell lymphoma 6 (BCL6) attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Here, we report that overexpression of BCL6 in a MM cell line, KMS12PE, induced transcriptional repression of ataxia telangiectasia mutated (ATM), a DDR signaling kinase, which was associated with a reduction in γH2AX formation after DNA damage. In contrast, transcription of known targets of BCL6 in GC B cells was not affected, suggesting a cell type-specific function of BCL6. To further investigate the effects of BCL6 overexpression on the MM cell line, we undertook mRNA sequence analysis and found an upregulation in the genomic mutator activation-induced cytidine deaminase (AID) with alteration in the gene expression profile, which is suggestive of de-differentiation from plasma cells. Moreover, interleukin-6 exposure to KMS12PE led to upregulation of BCL6 and AID, downregulation of ATM, and attenuation of DDR, which were consistent with the effects of BCL6 overexpression in this MM cell line. Taken together, these results indicated that overexpression of BCL6 alters gene expression profile and confers decreased DDR in MM cells. This phenotypic change could be reproduced by interleukin-6 stimulation, suggesting an important role of external stimuli in inducing genomic instability, which is a hallmark of MM cells.


Asunto(s)
Daño del ADN , Perfilación de la Expresión Génica/métodos , Mieloma Múltiple/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Análisis de Secuencia de ARN/métodos , Regulación hacia Arriba , Proteínas de la Ataxia Telangiectasia Mutada/genética , Línea Celular Tumoral , Citidina Desaminasa/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Inestabilidad Genómica , Humanos , Fenotipo
12.
Acta Haematol ; 137(3): 141-147, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28380473

RESUMEN

Autoimmune hemophilia-like disease (hemorrhaphilia) due to anti-factor XIII (FXIII) antibodies (AH13) is a very rare, life-threatening bleeding disorder. A 77-year-old woman developed macrohematuria and a right renal pelvic hematoma. The coagulation times were not prolonged, but FXIII activity and antigen levels were severely and moderately reduced to 9 and 29% of normal values, respectively. Accordingly, the FXIII-specific activity turned out to be low. FXIII inhibitor and anti-FXIII-A subunit autoantibodies were detected by a 1:1 crossmixing test and immunoblot and immunochromatographic assays. She was therefore diagnosed with "definite AH13" and treated with plasma-derived FXIII concentrates to arrest the hemorrhage. In addition to a highly compressed inferior vena cava by a huge renal pelvic hematoma, deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) were identified by systemic computed tomography. The patient was immediately started on anticoagulation therapy with low-dose heparin. Emboli disappeared quickly, probably because under-crosslinked thrombi caused by severe FXIII deficiency are vulnerable to fibrinolysis. After about 1.5 years, anti-FXIII-A subunit autoantibodies still remained despite the use of rituximab, steroid pulse therapy, oral prednisolone, and oral cyclophosphamide treatments. In conclusion, an extremely rare AH13 case complicated by DVT and PE was successfully managed by balancing anticoagulation therapy with hemostatic therapy.


Asunto(s)
Autoanticuerpos/sangre , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/terapia , Deficiencia del Factor XIII/complicaciones , Deficiencia del Factor XIII/terapia , Factor XIII/antagonistas & inhibidores , Factor XIII/inmunología , Embolia Pulmonar/complicaciones , Anciano , Anticoagulantes/uso terapéutico , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Ciclofosfamida/uso terapéutico , Factor XIII/uso terapéutico , Deficiencia del Factor XIII/inmunología , Femenino , Hematoma/complicaciones , Hematoma/diagnóstico por imagen , Heparina/uso terapéutico , Humanos , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico por imagen , Rituximab/uso terapéutico , Trombosis de la Vena/complicaciones
13.
Int J Hematol ; 103(2): 219-26, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26588928

