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1.
Int J Hematol ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34591291

RESUMO

Human herpesvirus-8 (HHV8)-positive, human immunodeficiency virus (HIV)-negative multicentric Castleman disease (MCD) is a rare and age-related lymphoproliferative disorder caused by cytokine storm. Rituximab treatment is currently recommended because B-cell depletion eliminates the primary reservoir for HHV8. We report the first case of effective rituximab treatment of a Japanese patient (an 87-year-old woman) with this disorder. Her inflammatory symptoms and lymphadenopathy improved after medium-dose steroid therapy, but these symptoms recurred during steroid tapering. After one course of rituximab therapy, she achieved sustained remission. HHV8-associated MCD should be considered as a possible diagnosis in HIV-negative patients with inflammatory symptoms and lymphadenopathy.

2.
J Immunol ; 207(4): 1078-1086, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34341172

RESUMO

Emergency granulopoiesis, also known as demand-adapted granulopoiesis, is defined as the response of an organism to systemic bacterial infections, and it results in neutrophil mobilization from reservoir pools and increased myelopoiesis in the bone marrow. Indirect and direct initiating mechanisms of emergency granulopoiesis have been hypothesized. However, the detailed mechanism of hyperactive myelopoiesis in the bone marrow, which leads to granulocyte left shift, remains unknown. In this study, we report that TLR4 is expressed on granulo-monocytic progenitors, as well as mobilized human peripheral blood CD34+ cells, which account for 0.2% of monocytes in peripheral blood, and ∼ 10% in bone marrow. LPS, a component of Gram-negative bacteria that results in a systemic bacterial infection, induces the differentiation of peripheral blood CD34+ cells into myelocytes and monocytes in vitro via the TLR4 signaling pathway. Moreover, CD34+ cells directly responded to LPS stimulation by activating the MAPK and NF-κB signaling pathways, and they produced IL-6 that promotes emergency granulopoiesis by phosphorylating C/EBPα and C/EBPß, and this effect was suppressed by the action of an IL-6 receptor inhibitor. This work supports the finding that TLR is expressed on human hematopoietic stem and progenitor cells, and it provides evidence that human hematopoietic stem and progenitor cells can directly sense pathogens and produce cytokines exerting autocrine and/or paracrine effects, thereby promoting differentiation.


Assuntos
Granulócitos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Receptor 4 Toll-Like/metabolismo , Adaptação Fisiológica/fisiologia , Antígenos CD34/metabolismo , Medula Óssea/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular/fisiologia , Citocinas/metabolismo , Regulação da Expressão Gênica/fisiologia , Células Precursoras de Granulócitos/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Monócitos/metabolismo , Mielopoese/fisiologia
3.
Int J Hematol ; 114(4): 509-516, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34406581

RESUMO

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2-34.5), 33.1 (21.2-40.3) and 27.7 (13.6-29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy.


Assuntos
Imidazóis/farmacocinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/farmacocinética , Adulto , Idoso , Terapia Combinada , Monitoramento de Medicamentos , Feminino , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Imidazóis/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Inibidores de Proteínas Quinases/administração & dosagem , Piridazinas/administração & dosagem , Resultado do Tratamento
4.
Cancer Sci ; 112(9): 3645-3654, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288263

RESUMO

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Translocação Genética/genética , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tretinoína/farmacologia
5.
Clin Exp Nephrol ; 25(11): 1193-1202, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34115234

RESUMO

BACKGROUND: Inhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients. METHODS: We analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients. RESULTS: All 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients. CONCLUSIONS: Histopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.

6.
Rinsho Ketsueki ; 62(5): 341-345, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34108311

RESUMO

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma that mostly affects women. Here, we report a case of primary breast DLBCL that affected an older man without any autoimmune disease or drug-related female hormones. The patient was a 65-year-old man whose chief complaints were gradually-increasing lump in the right chest and swelling of the right axillary lymph nodes. He was diagnosed with malignant lymphoma through a needle biopsy on suspicion of right breast cancer with right axillary lymph node metastasis. Since the histological type could not be confirmed, right breast mass resection was performed. The patient was referred to our department for treatment because of the diagnoses of primary breast DLBCL, germinal center B-cell type (Hans classification), and clinical stage IIA. In addition to the six courses of R-CHOP therapy, intrathecal injections were used in combination to prevent CNS infiltration. He has been in complete remission for 5 years. Although rare, breast lymphoma can also occur in men; therefore, early histological diagnosis and response to CNS recurrence prevention are important.


