RESUMO
This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.
Assuntos
Infarto Cerebral , Leucemia Mielogênica Crônica BCR-ABL Positiva , Isquemia Miocárdica , Doença Arterial Periférica , Inibidores de Proteínas Quinases , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Infarto Cerebral/induzido quimicamente , Infarto Cerebral/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/induzido quimicamente , Isquemia Miocárdica/epidemiologia , Doença Arterial Periférica/induzido quimicamente , Doença Arterial Periférica/epidemiologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Fatores de RiscoRESUMO
A 67-year-old woman presented with a swelling on both sides of the neck. Biopsy of an enlarged cervical lymph node on the left side and flow cytometric analysis revealed CD56-positive CD4(+)CD8(+) abnormal NK/T cells. A Southern blot analysis of the cervical lymph node biopsy specimen showed a human T-cell leukemia virus type 1 provirus DNA monoclonal band. Based on these findings, the patient was diagnosed with CD56-positive adult T-cell leukemia/lymphoma. After five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, the general condition of the patient gradually declined, indicating resistance to treatment, and approximately 9 months after the onset of symptoms, the patient died. CD56 is recognized as an unfavorable prognostic marker in cases of acute myeloid leukemia with t(8;21), acute promyelocytic leukemia, and anaplastic large cell lymphoma. Only eight cases of CD56-positive adult T-cell leukemia/lymphoma have been reported so far in the literature. Most of these cases were in the advanced stage at diagnosis and had poor outcomes. It appears that the correlation between CD56 expression and outcomes in patients with adult T-cell leukemia/lymphoma should be clarified by investigating a larger number of cases in the future.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CD56/metabolismo , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Idoso , DNA Viral/genética , Feminino , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-I/tratamento farmacológico , Infecções por HTLV-I/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Leucemia-Linfoma de Células T do Adulto/metabolismo , Resultado do TratamentoAssuntos
Bases de Dados Factuais , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Fumar/mortalidade , Idoso , Doença Crônica , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Objective Pleural effusion (PE) is a common adverse event that occurs during dasatinib therapy for chronic myeloid leukemia (CML). However, the pathomechanism of PE and appropriate management of Asian patients with CML have not been elucidated. This study investigated the incidence rate, risk, and appropriate management of PE in Asian patients with CML treated with dasatinib. Methods We retrospectively collected data on patients in the chronic phase of CML who received first-line dasatinib therapy and were registered in the CML-Cooperative Study Group database. Patients We identified 44 cases of PE in a series of 89 patients and analyzed previously reported risk factors and effective management of PE. Results A univariate analysis revealed that age, diabetes mellitus, chronic renal failure, hypertension, the history of cardiovascular events, and dasatinib dose were significantly associated with PE. A multivariate analysis revealed that age ≥65 years old was the only independent risk factor for PE. Dasatinib dose reduction and switching to a tyrosine kinase inhibitor showed a statistically significant difference in effectively reducing PE volume compared to single diuretic use. Conclusion Although further studies are warranted, our observations showed that advanced age is a significant risk factor for PE, and tyrosine kinase inhibitor dose reduction or replacement of dasatinib may be an effective management strategy for PE in Asian CML patients who received first-line treatment with dasatinib in real-world clinical practice.
Assuntos
Dasatinibe , Leucemia Mielogênica Crônica BCR-ABL Positiva , Derrame Pleural , Idoso , Humanos , Dasatinibe/efeitos adversos , População do Leste Asiático , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Derrame Pleural/induzido quimicamente , Derrame Pleural/epidemiologia , Derrame Pleural/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5 . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR4.5 . The MR4.5 rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP.
Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Pirimidinas/normas , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
The European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) score predicts disease-specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML-related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML-CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML-CSG), which included patients diagnosed with CML-CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first-line therapy. Among 342 eligible patients, the ELTS scores indicated low-, intermediate-, and high-risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease-specific mortality and worse event-free survival, progression-free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low-, intermediate-, and high-risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML-CP.