RESUMEN

The incidence of chronic lymphocytic leukemia (CLL) is low in Japan. The clinical course ranges from very indolent to rapidly progressive. Recently, several reports have indicated that mutation of the splicing factor 3b, subunit 1 (SF3B1) gene in CLL is predictive of a poor prognosis. Here, we investigated the SF3B1 mutational status of Japanese CLL patients and clarified the association between SF3B1 mutational status and prognostic factors. One hundred and two patients that were referred to our institutions between 1999 and 2013 were enrolled. Mutation analysis of SF3B1 (n = 87) and of the immunoglobulin heavy chain gene (IGHV) (n = 102) was performed at diagnosis. FISH analysis of del(11)(q22) was performed for 17 patients. Seven patients have SF3B1 mutation (8.0 %: K700E, 5/7; G742D, 1/7 and Y623C, 1/7). The median survival times for patients with mutated and non-mutated SF3B1 were 53 and 130 months, respectively. Overall survival of the mutated SF3B1 group was significantly lower than that of the non-mutated group (p = 0.0187). No relationship was observed between IGHV mutational status and SF3B1 mutation. There was no patient with SF3B1 mutation in the IGHV1-69 population (0/2). In conclusion, mutation of SF3B1 at diagnosis in Japanese CLL patients is predictive of a poor prognosis.


Asunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Fosfoproteínas/genética , Factores de Empalme de ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Grupo de Ascendencia Continental Asiática , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico
14.
Rinsho Ketsueki ; 56(12): 2441-6, 2015 12.
Artículo en Japonés | MEDLINE | ID: mdl-26725352

RESUMEN

An 80-year-old man, presenting with gait disturbance and memory loss, had findings of normal pressure hydrocephalus. Primary leptomeningeal lymphoma (PLML) was diagnosed based on cytology and flow cytometry of cerebrospinal fluid obtained by examination. Gadolinium-enhanced MRI showed enhancement of the brain and spinal cord but FDG-PET/CT revealed no lymph node swelling. With intrathecal chemotherapy, meningeal lesions disappeared and the gait disturbance and memory loss improved. However, the disease recurred three months later, manifesting as left facial nerve palsy, but the symptoms disappeared in response to intrathecal chemotherapy and systemic rituximab administration. Although a tumor lesion in the spinal canal was suggested by MRI examination, the patient has maintained a good clinical course for four years with intrathecal chemotherapy every three months. PLML is a very rare disease and its diagnosis is difficult. Repeated intrathecal chemotherapy appeared to be effective against PLML in this case.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hidrocéfalo Normotenso/tratamiento farmacológico , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamiento farmacológico , Carcinomatosis Meníngea/diagnóstico , Carcinomatosis Meníngea/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anciano de 80 o más Años , Dexametasona/administración & dosificación , Humanos , Hidrocéfalo Normotenso/complicaciones , Hidrocéfalo Normotenso/etiología , Linfoma de Células B/complicaciones , Masculino , Carcinomatosis Meníngea/complicaciones , Recurrencia Local de Neoplasia/complicaciones , Recurrencia Local de Neoplasia/diagnóstico , Rituximab/administración & dosificación , Resultado del Tratamiento
15.
Rinsho Ketsueki ; 55(6): 687-91, 2014 Jun.
Artículo en Japonés | MEDLINE | ID: mdl-24975338

RESUMEN

Herein, we report a patient with polycythemia vera (PV) who exhibited Philadelphia chromosome (Ph) positive CML-like clinical features after 13 years of hydroxycarbamide administration and successful treatment with a tyrosine kinase inhibitor (TKI). She was 64 years old when initially diagnosed with PV and was confirmed to be negative for BCR-ABL translocation. Thirteen years later, with increasing white blood cell and platelet counts, a BCR-ABL positive clone emerged and the JAK2V617F mutation disappeared. After TKI treatment, the BCR-ABL copy number decreased and the JAK2V617F mutation was again detected. Furthermore, MPN clinical features were observed. This case provides insights into the clonal divergence and growth advantage of the Ph positive clone over the MPN clone. Whether JAK2V617F is an MPN initiating event or a secondary mutation has been a point of discussion for the past several years. This issue is also considered in the present report.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Policitemia Vera/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Dasatinib , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Janus Quinasa 2/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Persona de Mediana Edad , Mutación , Policitemia Vera/complicaciones , Policitemia Vera/genética , Factores de Tiempo
16.
PLoS One ; 8(11): e81722, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24312342

