RESUMEN
BACKGROUND AND OBJECTIVES: Geographical limitations in remote island medical facilities result in excessive wastage of blood products. To address this, we explored the feasibility of a novel blood rotation system, which enables the return and redelivery of blood products to/from the blood bank while ensuring the management of product quality, including temperature control. This study aimed to enhance the supply of blood products to these facilities. MATERIALS AND METHODS: The Japan Red Cross Nagasaki Blood Center, Nagasaki Goto Chuoh Hospital (NGCH) and Nagasaki University Hospital collaborated to coordinate the transport and supply of red blood cell (RBC) products. Type O, RhD-positive, irradiated RBC products were stored at a precise 4.0 ± 2.0°C in an active transport refrigerator (ATR). After transport from the Japan Red Cross Nagasaki Blood Center to NGCH, RBC products were held for 1 week in the ATR, and unused products were returned. Eligible returned products were reissued to the Nagasaki University Hospital. RESULTS: All the returned RBC products met the redelivery criteria. Among the 103 redelivered RBC preparations, 101 bags (98.1%) were successfully used. NGCH utilized 597 RBC products and discarded 80 samples. The ATR supplied 107 type O RBC bags without any wastage. The overall wastage rate was 10.2% during the study period compared with 24.2% in the same period in the previous year. CONCLUSION: This innovative supply and operation system ensures a consistent and secure RBC product supply to remote islands while maximizing blood product use.
Asunto(s)
Estudios de Factibilidad , Humanos , Conservación de la Sangre/métodos , Eritrocitos , Bancos de Sangre , Japón , Islas , Transfusión de EritrocitosRESUMEN
Objective The standard treatment for chronic myeloid leukemia (CML) is the continuous use of tyrosine kinase inhibitors (TKIs), which results in a favorable prognosis for the majority of patients. Recent studies have identified cardiovascular diseases (CVDs) as late adverse events (AEs) related to TKIs. In this study, we evaluated the long-term efficacy and AEs of TKIs, focusing on CVDs. Methods We performed a retrospective survey of CML patients (diagnosed from 2001 to 2016) treated with TKIs in Nagasaki Prefecture. Clinical data were obtained from their medical records. We analyzed the survival, estimated cumulative incidence of CVDs, and risk factors for CVD among CML patients treated with TKIs. Results The overall survival rate of 264 CML patients treated with TKIs (median age 58 years old) was 89.6% [95% confidence interval (CI), 84.9-92.9%], and 80.5% (95% CI, 73.4-85.9%) at 5 and 10 years after the CML diagnosis, respectively. CVD events occurred in 26 patients (9.8%, median age 67.5 years old) with a median 65.5 months of TKI treatment. The cumulative incidences at 2 and 5 years was 2.4% (95% CI, 1.0-4.8%) and 5.2% (95% CI, 2.8-8.6%), respectively. Hypertension and a high SCORE chart risk at the diagnosis of CML were associated with CVD events during TKI treatment. Conclusion TKI treatment contributed to the long-term survival of CML patients in Nagasaki Prefecture in a "real-world" setting, but the incidence of CVDs seemed to be increased in these patients. A proper approach to managing risk factors for CVD is warranted to reduce CVD events during TKI treatment.
Asunto(s)
Enfermedades Cardiovasculares , Leucemia Mielógena Crónica BCR-ABL Positiva , Anciano , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
In the original publication of the article, the authors would like to alter the color of characters in the Supplemental Table 1 and 2.
RESUMEN
Programmed death 1 ligand (PD-L1) is an immunomodulatory molecule expressed by cancer cells, and it has been widely demonstrated to inhibit host antitumor responses. The aim of the present study was to identify clinicopathological features associated with PD-L1 expression in the secondary solid cancers of patients after allogeneic hematopoietic stem cell transplantation. In this database of 530 patients who received allo-HSCT between 1990 and 2017, 15 developed solid cancers with a median interval of 3487 days after transplantation. Three patients had 2 different solid cancers. Eighteen solid cancer cases were identified. A multivariate analysis showed that chronic graft-versus-host disease (GVHD) was associated with an increased risk of solid cancer. The presence of chronic GVHD was observed in 8 out of 18 cases at the diagnosis of secondary malignancies. PD-L1 expression levels in cancers were significantly higher in patients with active chronic GVHD than in those without chronic GVHD (P = 0.020). Five cases of cancer that developed in the involved organs of chronic GVHD showed 30% or higher PD-L1 positivity. The present results revealed distinct PD-L1 expression in the secondary solid cancers of post-transplant patients with chronic GVHD.