Assuntos
Biomarcadores Tumorais/genética , Técnicas de Apoio para a Decisão , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Progressão da Doença , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/uso terapêutico , Japão , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
Tyrosine kinase inhibitor (TKI) treatment is the standard of care for patients with chronic myeloid leukemia (CML). Even in the imatinib era, the presence of 'clonal chromosomal abnormalities' in the Philadelphia chromosome (CCA/Ph+) at diagnosis reportedly increased the risk of disease progression and predicted shorter survival. However, it remains unclear whether CCA/Ph+ is a poor prognostic marker in the era of newgeneration TKIs. The data of patients with CML in the chronic phase (CP) that were extracted from the CML Cooperative Study Group database were retrospectively analyzed. Of the 328 eligible patients, 33 (10.1%) had CCA/Ph+, including 9 major route and 24 minor route aberrations. The characteristics of patients with and without CCA/Ph+ were similar; however, the proportion of blasts was higher among patients with CCA/Ph+. Notably, the survival rate of patients with CCA/Ph+ was not inferior to that of patients without CCA/Ph+, and there were no differences in responses to TKIs. All 9 patients with major route CCA/Ph+ attained a major molecular response (MMR) with no disease progression, and 8 ultimately achieved a deep molecular response. In particular, the median interval between TKI initiation and achievement of MMR was shorter in patients initially treated with a secondgeneration TKI than in those treated with imatinib (5 vs. 10 months). The present retrospective study, thus, revealed favorable treatment outcomes in CMLCP patients with CCA/Ph+ treated with secondgeneration TKIs. The data indicated that administering secondgeneration TKIs as firstline treatments is preferable in CMLCP patients with CCA/Ph+.
Assuntos
Evolução Clonal/efeitos dos fármacos , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas/efeitos dos fármacos , Evolução Clonal/genética , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Our study aims to highlight the critical role of the introduction of second generation tyrosine kinase inhibitors (2nd TKIs) on the prognosis of patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP), as determined by European Treatment and Outcome Study (EUTOS) system. Patients who were diagnosed with CML-CP before March 2009 were classified into the imatinib group, and those diagnosed after April 2009 were classified into the 2nd TKI group. EUTOS high-risk patients exhibited significantly worse outcomes in terms of event-free survival (EFS), progression-free survival (PFS), and CML-associated death than those considered to be low-risk. Risk stratification by EUTOS score was predictive of risk-associated clinical outcomes in patients classified into the imatinib group; however, the EUTOS score failed to predict the outcomes of patients classified into the 2nd TKI group. Our data suggest that the introduction of 2nd TKIs might have improved treatment outcomes, particularly in EUTOS high-risk patients.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Projetos de Pesquisa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Retratamento , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Treatment with a tyrosine kinase inhibitor (TKI) is the standard of care for patients with chronic myeloid leukemia (CML). The new-generation TKIs, nilotinib and dasatinib, are found to have deeper and faster treatment response rates compared to imatinib in the first-line setting. However, a direct comparison between nilotinib and dasatinib has never been reported previously. Our study aims to compare the outcomes and molecular responses achieved following the first-line use of these two agents in patients with CML-CP. The database of the CML Cooperative Study Group was reviewed and patients with CML in the chronic phase (CP) who were given nilotinib or dasatinib as first-line therapy were identified. Out of 361 patients with CML-CP enrolled in our database, 58 and 63 had been treated with conventional doses of nilotinib (300 mg twice daily) and dasatinib (100 mg once daily), respectively, as first-line therapy. The patient demographics did not show significant differences between the groups. The event-free survival rates did not differ between these two groups. The major molecular response (MMR) and the deep molecular response (DMR) rates by 6, 12, 18, and 24 months did not differ between groups. Among the three scoring systems, only the Hasford score could predict the achievement of DMR, and all of them failed to predict the achievement of MMR in the entire cohort. Our data suggest that both nilotinib and dasatinib have comparable efficacies and promising outcomes.
