RESUMO
This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Estudos Prospectivos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Resposta Patológica Completa , Estudos RetrospectivosRESUMO
CEBPA-IGH, a fusion gene of the immunoglobulin heavy-chain locus (IGH) and the CCAAT enhancer-binding protein α (C/EBPα) gene, is recurrently found in B-ALL cases and causes aberrant expression of C/EBPα, a master regulator of granulocyte differentiation, in B cells. Forced expression of C/EBPα in B cells was reported to cause loss of B-cell identity due to the inhibition of Pax5, a master regulator of B-cell differentiation; however, it is not known whether the same mechanism is applicable for B-ALL development by CEBPA-IGH. It is known that a full-length isoform of C/EBPα, p42, promotes myeloid differentiation, whereas its N-terminal truncated isoform, p30, inhibits myeloid differentiation through the inhibition of p42; however, the differential role between p42 and p30 in ALL development has not been clarified. In the present study, we examined the effect of the expression of p42 and p30 in B cells by performing RNA-seq of mRNA from LCL stably transfected with p42 or p30. Unexpectedly, suppression of PAX5 target genes was barely observed. Instead, both isoforms suppressed the target genes of MEF2 family members (MEF2s), other regulators of B-cell differentiation. Similarly, MEF2s target genes rather than PAX5 target genes were suppressed in CEBP-IGH-positive ALL (n = 8) compared with other B-ALL (n = 315). Furthermore, binding of both isoforms to MEF2s target genes and the reduction of surrounding histone acetylation were observed in ChIP-qPCR. Our data suggest that the inhibition of MEF2s by C/EBPα plays a role in the development of CEBPA-IGH-positive ALL and that both isoforms work co-operatively to achieve it.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT , Leucemia , Humanos , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular , Hematopoese , Isoformas de Proteínas/genética , Fatores de Transcrição MEF2/metabolismoRESUMO
Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic primary immune thrombocytopenia (ITP) in the United States, Canada and some European countries. We conducted a phase 3, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of fostamatinib in Japanese patients with primary ITP. Thirty-four patients were randomised to fostamatinib (n = 22) or placebo (n = 12) at 100-150 mg twice a day for 24 weeks. Stable responses (platelet ≥50 000/µl at ≥4 of the 6 visits from weeks 14 to 24) were observed in eight (36%) patients on fostamatinib and in none of the patients on placebo (p = 0.030). Overall responses (platelet ≥50 000/µl at ≥1 of the 6 visits from weeks 2 to 12) were seen in 10 (45%) patients on fostamatinib and in none of the patients on placebo (p = 0.006). Patients on fostamatinib required rescue medication less often and experienced fewer bleeding symptoms than patients on placebo. Adverse events observed were mild or moderate and were manageable. No new safety signals were identified in Japanese patients with ITP.