Asunto(s)
Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Expresión Génica , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/genética , Adolescente , Adulto , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
Although several pedigrees of familial myelodysplastic syndromes/acute myeloid leukemia (fMDS/AML) have been reported, the epidemiology and clinical features has been poorly understood. To explore the epidemiology of this entity, we performed a retrospective nationwide epidemiological survey in Japan using questionnaire sheets. The questionnaire was sent to 561 institutions or hospitals certified by Japanese Society of Hematology, unearthing the existence of 41 pedigrees of fMDS/AML. Among them, we obtained the clinical information of 31 patients in 20 pedigrees. The median age of the initial diagnosis was 51 years (range 9-88 years) and the WHO classification 2008 ranged from refractory anemia (RA) to AML. Focusing on the familial MDS patients, refractory anemia with excess blasts (RAEB)-2 was the largest group (27.3%). The median overall survival (OS) of fMDS and fAML in this study were 71.6 and 12.4 months, and the five-year OS were 61.3 and 50%, respectively.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Humanos , Japón/epidemiología , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/genética , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/genética , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. Our previous analyses demonstrated that MDS among these survivors had a significantly higher frequency of complex karyotypes and structural alterations of chromosomes 3, 8, and 11. However, there was no difference in the median survival time between MDS among survivors compared with those of de novo origin. This suggested that a different pathophysiology may underlie the causative genetic aberrations for those among survivors. In this study, we performed genome analyses of MDS among survivors and found that proximally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM were significantly more frequent in proximally exposed group with mutations identified on the remaining allele in 2 out of 5 cases. TP53, which is frequently mutated in therapy-related myeloid neoplasms, was equally affected between proximally and distally exposed patients. These results suggested that the genetic aberration profiles in MDS among atomic bomb survivors differed from those in therapy-related and de novo origin. Considering the role of ATM in DNA damage response after radiation exposure, further studies are warranted to elucidate how 11q deletion and aberrations of ATM contribute to the pathogenesis of MDS after radiation exposure.
Asunto(s)
Supervivientes a la Bomba Atómica , Síndromes Mielodisplásicos , Aberraciones Cromosómicas , Humanos , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/genética , Factores de Riesgo , SobrevivientesRESUMEN
The patient was a 73-year-old man diagnosed with low-grade B-cell lymphoma not otherwise specified based on a biopsy of the enlarged cervical lymph nodes. He remained untreated and was monitored during follow-up visits only. Progressive anemia developed after 5 years. Enteroscopy revealed stricture and ulcerative lesions involving the entire circumference of the middle section of the small intestine. Based on the biopsy results, he was diagnosed with enteropathy-associated T-cell lymphoma (EATL). Biopsy of an enlarged axillary lymph node simultaneously revealed Epstein-Barr virus-negative diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma not otherwise specified (PTCL, NOS) as well as rearrangement of immunoglobulin heavy-chain and T-cell receptor beta and gamma chain genes. These findings suggested that the axillary lymph node contained composite lymphoma comprising DLBCL and PTCL and that EATL represented a discordant lymphoma. The present case emphasizes the importance of re-biopsy and genetic analysis following an atypical clinical course.
Asunto(s)
Linfoma Compuesto/complicaciones , Linfoma de Células T Asociado a Enteropatía/complicaciones , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células T Periférico/complicaciones , Anciano , Herpesvirus Humano 4 , Humanos , Ganglios Linfáticos/patología , MasculinoRESUMEN
In acute myeloid leukemia (AML), patients may harbor pre-leukemic hematopoietic stem cells (HSCs) containing some, but not all, of the mutations observed in the leukemic cells. These pre-leukemic HSCs may survive induction chemotherapy and contribute to AML relapse by obtaining additional mutations. We report here an acute monoblastic leukemia (AMoL) patient who later developed an unclassifiable myeloproliferative neoplasm (MPN-U). Whole-exome sequencing and cluster analysis demonstrated the presence of three distinct major clones during the clinical course: (1) an AMoL clone with ASXL1, CBL, and NPM1 somatic mutations, likely associated with the pathogenesis, and GATA2, SRSF2, and TET2 mutations, (2) an AMoL remission clone, with mutated GATA2, SRSF2, and TET2 only (possibly the founding clone (pre-leukemic HSC) that survived chemotherapy), (3) a small subclone which had JAK2 mutation during the AMoL remission, appearing at MPN-U manifestation with additional mutations. These findings suggest that pre-leukemic HSCs in AML patients may give rise to non-AML myeloid malignancies. This is the first report to analyze the clonal evolution from AMoL to MPN-U, which may provide new insight into the development of myeloid malignancies.