RESUMEN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy. Plasmacytoid DCs (pDCs), which are defined as lineage marker (Lin)(-)HLA-DR(+)CD56(-)CD123(+)CD11c(-) cells, are considered to be the normal counterpart of BPDCNs. However, BPDCN can be distinguished from pDCs by uniform expression of CD56. In this study, to identify a normal counterpart of BPDCN, we searched for a Lin(-)HLA-DR(+)CD56(+) population and focused on a minor subpopulation of Lin(-)DR(+)CD56(+)CD123(+)CD11c(-) cells that we designated as pDC-like cells (pDLCs). pDLC constituted 0.03% of peripheral blood mononuclear cells (PBMCs), and the pDLC/pDC ratio was higher in bone marrow cells than in PBMCs. pDLC clearly expressed BDCA2, BDCA4, and myeloid antigens, which are frequently expressed by BPDCN. pDLCs exhibited modest expression of Toll-like receptors and produced less interferon-α after CpG stimulation, but presented very low endocytic ability unlike mDCs. These functional differences were attributed to the expression profile of transcriptional factors. After in vitro culture with Flt3-ligand and GM-CSF, pDLCs expressed CD11c and BDCA1. These data suggested that pDLCs are a distinct subpopulation, with an immunophenotype similar to BPDCNs. Moreover, our results indicate that pDLCs might be immature DCs and might contribute to the immunophenotypical diversity of BPDCNs.


Asunto(s)
Antígeno CD56/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Neoplasias Hematológicas/inmunología , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Citocinas/biosíntesis , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Antígenos HLA-DR/metabolismo , Humanos , Proteínas de la Membrana/farmacología , Fenotipo , Receptores Toll-Like/metabolismo , Factores de Transcripción/metabolismo
17.
Rinsho Ketsueki ; 54(2): 214-8, 2013 Feb.
Artículo en Japonés | MEDLINE | ID: mdl-23470830

RESUMEN

A 45-year-old woman with acute myelogenous leukemia developed platelet transfusion refractoriness (PTR) after the engraftment of an allogeneic peripheral blood stem cell transplantation (PBSCT) from her multiparous sister, which was attributed to HLA antibodies that could not be detected in the patient's serum before transplantation. She achieved neutrophil engraftment by day 18 and megakaryocytopoiesis and complete donor chimerism was confirmed in the bone marrow on day 21. IgG-class HLA antibodies were detected in her serum on day 24 after PBSCT; however, on day 15, no HLA antibodies were detected. The specificity of the antibodies that emerged in the patient closely resembled that of the antibodies found in the donor. The donor had probably been immunized during pregnancy by their partner's HLA-antigens expressed by the fetus. Consequently, transplanted donor-derived cells provoked HLA antibodies in the recipient early after PBSCT, and those HLA antibodies induced PTR. The presence of HLA antibodies should be examined at least in pregnant female donors whose recipients developed PTR attributable to HLA antibodies after SCT.


Asunto(s)
Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas , Isoanticuerpos/inmunología , Leucemia Mieloide Aguda/terapia , Transfusión de Plaquetas , Trombocitopenia/etiología , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/inmunología , Persona de Mediana Edad , Transfusión de Plaquetas/métodos , Hermanos , Trombocitopenia/inmunología , Donantes de Tejidos , Trasplante Homólogo
18.
J Thorac Dis ; 4(3): 259-64, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22754664

RESUMEN

BACKGROUND: Pulmonary rehabilitation has generally relieved symptoms, strengthened exercise endurance and improved health-related quality of life (QOL) in patients with COPD, but recovery of pulmonary function remains questionable. This analysis of our innovative rehabilitation program is directed at documenting changes in patients' expiratory airflow limitation, pulmonary symptoms and QOL. This program is designed to provide "respiratory conditioning", a physical therapist-assisted intensive flexibility training that focuses on stretching and rib cage mobilization. METHODS: Thirty-one patients with COPD who attended rehabilitation sessions at Juntendo University Hospital from 1999 to 2006 were analyzed. Pulmonary function, expiratory flow limitation during tidal breathing, six minute walk distance (6MWD), respiratory muscle strength, and St. George Respiratory Questionnaire (SGRQ) were measured before and after pulmonary rehabilitation. RESULTS: In participants ages 68±7 years, the FEV(1)% predicted was 39.3±15.7%. 6MWD, SGRQ and respiratory muscle strength were significantly improved after pulmonary rehabilitation. Although neither FEV(1)% predicted nor FEV(1)/FVC was affected to a significant extent, indicating little effect on airflow limitation, expiratory flow limitation in supine as well as seated during tidal breathing improved significantly. Moreover, rehabilitation significantly diminished TLC% predicted, FRC% predicted, RV% predicted and RV/TLC values, thus indicating a reduction of hyperinflation of the lungs at rest. CONCLUSIONS: The present results suggest that our rehabilitation program with respiratory conditioning significantly lowered the hyperinflation of lungs at rest as well as the expiratory flow limitation during tidal breathing. In patients with COPD, overall pulmonary function improved, exercise endurance increased and health-related QOL was enhanced.