Assuntos
Púrpura Trombocitopênica Idiopática , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , População do Leste Asiático , Resultado do Tratamento , Oxazinas/farmacologia , Piridinas , Método Duplo-CegoRESUMO
The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Segunda Neoplasia Primária , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/complicações , Agentes de Imunomodulação , Inibidores de Proteassoma/efeitos adversos , Estudos Retrospectivos , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Transplante Autólogo/efeitos adversos , Fatores de Risco , Transplante de Células-TroncoRESUMO
BACKGROUND AIMS: The prognostic impact of platelet recovery after autologous hematopoietic cell transplantation (AHCT) on clinical outcomes remains to be elucidated. We aimed to clarify the impact of platelet recovery on clinical outcomes, risk factors of delayed platelet recovery and the necessary dose of CD34+ cells for prompt platelet recovery in each patient. METHODS: Using a nationwide Japanese registry database, we retrospectively analyzed clinical outcomes of 5222 patients with aggressive non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). RESULTS: At a landmark of 28 days after AHCT, a delay of platelet recovery was observed in 1102 patients (21.1%). Prompt platelet recovery was significantly associated with superior overall survival (hazard ratio [HR] 0.32, P < 0.001), progression-free survival (HR 0.48, P < 0.001) and decreased risks of disease progression (HR 0.66, P < 0.001) and non-relapse/non-progression mortality (HR 0.19, P < 0.001). The adverse impacts of a delay of platelet recovery seemed to be more apparent in NHL. In addition to the dose of CD34+ cells/kg, disease status, performance status and the hematopoietic cell transplant-specific comorbidity index in both diseases were associated with platelet recovery. We then stratified the patients into three risk groups according to these factors. For the purpose of achieving 70% platelet recovery by 28 days in NHL, the low-, intermediate- and high-risk groups needed more than 2.0, 3.0 and 4.0 × 106 CD34+ cells/kg, respectively. In MM, the low-risk group needed approximately 1.5 × 106 CD34+ cells/kg, whereas the intermediate- and high-risk groups required 2.0 and 2.5 × 106 CD34+ cells/kg to achieve about 80% platelet recovery by 28 days. CONCLUSIONS: A delay of platelet recovery after AHCT was associated with inferior survival outcomes.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Mieloma Múltiplo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/etiologia , Plaquetas , Antígenos CD34 , Transplante AutólogoRESUMO
Here we describe two patients that required interruption of a busulfan (BU) containing conditioning regimen due to severe mental disorder before stem cell transplantation. The first patient was a 66-year-old man scheduled for unrelated peripheral blood stem cell transplantation with fludarabine/BU conditioning for myelodysplastic syndrome. He received 9.6 mg/kg BU and developed hallucinations that worsened the next day. BU was stopped on the final day, but the patient became comatose (grade 4). He recovered the next day. The second patient was a 69-year-old man scheduled for autologous peripheral blood stem cell transplantation with thiotepa (TT)/BU conditioning for cerebral nervous system relapse of mantle cell lymphoma. He received 12.8 mg/kg BU and developed hallucinations. His mental symptoms worsened on the next day, and thus administration was stopped on the second day of TT. His symptoms improved the next day. Both patients were over 65 years old, and their psychiatric symptoms worsened 1-2 days after the final dose of BU. Our findings suggest that BU may cause psychiatric disorders in elderly patients. When performing BU conditioning, it may be necessary to avoid azole antifungal medication and acetaminophen and to reduce the dose or perform therapeutic dose monitoring for elderly patients.
Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Idoso , Humanos , Masculino , Bussulfano/efeitos adversos , Ciclofosfamida , Alucinações/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Recidiva Local de Neoplasia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/efeitos adversos , VidarabinaRESUMO
A 56-year-old woman was referred to our hospital with symptoms of swelling, purpura, and pain in her limbs. Prior to referral, bleeding in her limbs had spontaneously appeared and disappeared several times. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged, and the factor II level was 17%. The plasma-mixing test indicated lupus anticoagulant (LA), which was confirmed using aPTT-LA and dilute Russell's viper venom time (dRVVT). Therefore, she was diagnosed with lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS). During screening for underlying disorders, chest computed tomography (CT) revealed a retrosternal mass. Biopsy was not performed because the administration of freshly frozen plasma failed to correct her coagulopathy. Prednisolone (PSL) treatment (1 mg/kg) was initiated, which normalized the coagulation tests. The retrosternal mass also disappeared. PSL was tapered without LAHPS recurrence; however, the follow-up CT revealed systemic lymphadenopathy. Follicular lymphoma was diagnosed using lymph-node biopsy. Considering the subsequent LAHPS recurrence, six cycles of bendamustine + rituximab were administered. Complete response with no LAHPS recurrence was observed at the time of drafting this report. LAHPS is rare and distinct from antiphospholipid syndrome because it can cause severe bleeding. Underlying disorders should be evaluated in cases of LAHPS.