Asunto(s)
Evolución Clonal/genética , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patología , Trastornos Mieloproliferativos/etiología , Trastornos Mieloproliferativos/genética , Anciano , Evolución Clonal/fisiología , Células Madre Hematopoyéticas/patología , Humanos , Quimioterapia de Inducción , Leucemia Monocítica Aguda/sangre , Leucemia Monocítica Aguda/complicaciones , Masculino , Mutación , Recurrencia Local de Neoplasia , Nucleofosmina , Secuenciación del ExomaRESUMEN
Ionizing radiation released by the atomic bombs at Hiroshima and Nagasaki, Japan, in 1945 caused many long-term illnesses, including increased risks of malignancies such as leukemia and solid tumours. Radiation has demonstrated genetic effects in animal models, leading to concerns over the potential hereditary effects of atomic bomb-related radiation. However, no direct analyses of whole DNA have yet been reported. We therefore investigated de novo variants in offspring of atomic-bomb survivors by whole-genome sequencing (WGS). We collected peripheral blood from three trios, each comprising a father (atomic-bomb survivor with acute radiation symptoms), a non-exposed mother, and their child, none of whom had any past history of haematological disorders. One trio of non-exposed individuals was included as a control. DNA was extracted and the numbers of de novo single nucleotide variants in the children were counted by WGS with sequencing confirmation. Gross structural variants were also analysed. Written informed consent was obtained from all participants prior to the study. There were 62, 81, and 42 de novo single nucleotide variants in the children of atomic-bomb survivors, compared with 48 in the control trio. There were no gross structural variants in any trio. These findings are in accord with previously published results that also showed no significant genetic effects of atomic-bomb radiation on second-generation survivors.
Asunto(s)
Desastres , Armas Nucleares , Polimorfismo de Nucleótido Simple , Sobrevivientes , Secuenciación Completa del Genoma , Adolescente , Adulto , Niño , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Japón , Masculino , Vigilancia en Salud Pública , Adulto JovenRESUMEN
INTRODUCTION: Recently, novel calreticulin (CALR) mutations were discovered in Janus kinase 2 (JAK2) non-mutated myelofibrosis (PMF) and essential thrombocythemia (ET) cases, with a frequency of 60-80%. We examined clinical correlations and CALR mutation frequency in our myeloproliferative neoplasms (MPN) cases, and introduce an effective test method for use in clinical practice. METHODS: We examined 177 samples previously investigated for the JAK2 mutation for differential diagnosis of MPN. JAK2 and CALR mutations were analyzed using melting curve analysis and microchip electrophoresis, respectively. Next, we constructed a test for simultaneous screening of the JAK2 and CALR mutations utilizing high resolution melting (HRM). RESULTS: Among 99 MPN cases, 60 possessed the JAK2 mutation alone. Of the 39 MPN cases without the JAK2 mutation, 14 were positive for the CALR mutation, all of which were ET. Using our novel screening test for the JAK2 and CALR mutations by HRM, the concordance rate of conventional analysis with HRM was 96% for the JAK2 mutation and 95% for the CALR mutation. CONCLUSION: Our novel simultaneous screening test for the JAK2 and CALR gene mutations with HRM is useful for diagnosis of MPN.
Asunto(s)
Calreticulina/genética , Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trastornos Mieloproliferativos/diagnósticoRESUMEN
There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS in Nagasaki atomic bomb survivors using the International Prognostic Scoring System (IPSS) and the revised version (IPSS-R). Subjects were 140 patients with primary MDS diagnosed between 1985 and 2011 and evaluable for IPSS, IPSS-R, and exposure distance. Of those, 31 were exposed at <1.5 km, 35 at 1.5-2.99 km, and 74 at ≥3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at ≥3.0 km, those exposed at <1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate/poor IPSS, and intermediate/poor/very poor IPSS-R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS-R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to overt leukemia among atomic bomb survivors.