Assuntos
Dasatinibe/administração & dosagem , Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
We performed a retrospective study to evaluate the incidence of second malignancies (SMs) in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). We analyzed data from 339 patients with CML who were extracted from the CML Cooperative Study Group database. The standardized incidence ratio (SIR) was calculated to assess the risk of SMs using data from the Cancer Registries in Japan. The median follow-up was 65 months. SMs developed in 14 patients (4.1%, 10 men, 4 women) after the start of TKIs. The median age was 69 years at the time of the CML diagnosis and 72.5 years at the time of the SM diagnosis. Ten patients were treated with imatinib, three with dasatinib, and one with nilotinib as the initial treatment. The SIR for all malignancies was 1.05 (95% CI 0.50-1.93) for men and 1.08 (95% CI 0.29-2.76) for women. The difference in the overall survival (OS) of patients with or without SMs was not statistically significant (5-year OS: 82.5% vs. 92.9%; p = 0.343). A subgroup analysis of 166 patients treated with second-generation TKIs (92 dasatinib, 74 nilotinib) showed that the SIRs for all malignancies were 1.33 (95% CI 0.36-3.41) for men and 0 for women. In conclusion, the incidence of SMs in CML patients during TKI treatment was the same as that in the general Japanese population. There was no evidence of an increase in the incidence of SMs during second-generation TKI treatment. Furthermore, the occurrence of SMs during TKI treatment did not affect the survival or mortality in our cohort.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Segunda Neoplasia Primária/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaAssuntos
Neoplasias Encefálicas/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Leucemia Linfocítica Granular Grande/patologia , Linfócitos T/patologia , Antineoplásicos/uso terapêutico , Evolução Fatal , Citometria de Fluxo/métodos , Humanos , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-IdadeRESUMO
This study was performed to investigate the features and outcome of patients with therapy-related chronic myeloid leukemia (TR-CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 308 patients with CML in the chronic phase who were extracted from the CML Cooperative Study Group database. Of these patients, 11 (3.6%) were identified as having TR-CML. No differences in age, sex, white blood cell count, hemoglobin level, platelet count, or European Treatment and Outcome Study risk were observed between patients with TR-CML vs. de novo CML. However, the responses of TR-CML patients to TKIs (6, 3, and 2 received imatinib, nilotinib, and dasatinib, respectively) were excellent; all achieved major or deep molecular response. Furthermore, the outcomes of TR-CML patients were relatively favorable; the 3-year event-free survival rates in the TR-CML and de novo CML patients were 100% and 94%, respectively; the difference was not statistically significant. In conclusion, our study showed that TR-CML patients could achieve a good clinical course with TKI therapy. Detailed investigations of TR-CML may provide new insights into CML biology.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Segunda Neoplasia Primária/diagnóstico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/mortalidade , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Chromosome 1q21-25 is one of the hotspots of chromosomal abnormalities including translocations and duplications in hematological malignancies. This would suggest that oncogene(s) reside in this region. We have cloned the junctional sequence of t(1;14)(q25;q32) in pre-B acute lymphoblastic leukemia cells by an inverse PCR method. A novel sequence was fused to the joining region of the immunoglobulin heavy chain gene. We confirmed this rearrangement by Southern blot analysis, genomic PCR and fluorescence in situ hybridization. We found a coding sequence which is homologous to the mouse Lhx4 cDNA sequence 17 kb from the breakpoint. The human Lhx4 gene encodes 390 amino-acids, including one tandem pair of LIM domains and one homeodomain. The human Lhx4 gene consists of six exons. Lhx4 protein is very homologous to human Lhx3 protein except in the N-terminal region. The transcripts of the Lhx4 gene were not detected in adult multiple tissues analysed by Northern blotting, but were detected in the leukemic cells carrying t(1;14)(q25;q32) by reverse-transcription PCR. The protein expression of Lhx4 in these leukemic cells was confirmed by Western blot analysis. Lhx4 activated the reporter gene carrying the mouse alpha-glycoprotein subunit promoter region, which is regulated by Lhx3. LIM protein and homeodomain protein genes are frequently involved in translocations of hematological malignancies. The Lhx4 gene is deregulated in the leukemic cells and Lhx4 protein may play an important role, possibly as an activator, in leukemogenesis.
Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 1 , Proteínas de Homeodomínio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Fatores de Transcrição , Translocação Genética , Doença Aguda , Sequência de Aminoácidos , Sequência de Bases , Feminino , Humanos , Hibridização in Situ Fluorescente , Proteínas com Homeodomínio LIM , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
Mxi1 protein is a basic helix-loop-helix, leucine zipper (bHLHZIP) transcriptional factor, which dimerizes with the Max protein. This heterodimer binds a specific DNA sequence (E-box) and suppresses transcription of target genes. On the other hand, c-Myc protein is also a bHLHZIP protein that dimerizes with Max, binds the identical E-box sequence but activates transcription of the target genes. We report that hematopoietic cells have three novel Mxi1 transcripts: Mxi-D lacks exon 3, which encodes the basic region; Mxi-ND lacks the N-terminal mSin3 binding region and the DNA binding region; and Mxi-NF lacks the N-terminal mSin3 binding region. In normal bone marrow and hematological cell lines, the dominantly expressed isoforms are Mxi-D and full-length Mxi1 (Mxi-F). In GST-pull down assays, the Mxi-D protein binds the Max protein and the PHA2 regions of mSin3 proteins. Whereas the Mxi-F/Max heterodimer binds the E-box sequence, Mxi-D/Max heterodimer can not bind this sequence in electrophoretic mobility shift assays. In reporter gene assay, Mxi-D suppresses transcription as strongly as Mxi-F. In colony formation assay using Rat1 fibroblast cells, Mxi-D cannot suppress clonal growth stimulated by c-Myc as strongly as Mxi-F. In summary, Mxi-D may play an important role in the c-Myc family protein network acting as a dominant negative isoform of Mxi-F since: i) Mxi-D can dimerize with Max in vitro; ii) Mxi-D/Max heterodimers cannot bind E-box in vitro, iii) Mxi-D cannot suppress clonal growth stimulated by c-Myc.