Assuntos
Síndrome Antifosfolipídica , Hipoprotrombinemias , Linfoma Folicular , Feminino , Humanos , Inibidor de Coagulação do Lúpus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Tempo de Tromboplastina Parcial , Tempo de ProtrombinaRESUMO
Conventional cytogenetic analyses and fluorescent in situ hybridization (FISH) are helpful for stratifying patients with multiple myeloma (MM) into high-risk [t(4;14), t(14;16), and/or del 17p] and standard-risk [t(11;14)] categories. However, the prognosis of patients with MM treated with autologous stem cell transplantation (ASCT) stratified according to these categories remains unclear. This retrospective observational study analyzed 97 patients with MM who received a single, planned ASCT after treatment with 200 mg/m2 melphalan between 2001 and 2011. The patients were grouped according to chromosomal abnormality, including t(11;14) (nâ¯=â¯45), t(4;14) (nâ¯=â¯31), del 17p (nâ¯=â¯10), t(11;14) with del 17p (nâ¯=â¯7), and t(4;14) with del 17p (nâ¯=â¯4). Median overall survival (OS) of the t(11;14) group (64.1 months) was not significantly different from that of the t(4;14) group (not reached), but it was significantly longer than that of the del 17p group (23.0 months; Pâ¯=â¯.002). G-banding revealed that the median OS of the t(11;14) group with additional chromosomal abnormalities (ACAs) (46.2 months) was significantly shorter than that of the t(11;14) group without ACAs (not reached; Pâ¯=â¯.005) and the t(4;14) group (not reached; Pâ¯=â¯.010). These findings highlight the importance of G-banding in patients with t(11;14) MM.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Translocação Genética/genética , Adulto , Idoso , Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Prognóstico , Estudos Retrospectivos , Medição de Risco , Transplante AutólogoAssuntos
Aminopiridinas , Morfolinas , Púrpura Trombocitopênica Idiopática , Pirimidinas , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Japão , Piridinas/efeitos adversos , Oxazinas/efeitos adversos , Método Duplo-Cego , Resultado do TratamentoRESUMO
POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, vascular endothelial growth factor elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation Transplant Registry Unified Management Program (TRUMP) database. Between January 2000 and December 2011, 95 patients (58 men) were registered to the TRUMP database with a median age of 53 years (range, 28 to 72). The conditioning regimen was melphalan in 93 of 94 patients (99%), and 69 patients (74.2%) received a melphalan dose ≥ 200 mg/m2. The median CD34 cell dose was 2.47 × 106/kg (range, .31 to 20). After ASCT, patient performance status was dramatically improved (Eastern Cooperative Oncology Group performance status 0 to 1: 20.0% versus 71.6%, P < .0001). Over a median follow-up of 46.6 months 10 patients died, and 5-year overall survival was 88.8% (n = 95). Progression-free survival at 3 years was 78.3% (n = 70; median follow-up, 54.4 months). These data support the promising role of ASCT in patients with POEMS syndrome for both prolonging survival and improving quality of life. However, disease recurrence remains a major issue for long-term survivors.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndrome POEMS/terapia , Sobreviventes , Transplante Autólogo/métodos , Adulto , Idoso , Bases de Dados Factuais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Síndrome POEMS/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/mortalidade , Resultado do TratamentoRESUMO
PAX5 is a transcription factor that is required for the development and maintenance of B cells. Promyelocytic leukemia (PML) is a tumor suppressor and proapoptotic factor. The fusion gene PAX5-PML has been identified in acute lymphoblastic leukemia with chromosomal translocation t(9;15)(p13;q24). We have reported previously that PAX5-PML dominant-negatively inhibited PAX5 transcriptional activity and impaired PML function by disrupting PML nuclear bodies (NBs). Here we demonstrated the leukemogenicity of PAX5-PML by introducing it into normal mouse pro-B cells. Arrest of differentiation was observed in PAX5-PML-introduced pro-B cells, resulting in the development of acute lymphoblastic leukemia after a long latency in mice. Among the transactivation targets of PAX5, B cell linker protein (BLNK) was repressed selectively in leukemia cells, and enforced BLNK expression abrogated the differentiation block and survival induced by PAX5-PML, indicating the importance of BLNK repression for the formation of preleukemic state. We also showed that PML NBs were intact in leukemia cells and attributed this to the low expression of PAX5-PML, indicating that the disruption of PML NBs was not required for the PAX5-PML-induced onset of leukemia. These results provide novel insights into the molecular mechanisms underlying the onset of leukemia by PAX5 mutations.