Asunto(s)
Desastres , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Armas Nucleares , Adulto , Anciano , Anciano de 80 o más Años , Desastres/historia , Progresión de la Enfermedad , Femenino , Historia del Siglo XX , Humanos , Incidencia , Estimación de Kaplan-Meier , Leucemia/epidemiología , Leucemia/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Evaluación del Resultado de la Atención al Paciente , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
OBJECTIVE: Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that transform to acute leukemia. Distinguishing MDS from other cytopenias is sometimes difficult even for trained hematologists. WT1, the gene mutated in Wilms' tumor, was found expressed in acute myeloid leukemia and MDS. The amount of WT1 in peripheral blood and bone marrow (BM) is low in low-risk MDS subtypes, and is high in high-risk MDS subtypes. However, the role of WT1 in the differential diagnosis between MDS and other diseases showing cytopenia has not been fully addressed. The present study evaluated whether WT1 expression level can assist in the differential diagnosis of MDS from other cytopenias. METHODS: The amount of WT1 message was evaluated among 56 MDS patients and 47 patients with cytopenia for various other reasons (cytopenia VR) at the Nagasaki University Hospital. RESULTS: The level of WT1 was significantly related to the percentage of blasts in BM among MDS cases, and the type of French-American-British classification of MDS; refractory anemia (RA) cases showed significantly lower WT1 level than patients with RA with excess blasts. WT1 level was significantly related to the prognostic risk categories of MDS by the International Prognostic Scoring System (IPSS) and the revised IPSS. Although the blast percentage in the BM of RA and cytopenia VR were both less than 5%, there was a significant difference in the level of WT1 between MDS and cytopenia VR. CONCLUSION: WT1 might be a good marker to differentiate low blast percentage MDS and cytopenia VR.
Asunto(s)
Médula Ósea/patología , Síndromes Mielodisplásicos/diagnóstico , Mioblastos/patología , Proteínas WT1/biosíntesis , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , ADN Complementario , Diagnóstico Diferencial , Femenino , Humanos , Leucemia/clasificación , Leucemia/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , ARN MensajeroAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Receptores CCR4/genética , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Citometría de Flujo , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Masculino , Persona de Mediana Edad , Patología Molecular , Reacción en Cadena de la Polimerasa , Interferencia de ARN/efectos de los fármacosRESUMEN
Myelodysplastic syndromes (MDSs) is a hematological neoplasm defined by ineffective hematopoiesis, dysplasia of hematopoietic cells, and risk of progression to acute leukemia. MDS occurs as de novo or secondary, and chemoradiotherapy for cancers is thought to increase the risk of MDS among patients. Recently, an epidemiological study for MDS among A-bomb survivors was performed, and it clearly demonstrated that the exposure to external radiation significantly increased the risk of MDS. Precise epidemiological data among survivors have revealed important clinical factors related to the risk of leukemias. In this review, by comparing data for secondary MDS and leukemia/MDS among survivors, several factors which would affect the risk of MDS, especially secondary MDS, are discussed.
Asunto(s)
Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/etiología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Armas NuclearesRESUMEN
VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1%, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6%, respectively. Eleven of 34 patients (32%) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7%, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Ciclofosfamida , Progresión de la Enfermedad , Doxorrubicina , Femenino , Humanos , Quimioterapia de Inducción , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/mortalidad , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona , Estudios Retrospectivos , Resultado del Tratamiento , VincristinaRESUMEN
Cryoglobulinemia (Cg) in multiple myeloma (MM) is rare and no standard treatment has yet been established. Herein, we report a case of MM with Cg, successfully treated with a combination of lenalidomide and dexamethasone. A 76-year-old woman suffering from skin ulcerations, extremity pain and peripheral neuropathy was diagnosed as having IgG-kappa MM with Cg in 1992. She intermittently received conventional chemotherapy, immunosuppressant therapy and plasma exchange. Despite these treatments, Cg-related symptoms eventually became uncontrollable. She was admitted to our hospital in 2012 because of worsening skin symptoms involving both ankles. Plasmapheresis proved ineffective. Improvement of skin ulcerations and numbness was achieved with administration of lenalidomide at 25 mg daily with weekly dexamethasone, which also decreased the cryoglobulin level. The course of this patient suggests that lenalidomide plus dexamethasone is a promising treatment for MM with Cg.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Crioglobulinemia/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Anciano , Crioglobulinemia/etiología , Dexametasona/administración & dosificación , Femenino , Humanos , Lenalidomida , Mieloma Múltiple/complicaciones , Plasmaféresis/métodos , Talidomida/administración & dosificación , Talidomida/análogos & derivadosRESUMEN
Adult T-cell leukemia-lymphoma (ATL), an aggressive neoplasm etiologically associated with HTLV-1, is a chemoresistant malignancy. Heat shock protein 90 (HSP90) is involved in folding and functions as a chaperone for multiple client proteins, many of which are important in tumorigenesis. In this study, we examined NVP-AUY922 (AUY922), a second generation isoxazole-based non-geldanamycin HSP90 inhibitor, and confirmed its effects on survival of ATL-related cell lines. Analysis using FACS revealed that AUY922 induced cell-cycle arrest and apoptosis; it also inhibited the growth of primary ATL cells, but not of normal PBMCs. AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKß, IKKγ, Cdk4, Cdk6, and survivin. Interestingly, AUY922 induced downregulation of the proviral integration site for Moloney murine leukemia virus (PIM) in ATL cells. The PIM family (PIM-1, -2, -3) is made up of oncogenes that encode a serine/threonine protein kinase family. As PIM kinases have multiple functions involved in cell proliferation, survival, differentiation, apoptosis, and tumorigenesis, their downregulation could play an important role in AUY922-induced death of ATL cells. In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines. Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.