Assuntos
Proteínas de Ligação a DNA/biossíntese , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Células da Medula Óssea , Proliferação de Células , Proteínas de Ligação a DNA/química , Genes Reporter , Sequências Hélice-Alça-Hélice , Humanos , Isoformas de Proteínas , Fatores de Transcrição/química , Células Tumorais Cultivadas , Proteínas Supressoras de TumorRESUMO
The patient was a 73-year-old male who came to our hospital with a chief complaint of pain and swelling of the left side of his jaw. Computed tomography revealed a mass in his left gingiva but no bone destruction. No lesions were observed at any other sites, and an incisional biopsy was performed on the gingival mass on the left side. Histologically, the mass was a diffuse large B-cell lymphoma (DLBCL), and it was CD20-positive, and CD5-negative, CD10-negative, surface immunoglobulin-negative, and Epstein-Barr virus-encoded RNA (EBER)-negative. A serum Human immunodeficiency virus (HIV)-antibody test was negative. A complete remission was achieved after 6 courses of systemic combination chemotherapy, and the complete remission has been maintained for approximately 3 years. According to the literature, primary gingival DLBCL have a high Ki-67-positive rate and many of the cases are stage I and international prognostic index low-risk. However, HIV patients have a high EBER-positive rate and a high risk of developing a CD20-negative, CD138-positive plasmablastic lymphoma, and they have a poor prognosis. By contrast, limited-stage primary gingival lymphomas whose data can be used have been rare in human immunodeficiency virus-negative patients, and only 12 cases, including our own, have ever been reported. Many of the patients have been around 65 years of age, and all of the cases have been CD20-positive, CD138-negative DLBCLs, and the CD5-negative, Epstein-Barr virus-positive rate has been low, with most cases having been non-germinal-center B-cell-like. The prognosis for relapse-free survival has been favorable.
Assuntos
Neoplasias Gengivais/patologia , Linfoma Difuso de Grandes Células B/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gengivais/tratamento farmacológico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , MasculinoRESUMO
The patient, a 42-year-old man, was diagnosed as having an anterior mediastinal tumor. Examination of the resected tumor showed findings consistent with a primary thymic mucosa-associated lymphoid tissue lymphoma, stage IA. Postoperative (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography demonstrated fluorodeoxyglucose accumulation at the site of tumor excision. This accumulation was interpreted as representing a residual lesion, and the patient was treated with rituximab. The patient has since been in a state of complete remission for about 3 years. Sporadic mucosa-associated lymphoid tissue lymphoma cells that appeared to have a propensity for differentiating into plasma cells in this case were analyzed for IgG and IgG subclass expression by immunohistochemical staining. The mucosa-associated lymphoid tissue lymphoma cells that showed a propensity for differentiating into IgG-positive plasma cells were IgG3-positive and IgG1-, IgG2- and IgG4-negative. An increase in IgG3 or IgG1 expression in immune cells has been previously demonstrated in immune responses to continuous exposure to the same proteins or peptide antigens and most mucosa-associated lymphoid tissue lymphomas show increased IgG3 and/or IgG1 expression. It is consistent with the fact that inflammation due to stimulation by a pathogenic antigen is considered to be etiologically responsible for the development of mucosa-associated lymphoid tissue lymphoma.