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Leucemia Experimental/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Fator de Transcrição PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Regulação para Baixo , Humanos , Leucemia Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/patologia , Proteína da Leucemia Promielocítica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Análise de Sobrevida , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Objective: Autologous stem cell transplantation is an important strategy for patients with relapsed or refractory lymphoma. Although various regimens for peripheral blood stem cell collection have been used, the optimal regimen has not yet been established. We aimed to evaluate the mobilization efficacy and safety of the regimen consisted of etoposide and cytarabine (EC regimen). Methods: We retrospectively analyzed the clinical data of 46 lymphoma patients who received peripheral blood stem cell mobilization with the EC regimen [etoposide (100 mg/m2/day, days 1-4) and cytarabine (100 mg/m2/day, days 1-4)] at Toyohashi municipal hospital from 2004 to 2013. Results: The median age of the patients was 55 years. The most common underlying diseases were diffuse large B-cell lymphoma (46%) and follicular lymphoma (26%). Three-quarters of patients were in their second complete or partial remission. The median total number of collected CD34+ cells was 10.6 × 106 kg-1. Forty-two patients (91%) yielded at least 2 × 106 kg-1 CD34+ cells within a median of 2 apheresis days, and 33 patients (72%) achieved it with only one apheresis. Successful mobilization was observed in five of six patients who failed to mobilize previously. Although febrile neutropenia occurred in 22 patients (48%), no fatal infection was observed. Conclusion: The EC regimen was highly effective in lymphoma patients, including patients who mobilized poorly with other regimens.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Etoposídeo/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Citarabina/administração & dosagem , Citarabina/farmacologia , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Little is known regarding the chimerism status after reduced-intensity conditioning transplantation when bone marrow is used as a stem cell source. We prospectively analyzed lineage-specific chimerism and retrospectively evaluated clinical outcomes in 80 adult patients who underwent unrelated donor bone marrow transplantation (URBMT) with fludarabine plus melphalan (FM) as the conditioning regimen. Mixed donor chimerism (MDC) was seen in 43 and 10 % of patients at days 14 and 28, respectively. Melphalan at ≤130 mg/m(2) was associated with an increased incidence of MDC at day 28 (P = 0.03). Patients with MDC at day 14 showed a marginally increased risk of primary graft failure and a marginally decreased risk of graft-versus-host disease. In multivariate analysis, MDC at day 14 was associated with higher overall mortality (hazard ratio (HR) = 2.1; 95 % confidence interval (CI), 1.1-4.2; P = 0.04) and relapse rate (HR = 3.0; 95 % CI, 1.2-7.5; P = 0.02), but not with non-relapse mortality (HR = 1.8; 95 % CI, 0.70-4.6; P = 0.23). Thus, the FM regimen yields prompt complete donor chimerism after URBMT, but the melphalan dose significantly impacts the kinetics of chimerism. Chimerism status evaluation at day 14 may be instrumental in predicting relapse after URBMT with the FM regimen.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Quimerismo/induzido quimicamente , Melfalan/administração & dosagem , Condicionamento Pré-Transplante/efeitos adversos , Doadores não Relacionados , Vidarabina/análogos & derivados , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto JovemAssuntos
Transplante de Células-Tronco Hematopoéticas , Vírus da Hepatite B , Hepatite B/mortalidade , Hepatite C/mortalidade , Linfoma/mortalidade , Linfoma/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Seguimentos , Hepacivirus , Hepatite B/etiologia , Hepatite B/terapia , Hepatite C/etiologia , Hepatite C/terapia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sociedades MédicasAssuntos