Assuntos
Neoplasias da Mama , Linfoma Difuso de Grandes Células B , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Recidiva Local de Neoplasia , Indução de Remissão
7.
Am J Pathol ; 191(7): 1303-1313, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964218

RESUMO

Neonatal hypoxic-ischemic encephalopathy (nHIE) is a major neonatal brain injury. Despite therapeutic hypothermia, mortality and sequelae remain severe. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with the pathophysiology of nHIE. In this study, morphologic change and microglial activation under the nHIE condition and LOX-1 treatment were investigated. The microglial activity and proliferation were assessed with a novel morphologic method, immunostaining, and quantitative PCR in the rat brains of both nHIE model and anti-LOX-1 treatment. Circumference ratio, the long diameter ratio, the cell area ratio, and the roundness of microglia were calculated. The correlation of the morphologic metrics and microglial activation in nHIE model and anti-LOX-1 treated brains was evaluated. LOX-1 was expressed in activated ameboid and round microglia in the nHIE model rat brain. In the evaluation of microglial activation, the novel morphologic metrics correlated with all scales of the nHIE-damaged and treated brains. While the circumference and long diameter ratios had a positive correlation, the cell area ratio and roundness had a negative correlation. Anti-LOX-1 treatment attenuated morphologic microglial activation and proliferation, and suppressed the subsequent production of inflammatory mediators by microglia. In human nHIE, round microglia and endothelial cells expressed LOX-1. The results indicate that LOX-1 regulates microglial activation in nHIE and anti-LOX-1 treatment attenuates brain injury by suppressing microglial activation.


Assuntos
Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Microglia/metabolismo , Receptores Depuradores Classe E/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Ratos , Ratos Sprague-Dawley
8.
Leukemia ; 35(6): 1631-1642, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33980976

RESUMO

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Assistência de Longa Duração/métodos , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Taxa de Sobrevida
10.
Nat Commun ; 12(1): 2833, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990592

RESUMO

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.


Assuntos
Crise Blástica/genética , Evolução Clonal/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Crise Blástica/tratamento farmacológico , Crise Blástica/patologia , Proteínas Sanguíneas/genética , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteína Proto-Oncogênica c-ets-2/genética , Sequenciamento Completo do Exoma , Adulto Jovem
11.
Surg Today ; 51(9): 1513-1520, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33829335

RESUMO

PURPOSE: The aim of this study was to examine the predictive scoring system of advanced liver fibrosis in severely obese Japanese patients. METHODS: Seventy-two patients underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies. We classified these patients into two groups: Brunt stage ≥ 2 (advanced fibrosis) and 0/1 (none/mild fibrosis). A logistic regression analysis was performed to identify the predictors of advanced fibrosis. RESULTS: Sixteen patients had advanced fibrosis, while 56 had no/mild fibrosis. The prevalence of type 2 diabetes mellitus (T2DM) in advanced fibrosis group was significantly higher than in none/mild fibrosis. An univariate analysis of the factors predicting advanced fibrosis showed significant differences in AST/ALT ratio, serum insulin levels, HOMA-IR, and type IV collagen 7S in the T2DM group. According to a multivariate analysis, type IV collagen 7S was an independent predictor and the cutoff value was 5.6 ng/mL. We created a flow chart; high risk (T2DM and type IV collagen 7S ≥ 5.6 ng/mL), moderate risk (T2DM and type IV collagen 7S < 5.6 ng/mL), and low risk (non-DM). For those at high risk, the sensitivity, specificity, positive predictive value, and negative predictive value were 56.2%, 94.4%, 75.0%, and 87.9%, respectively. CONCLUSION: This classification system has the potential to accurately categorize the risk of liver fibrosis.

12.
Int J Hematol ; 114(2): 199-204, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33907977

RESUMO

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive leukemia that occurs in 20-40% of adult patients. Ph + ALL is caused by the Philadelphia chromosome (Ph), which consists of a t(9;22)(q34;q11) reciprocal translocation leading to the formation of a BCR-ABL1 fusion gene. The disease is treated with targeted therapy comprising ABL1 tyrosine kinase inhibitors (TKIs). Ponatinib is a third generation TKI that demonstrates higher binding affinity for ABL1 than first/second generation TKIs. Although intensive combined immunotherapy with ponatinib greatly improves the prognosis of Ph + ALL, the safety and efficacy profiles of ponatinib in Japanese patients are unclear. This retrospective study investigated five cases of Ph + ALL at a single institute to evaluate safety and efficacy profiles. Three patients achieved a deep molecular response (DMR) following combined intensive treatment with ponatinib as induction chemotherapy. Four patients received consolidative allogenic stem cell transplantation (allo-SCT) during their first complete response. Three of the four experienced early relapse within 100 days; they subsequently received ponatinib, and one of the three achieved a DMR. No patient experienced severe cardiovascular events. This case series suggests that ponatinib at a concentration of least 30 mg exhibits anti-leukemia effects in Japanese patients with Ph + ALL.


Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Gerenciamento Clínico , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
13.
JSLS ; 25(1)2021.
Artigo em Inglês | MEDLINE | ID: mdl-33879993

RESUMO

Objectives: The Tokyo Guidelines 2018 have been widely adopted since their publication. However, the few reports on clinical outcomes following laparoscopic cholecystectomy have not taken into account the severity of the acute cholecystitis and the patient's general condition, as estimated by the Charlson comorbidity index. This study aimed to assess the relationships between severity, Charlson comorbidity index, and clinical outcomes subsequent to laparoscopic cholecystectomy. Methods: We extracted the retrospective data for 370 Japanese patients who underwent emergency or scheduled early laparoscopic cholecystectomy within 72 hours from onset between February 2015 and August 2018. We compared postoperative factors in relationship to severity (grade I versus grade II/III). Then, we made a similar comparison between those with low (< 4) and high Charlson comorbidity index (≥ 4). Results: According to the Tokyo guideline 2018 levels of severity, there were 282 (76.2%), 61 (16.5%), and 27 (7.3%) patients in grades I, II, and III, respectively. With regards to surgical outcomes, the mean operating time was 62.3 minutes and the mean blood loss was 24.4 mL. The mean hospital stay was 3.6 days, with no mortalities. Blood loss was the only factor affected by severity (20.9 mL versus 60.1 mL, P = 0.0164), and operating time was the only factor affected by high Charlson comorbidity index (53.4 versus 67.8 minutes, P = 0.0153). Conclusion: Our aggressive strategy is acceptable, and severity and Charlson comorbidity index are not critical factors suggesting the disqualification of early laparoscopic cholecystectomy in patients with any grade acute cholecystitis.


Assuntos
Colecistectomia Laparoscópica , Colecistite Aguda/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistite Aguda/patologia , Estudos de Viabilidade , Feminino , Humanos , Japão , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Índice de Gravidade de Doença
14.
Intern Med ; 60(18): 2985-2989, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-33776000

RESUMO

There are an increasing number of reports on the safe use of rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, in pregnant women with hematological malignancies or refractory autoimmune diseases. In 2014, the use of RTX for patients with complicated steroid-dependent nephrotic syndrome (SDNS) was approved in Japan. We herein report a woman with childhood-onset complicated SDNS due to focal and segmental glomerulosclerosis, who had two successful pregnancies while receiving RTX maintenance therapy. No adverse complications were observed during the pregnancies, and she delivered healthy newborns. This case suggested that RTX may be used safely in pregnant women complicated with SDNS.


Assuntos
Glomerulosclerose Segmentar e Focal , Síndrome Nefrótica , Criança , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Imunossupressores , Recém-Nascido , Japão , Síndrome Nefrótica/tratamento farmacológico , Gravidez , Rituximab/efeitos adversos , Esteroides , Resultado do Tratamento
15.
Sci Rep ; 11(1): 6362, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737618

RESUMO

The purpose of this study was to investigate the effects of SLC22A2 808G>T polymorphism and trough concentrations (C0) of bosutinib on serum creatinine in 28 patients taking bosutinib. At 1, 3, 6, 12, 24, and 36 months after administration, analysis of bosutinib C0 and creatinine was performed at the same time of day. Significant correlations were observed between bosutinib C0 and the change rate of serum creatinine or the estimated glomerular filtration rate (eGFR; r = 0.328, P < 0.001 and r = - 0.315, P < 0.001, respectively). These correlations were particularly high in patients having the SLC22A2 808G/G genotype (r = 0.345 and r = - 0.329, respectively); however, in patients having the 808T allele, there were no significant differences. In multivariate analyses, the SLC22A2 808G/G genotype, patient age, bosutinib C0 and second-line or later bosutinib were independent factors influencing the change rate of creatinine. Bosutinib elevated serum creatinine through organic cation transporter 2 (OCT2). We observed a 20% increase in serum creatinine with a median bosutinib C0 of 63.4-73.2 ng/mL. Periodic measurement of serum creatinine after bosutinib therapy is necessary to avoid progression to severe renal dysfunction from simple elevation of creatinine mediated by OCT2 following bosutinib treatment.