Assuntos
Imunoglobulina G/imunologia , Linfoma de Zona Marginal Tipo Células B/patologia , Neoplasias do Timo/patologia , Trissomia , Adulto , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 3/genética , Humanos , Imuno-Histoquímica , Linfoma de Zona Marginal Tipo Células B/imunologia , Masculino , Neoplasias do Mediastino/imunologia , Neoplasias do Mediastino/patologia , Plasmócitos/imunologia , Plasmócitos/patologia , Neoplasias do Timo/imunologiaRESUMO
A 39-year-old woman with a right frontal mass underwent a cranial bone tumor biopsy. Histopathologic examination of hematoxylin and eosin-stained slides showed spindle-shaped tumor cells in a storiform pattern, appearing somewhat like a sarcoma. However, the tumor cells were CD20-positive by immunohistochemical staining. Therefore, a diagnosis of spindle-shaped diffuse large B-cell lymphoma (Sp-DLBCL) was made. There have been at least 35 cases of Sp-DLBCL documented in the literature, and most were of the germinal center type, while the present case is the first report of a vimentin-positive primary Sp-DLBCL of the skull. The DLBCL in this case was immunohistochemically stained for six representative cytokines that might give rise to fibrosis, due to the evidence of fibroblastic proliferation. The DLBCL cells were positive for platelet-derived growth factor (PDGF), and some cells were also positive for tumor necrosis factor (TNF) α. Based on these findings, it was inferred that the PDGF and TNFα produced by DLBCL cells induced fibroblastic proliferation. The resultant conspicuous fibrosis caused interfibrous impingement on the DLBCL cells, which deformed them into a spindle shape. The present case is the first reported case of a PDGF-producing Sp-DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B/patologia , Fator de Crescimento Derivado de Plaquetas/biossíntese , Neoplasias Cranianas/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Feminino , Fibrose/patologia , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Neoplasias Cranianas/metabolismoRESUMO
A 22-year-old man sought medical advice for a swelling in the right side of the neck in December 2011. Histopathological examination of the lymph node biopsy initially suggested reactive lymphadenitis, on account of the only sparse presence of tumor cells. Bone marrow examination was performed in February 2012 revealed findings consistent with a diagnosis of T-cell lymphoblastic leukemia/lymphoma (T-LBL), and the patient was begun on remission induction therapy. The bone marrow showed an immature thymocytic pattern: cytoplasmic CD3+, surface CD3-, CD5+, CD4-, and CD8-. Re-assessment of the lymph node specimens revealed the same phenotype of the cells in the lymph node as that of the blasts in the bone marrow. In addition, a chromosomal aberration t(7;14)(p15;q32) was noted. The lymph node biopsy specimens were examined by paraffin-embedded tissue section-fluorescence in situ hybridization (PS-FISH), which revealed a fusion signal of T-cell receptor (TCR)γ gene (7p15) with T-cell leukemia/lymphoma 1A (TCL1A) gene (14q32.13). There have been at least 10 reported cases of T-LBL with t(7;14)(p15;q32), including the present case. However, this is the first reported case in which TCRγ-TCL1A translocation was confirmed by FISH.
Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 7 , Genes Codificadores da Cadeia gama de Receptores de Linfócitos T , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética , Adolescente , Biomarcadores Tumorais/análise , Biópsia , Exame de Medula Óssea , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Indução de Remissão , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
The patient was a 52-year old woman with a history of mosquito-bite hypersensitivity since childhood. In July 2011, she developed pyrexia, headaches, and nausea, and Epstein-Barr virus (EBV)-positive aggressive natural killer leukemia (ANKL) was diagnosed on the basis of both a peripheral blood and bone marrow examination. An inguinal lymph node biopsy, on the other hand, revealed EBV-positive cytotoxic T-cell lymphoma plus the presence of a small number of EBV-positive ANKL cells, and a diagnosis of EBV-positive composite lymphoma was made. Both the cytotoxic T-cell lymphoma and ANKL exhibited EBV terminal repeat (Southern blot analysis) monoclonal patterns, and they were almost the same size, approximately 9.0 kb. If it was the identical EBV clone, it is possible that EBV infected progenitor cells common to both NK cells and T cells, that the progenitor cells then differentiated into NK cells and T cells, a chronic active Epstein-Barr virus infection developed, and neoplastic transformation occurred. If it was not the identical EBV clone, fairly similar EBVs must have infected NK cells and T cells separately, and they then underwent neoplastic transformation. Because the mechanism by which EBV infects NK cells or T cells is still unknown, we concluded that this case is also important from the standpoint of elucidating it. We are currently in the process of conducting gene analyses to determine whether the fairly similar EBVs that infected the ANKL and cytotoxic T-cell lymphoma are the identical clone.