19.
Proc Natl Acad Sci U S A ; 109(27): 10972-7, 2012 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-22711821

RESUMEN

Human Burkitt lymphomas are divided into two main clinical variants: the endemic form, affecting African children infected with malaria and the Epstein-Barr virus, and the sporadic form, distributed across the rest of the world. However, whereas sporadic translocations decapitate Myc from 5' proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc. The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. We here recapitulate endemic Burkitt lymphoma-like translocations in plasmacytomas from uracil N-glycosylase and activation-induced cytidine deaminase-deficient mice. Mapping of translocation breakpoints using an acetylated histone H3 lysine 9 chromatin immunoprecipitation sequencing approach reveals Igh fusions up to ∼350 kb upstream of Myc or the related oncogene Mycn. A comprehensive analysis of epigenetic marks, PolII recruitment, and transcription in tumor cells demonstrates that the 3' Igh enhancer (Eα) vastly remodels ∼450 kb of chromatin into translocated sequences, leading to significant polymerase occupancy and constitutive oncogene expression. We show that this long-range epigenetic reprogramming is directly proportional to the physical interaction of Eα with translocated sites. Our studies thus uncover the extent of epigenetic remodeling by Ig 3' enhancers and provide a rationale for the long-range deregulation of translocated oncogenes in endemic Burkitt lymphomas. The data also shed light on the origin of endemic-like chromosomal rearrangements.


Asunto(s)
Linfoma de Burkitt/genética , Regulación Neoplásica de la Expresión Génica/genética , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Genes myc/genética , Cambio de Clase de Inmunoglobulina/genética , Translocación Genética/genética , Animales , Linfocitos B/citología , Linfocitos B/fisiología , Linfoma de Burkitt/epidemiología , Células Cultivadas , Citidina/genética , Modelos Animales de Enfermedad , Enfermedades Endémicas , Elementos de Facilitación Genéticos/genética , Epigénesis Genética/genética , Reordenamiento Génico de Linfocito B/genética , Humanos , Ratones , Proteínas de Fusión Oncogénica/genética , Células Plasmáticas/citología , Células Plasmáticas/fisiología , Sitio de Iniciación de la Transcripción/fisiología , Uracil-ADN Glicosidasa/genética
20.
J Exp Med ; 205(9): 1949-57, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18678733

RESUMEN

Immunoglobulin (Ig) isotype switching is a recombination event that changes the constant domain of antibody genes and is catalyzed by activation-induced cytidine deaminase (AID). Upon recruitment to Ig genes, AID deaminates cytidines at switch (S) recombination sites, leading to the formation of DNA breaks. In addition to their role in isotype switching, AID-induced lesions promote Igh-cMyc chromosomal translocations and tumor development. However, cMyc translocations are also present in lymphocytes from healthy humans and mice, and thus, it remains unclear whether AID directly contributes to the dynamics of B cell transformation. Using a plasmacytoma mouse model, we show that AID(+/-) mice have reduced AID expression levels and display haploinsufficiency both in the context of isotype switching and plasmacytomagenesis. At the Ig loci, AID(+/-) lymphocytes show impaired intra- and inter-switch recombination, and a substantial decrease in the frequency of S mutations and chromosomal breaks. In AID(+/-) mice, these defects correlate with a marked decrease in the accumulation of B cell clones carrying Igh-cMyc translocations during tumor latency. These results thus provide a causality link between the extent of AID enzymatic activity, the number of emerging Igh-cMyc-translocated cells, and the incidence of B cell transformation.


Asunto(s)
Linfocitos B/patología , Citidina Desaminasa/biosíntesis , Citidina Desaminasa/fisiología , Regulación Neoplásica de la Expresión Génica , Neoplasias Experimentales/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Secuencia de Aminoácidos , Animales , Linfocitos B/metabolismo , Humanos , Sistema Inmunológico , Hibridación Fluorescente in Situ , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Recombinación Genética , Translocación Genética
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