Assuntos
Compostos de Anilina/administração & dosagem , Biomarcadores Farmacológicos/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/administração & dosagem , Transportador 2 de Cátion Orgânico/genética , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Compostos de Anilina/sangue , Creatinina/sangue , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Nitrilas/sangue , Polimorfismo de Nucleotídeo Único/genética , Quinolinas/efeitos adversos , Quinolinas/sangue
16.
Intern Med ; 60(13): 2115-2118, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33518561

RESUMO

A 17-year-old girl was diagnosed with acute lymphoblastic leukemia (ALL). After the administration of high-dose methotrexate (MTX) or intrathecal MTX, the patient experienced transient hemiparesis and motor aphasia. Diffusion-weighted magnetic resonance imaging showed a high-intensity lesion in the bilateral centrum semiovale, and a vasospasm was detected in the proximal segment of bilateral A1 on magnetic resonance angiography. Edaravone was administered, and leucovorin rescue treatment was continued; eventually, the patient's neurological symptoms completely resolved. This finding suggested that vasospasm might be a mechanism underlying MTX-induced transient encephalopathy in adolescent and young adult patients with ALL.


Assuntos
Encefalopatias , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Metotrexato/efeitos adversos , Paresia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
17.
Sci Rep ; 11(1): 3381, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33564054

RESUMO

Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.

18.
Int J Hematol ; 113(4): 600-605, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33387296

RESUMO

Blinatumomab enhances survival in patients with B-cell precursor acute lymphoblastic leukemia (B-ALL) by inducing T cell activation. However, approximately 50% of patients with relapsed or refractory B-ALL do not respond to blinatumomab, and the correlation between T cell phenotype and blinatumomab response remains unclear. To assess this correlation, we longitudinally compared immune checkpoint molecules in T cells before and during blinatumomab treatment between a responder and non-responder. In the responder, the expression level of granzyme B increased following infusion of blinatumomab and complete remission was achieved. On the other hand, the non-responder consistently expressed higher levels of programmed death-1 (PD-1), T cell immunoglobulin and mucin domain 3 (Tim-3), and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) in CD8 + T cells than the responder during blinatumomab treatment and showed no response despite the addition of two donor lymphocyte infusions. Furthermore, the residual tumors in bone marrow after blinatumomab treatment showed increased expression of immune checkpoint ligands: PD-L1 (PD-1 ligand), Galectin-9 (Tim-3 ligand), PD-L2 (PD-1 ligand) and CD155 (TIGIT ligand). In conclusion, immune checkpoint molecule levels could correlate with response to blinatumomab.


Assuntos
Anticorpos Biespecíficos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Checkpoint Imunológico/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Anticorpos Biespecíficos/uso terapêutico , Medula Óssea/patologia , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Imunofenotipagem , Ativação Linfocitária , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia
19.
Int J Hematol ; 113(1): 100-105, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33025461

RESUMO

Nilotinib is a substrate of the breast cancer resistance protein (BCRP), which is a drug efflux transporter encoded by ABCG2 and regulates the pharmacokinetics of its substrates. We investigated the interaction between nilotinib and BCRP in chronic myeloid leukemia (CML) cells. An imatinib-resistant K562 cell line (K562/IM-R) treated with nilotinib was analyzed for BCRP expression, proliferation, apoptosis, and intracellular nilotinib concentration. K562/IM-R cells cultured with tyrosine kinase inhibitors (TKIs) showed an increased cell count and retained viability, whereas the growth of parental K562 cells was severely inhibited, suggesting that BCRP is involved in developing resistance to TKIs. Nilotinib-treated K562/IM-R cells showed a reduction in apoptosis; however, febuxostat pretreatment resulted in increased apoptosis. The intracellular concentration of nilotinib in K562/IM-R cells was significantly reduced compared to that in parental K562 cells, and febuxostat-pretreated K562/IM-R cells showed an increased intracellular nilotinib level compared to cells without pretreatment. The reduction in nilotinib levels caused by BCRP in CML cells might play a crucial role in resistance to TKIs. Moreover, febuxostat, as a BCRP inhibitor, could enhance nilotinib sensitivity, and combination therapy with nilotinib and febuxostat may represent a promising strategy for treatment of CML.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Febuxostat/farmacologia , Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Pirimidinas/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Febuxostat/uso terapêutico , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico
20.
J Clin Pharm Ther ; 46(1): 219-222, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32985698

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Some patients with chronic myeloid leukaemia (CML) cannot continue tyrosine kinase inhibitor (TKI) treatment due to intolerance associated with higher plasma concentration. CASE SUMMARY: A 76-year-old woman with chronic-phase CML who showed resistance/intolerance to pre-TKIs has been treated with ponatinib. A high ponatinib bioavailability was noted; therefore, we administered ponatinib 15 mg/3 d to avoid adverse events due to high exposure. Eventually, the patient achieved a major molecular response. WHAT IS NEW AND CONCLUSION: Monitoring of the ponatinib plasma concentration led to safe and effective CML management in a patient with higher drug bioavailability.

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