Colite , Colonoscopia , Dasatinibe/efeitos adversos , Hemorragia Gastrointestinal , Leucemia Mielogênica Crônica BCR-ABL Positiva , Sangue Oculto , Adulto , Colite/induzido quimicamente , Colite/diagnóstico por imagem , Colite/patologia , Dasatinibe/administração & dosagem , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MasculinoRESUMO
Plasma cell differentiation is initiated by Ag stimulation of BCR. Until BCR stimulation, B lymphocyte-induced maturation protein 1 (BLIMP1), a master regulator of plasma cell differentiation, is suppressed by PAX5, which is a key transcriptional repressor for maintaining B cell identity. After BCR stimulation, upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed and thought to be the trigger of plasma cell differentiation; however, the trigger that derepresses BLIMP1 expression is yet to be revealed. In this study, we demonstrated PAX5 phosphorylation by ERK1/2, the main component of the BCR signal. Transcriptional repression on BLIMP1 promoter by PAX5 was canceled by PAX5 phosphorylation. BCR stimulation induced ERK1/2 activation, phosphorylation of endogenous PAX5, and upregulation of BLIMP1 mRNA expression in B cells. These phenomena were inhibited by MEK1 inhibitor or the phosphorylation-defective mutation of PAX5. These data imply that PAX5 phosphorylation by the BCR signal is the initial event in plasma cell differentiation.
Assuntos
Sistema de Sinalização das MAP Quinases/imunologia , Fator de Transcrição PAX5/metabolismo , Plasmócitos/citologia , Receptores de Antígenos de Linfócitos B/metabolismo , Proteínas Repressoras/metabolismo , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Ensaio de Desvio de Mobilidade Eletroforética , Imunofluorescência , Humanos , Immunoblotting , Ativação Linfocitária/imunologia , Linfoma/imunologia , Linfoma/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator de Transcrição PAX5/imunologia , Fosforilação , Plasmócitos/imunologia , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos B/imunologia , Proteínas Repressoras/imunologia , TransfecçãoRESUMO
Objective Several institutions outsource CD34+ cell counting of leukapheresis products, limiting rapid measurements, as results are obtained the next day. This problem is compounded with plerixafor use, a stem cell-mobilizing drug that increases leukapheresis efficiency but requires administration the day before leukapheresis. Use of this drug for a second leukapheresis procedure before the first-day leukapheresis CD34+ count results are confirmed causes unnecessary leukapheresis and expensive plerixafor administration. We investigated whether or not measuring hematopoietic progenitor cells in leukapheresis products (AP-HPCs) using a Sysmex XN-series analyzer could resolve this problem. Methods We retrospectively compared the absolute AP-HPC value per body weight with the CD34+ (AP-CD34+) count in 96 first-day leukapheresis product samples obtained between September 2013 and January 2021. Comparisons were also conducted according to regimen: granulocyte colony-stimulating factor (G-CSF) monotherapy, chemotherapy plus G-CSF, or plerixafor mobilization. Results AP-CD34+ and AP-HPC counts correlated strongly (rs=0.846) overall and, in particular, under chemotherapy plus G-CSF (rs=0.92) but correlated mildly under G-CSF monotherapy (rs=0.655). AP-HPCs could not completely be dichotomized based on an AP-CD34+ threshold of 2×106/kg for any stimulation procedure. In most cases with AP-HPCs >6×106/kg, the AP-CD34+ count exceeded 2.0×106/kg, but in 5.7% of these cases, the AP-CD34+ count was <2.0×106/kg. A cut-off of AP-HPCs >4.843×106/kg yielded a sensitivity of 71% and specificity of 96% for predicting AP-CD34+≥2×106/kg. Conclusion AP-HPCs can identify cases in which sufficient stem cells have been collected.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico , Humanos , Leucaférese , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco de Sangue Periférico/metabolismo , Estudos Retrospectivos , Transplante Autólogo , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Antígenos CD34/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismoRESUMO
BACKGROUND: Gastrointestinal mucormycosis is a rapidly progressing and often fatal disease, predominantly affecting immunocompromised patients. Surgical intervention, in addition to antifungal therapy, is essential. Herein, we describe the successful management of appendiceal mucormycosis in a patient with acute promyelocytic leukemia through rapid surgical intervention and antifungal therapy. CASE PRESENTATION: A 29-year-old woman underwent autologous peripheral blood stem cell transplantation for acute promyelocytic leukemia (APL). Subsequently, her condition relapsed, and remission induction therapy was initiated. During the immunosuppressive period, she developed a fever and severe abdominal pain. Computed tomography revealed severe edema of the ileum, cecum, and ascending colon. Despite receiving multiple antibiotics, antivirals, and antifungals, her condition showed no improvement. Consequently, she underwent exploratory laparotomy, with no bowel perforation noted, revealing severe inflammation in the ileum, cecum, and ascending colon, as well as appendiceal necrosis. Appendectomy was performed, and histopathological analysis revealed hyphae in the vessels and layers of the appendiceal wall, suggestive of mucormycosis. The patient was diagnosed with appendiceal mucormycosis, and liposomal amphotericin B was administered. Subsequent monitoring showed no recurrence of mucormycosis. Genetic analysis of the resected tissue revealed Rhizopus microspores as the causative agent. CONCLUSIONS: Rapid surgical intervention and antifungal drug administration proved successful in managing appendiceal mucormycosis in a patient with APL. Early recognition and aggressive surgical intervention are imperative to improve outcomes in such patients.
RESUMO
In Waldenström macroglobulinemia (WM), confirming the presence of Bing-Neel syndrome (BNS) is important because drugs that penetrate the central nervous system (CNS) must be selected. We report the case of a 75-year-old man for whom tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor (BTKi), was useful in treating WM-associated peripheral neuropathy (PN) with BNS. Numbness and muscle weakness in the fingers occurred three years after the initial treatment of WM. WM-associated PN due to demyelinating disease was diagnosed based on the results of a nerve conduction study and magnetic resonance imaging showing bilateral symmetric swelling of the brachial plexus. The cerebrospinal fluid (CSF) cytology results were initially negative; however, the CSF test was repeated because of extremely high protein levels (984 mg/dL) and slightly elevated leukocyte counts (14/µL). The second test revealed abnormal lymphoplasmacytic cells (189/µL), indicating BNS. Rituximab and high-dose methotrexate-containing chemotherapy were administered. Despite the subsequent negative CSF cytology results, his neurological symptoms persisted but subsided soon after the initiation of tirabrutinib. The therapeutic effects of tirabrutinib persisted for 25 months. This case suggested that a careful search for concurrent BNS is important when lesions are close to the CNS or when atypical CSF findings are obtained in patients with WM-associated PN, especially when BTKi options are available.
RESUMO
Background: To investigate whether the addition of eltrombopag (EPAG) to rabbit anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) for newly diagnosed severe aplastic anemia (SAA) improves outcomes and affects the cumulative incidence of clonal evolution (CE), we conducted a multicenter retrospective analysis. Methods: Data were collected from 101 patients, aged 15 - 65 years, undergoing initial IST. Results: No significant imbalance in age, sex, or severity was observed between the EPAG (n = 20) and non-EPAG (n = 81) groups. The median duration of EPAG administration in EPAG group was 16.1 months (range: 0.6 - 41.1 months). Six months after the initiation of IST, the complete response (CR) rate significantly improved in the EPAG group (P < 0.01). The cumulative incidence of allogeneic stem cell transplantation (allo-SCT) at 2 years and the 2-year overall survival (OS) were not significantly different between the two groups (allo-SCT, P = 0.31; OS, P = 0.64). Grade 3-4 adverse events in the EPAG group and the cumulative incidence of CE (P = 0.96) showed no increase. Conclusion: In summary, IST showed significantly better initial efficacy in the EPAG group. Although the addition of EPAG did not reduce the need for allo-SCT, no increase was observed in the incidence of CE with long-term EPAG use.