Asunto(s)
Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoxazoles/farmacología , Leucemia-Linfoma de Células T del Adulto/patología , Resorcinoles/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológicoRESUMEN
Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-2'-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease progression and how DNA methylation contributes to MDS remain unclear. We analyzed global DNA methylation in purified CD34+ hematopoietic progenitors from MDS patients undergoing multiple rounds of AZA treatment. Differential methylation between MDS phenotypes was observed primarily at developmental regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS patients. Haploinsufficiency in mice of one of these genes (NR4A2) has been shown to lead to excessive HSC proliferation, and our data suggest that suppression of NR4A2 by DNA methylation may be involved in MDS progression.
Asunto(s)
Metilación de ADN/genética , Células Madre Hematopoyéticas/metabolismo , Síndromes Mielodisplásicos/genética , Antígenos CD34/metabolismo , Azacitidina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Estudios Longitudinales , Síndromes Mielodisplásicos/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , TranscriptomaRESUMEN
BACKGROUND: Common variable immune deficiency is the most frequently encountered immunodeficiency in adults, which is characterized by low levels of serum immunoglobulins. Common variable immune deficiency can present with inflammatory bowel disease-like colitis because of the dysregulated immune system; paradoxically activated T cell receptor pathways are thought to be pivotal in pathogenesis of common variable immune deficiency-related colitis. Treatment for severe complications, such as gastrointestinal bleeding, is not established. We report a case of common variable immune deficiency-related Crohn's-like disease presenting massive melena, which was successfully treated by short course infliximab therapy. CASE PRESENTATION: A 26-year-old Japanese man with history of common variable immune deficiency presented with diarrhea, abdominal pain, and fever. Venous administration of antibiotics did not improve his symptoms. Colonoscopy revealed multiple longitudinal ulcers as well as cobblestone-like change in the ileum end and the ascending colon. Histopathological examination of biopsy specimen showed erosion and infiltration of T lymphocytes with lack of B cells. Intravenous hyperalimentation, mesalazine, and steroid did not improve the symptoms and the patient subsequently presented with massive melena. Colonoscopy revealed a protuberant vessel on one of the ulcers in the ascending colon. Endoscopic clipping was repeatedly performed for hemostasis, which was only temporarily successful. In an attempt to manage the bleeding and colitis, a trial of infliximab was given on week 0, week 2 and week 6. Gastrointestinal hemorrhage from the ulcer halted immediately after the first infliximab injection. Colonoscopy performed after the third infliximab showed remarkable improvement in the ileocolitis. No evidence of increased susceptibility to infections was observed and the patient has been in clinical remission for 3 years. CONCLUSIONS: We present this case together with review of literature to share our experience of encountering common variable immune deficiency complicating severe Crohn's-like disease and to support that infliximab is a safe and effective treatment that can promptly manage life-threatening intestinal hemorrhage in common variable immune deficiency-related colitis.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunodeficiencia Variable Común/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Hemorragia Gastrointestinal/prevención & control , Adulto , Enfermedad de Crohn/etiología , Fármacos Gastrointestinales/uso terapéutico , Hemorragia Gastrointestinal/etiología , Humanos , Infliximab , Resultado del TratamientoRESUMEN
An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment.