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1.
Anticancer Res ; 39(12): 6499-6505, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810914

RESUMO

BACKGROUND/AIM: Development of new potential drugs to overcome multidrug resistance to chemotherapy is a big challenge for cancer treatment. Attention is also given to the natural compounds and their derivatives. The study aimed at evaluating the impact of a new chalcone derivative (1C) on multidrug resistant cell lines, focusing on P-glycoprotein (P-gp, ABCB1) inhibition, as well as 1C-doxorubicin interaction in vitro. MATERIALS AND METHODS: Cytotoxic and antiproliferative effects of the 1C compound were assessed by thiazolyl blue tetrazolium bromide (MTT) method in mouse T-cell lymphoma and human colon adenocarcinoma cells expressing ABCB1. Alterations in ABCB1 activity were evaluated by rhodamine 123 accumulation assay using flow cytometry. Drug-drug interaction was studied using combination assay. RESULTS: Our results confirmed antiproliferative, cytotoxic, as well as ABCB1 inhibitory potential of 1C in both tested ABCB1-expressing cancer cell lines. Furthermore, 1C displayed synergistic interaction with doxorubicin. CONCLUSION: Our results suggest the 1C chalcone derivative as a promising compound against resistant lymphoma and colon cancer, which could be used in monotherapy or in combination with other chemotherapeutics.


Assuntos
Adenocarcinoma/metabolismo , Chalconas/farmacologia , Neoplasias do Colo/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma de Células T/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Células T/tratamento farmacológico
2.
BMC Cancer ; 19(1): 936, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601188

RESUMO

BACKGROUND: The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients. METHODS: We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation. RESULTS: Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects. CONCLUSIONS: IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucina-6/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/metabolismo , Terapia de Alvo Molecular/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Interleucina-6/genética , Isoquinolinas/farmacologia , Inibidores de Janus Quinases/farmacologia , Linfoma de Células B/patologia , Linfoma de Células T/patologia , Purinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transfecção , Proteínas Supressoras de Tumor/metabolismo
3.
Blood ; 134(17): 1395-1405, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31471376

RESUMO

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
4.
Blood ; 134(17): 1430-1440, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31383641

RESUMO

Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphoma (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs, whereas major histocompatibility complex (MHC) class I, which can also suppress phagocytosis, is ubiquitous. Multiple monoclonal antibodies (mAbs) that block CD47-SIRPα interaction promoted phagocytosis of TCL cells, which was enhanced by cotreatment with antibodies targeting MHC class I. Expression levels of surface CD47 and genes that modulate CD47 pyroglutamation did not correlate with the extent of phagocytosis induced by CD47 blockade in TCL lines. In vivo treatment of multiple human TCL patient-derived xenografts or an immunocompetent murine TCL model with a short course of anti-CD47 mAb markedly reduced lymphoma burden and extended survival. Depletion of macrophages reduced efficacy in vivo, whereas depletion of neutrophils had no effect. F(ab')2-only fragments of anti-CD47 antibodies failed to induce phagocytosis by human macrophages, indicating a requirement for Fc-Fcγ receptor interactions. In contrast, F(ab')2-only fragments increased phagocytosis by murine macrophages independent of SLAMF7-Mac-1 interaction. Full-length anti-CD47 mAbs also induced phagocytosis by Fcγ receptor-deficient murine macrophages. An immunoglobulin G1 anti-CD47 mAb induced phagocytosis and natural killer cell-mediated cytotoxicity of TCL cells that was augmented by cotreatment with mogamulizumab, an anti-CCR4 mAb, or a mAb blocking MHC class I. These studies help explain the disparate activity of monotherapy with agents that block CD47 in murine models compared with patients. They also have direct translational implications for the deployment of anti-CD47 mAbs alone or in combination.


Assuntos
Antígenos de Diferenciação/imunologia , Antineoplásicos Imunológicos/farmacologia , Antígeno CD47/imunologia , Linfoma de Células T/tratamento farmacológico , Receptores de IgG/imunologia , Receptores Imunológicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno CD47/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Camundongos , Receptores Fc/imunologia
5.
Medicine (Baltimore) ; 98(31): e16688, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374054

RESUMO

The objectives of this study were to analyze the clinical features of patients with bone involved lymphoma and identify the prognostic factors and to explore the optimized treatment strategy for bone involved lymphoma.A total of 1948 patients with lymphoma in our cancer center from September 2006 to October 2017 were retrospectively evaluated. Among these, 109 patients with skeletal involvement in lymphoma were enrolled. According to the pathologic subtypes, the patients were divided into 3 subgroups: classic Hodgkin lymphoma (cHL), B-cell non-Hodgkin lymphoma (B-NHL), and T-cell non-Hodgkin lymphoma (T-NHL). The clinical characteristics and overall survival (OS) of 3 groups of patients were reviewed, and the prognostic factors were analyzed.There were 9 (3 unifocal, 6 multifocal) patients with primary bone lymphoma. The 5-year OS of cHL, B-NHL, and T-NHL patients was 88.24%, 54.09%, and 61.58%, respectively. Advanced stage, elevated lactate dehydrogenase (LDH), age above 60, high International Prognostic Index score, and treatment without radiotherapy for the bone involved were significant poor prognostic factors for OS of all patients in univariate analysis. There was a trend toward better OS not only in limited-stage but also in advanced-stage patients with radiotherapy for the bone involved compared with the patients without radiotherapy. Elevated LDH level and age above 60 were the independent unfavorable prognostic factor in multivariate analysis.Elevated LDH level and age above 60 predict the poor prognosis of patients with bone involvement. The potential for long-term survival suggests that additional consolidative radiotherapy for the site of skeleton involvement may have a better chance of long-term success.


Assuntos
Neoplasias Ósseas/radioterapia , Doença de Hodgkin/radioterapia , Linfoma de Células B/radioterapia , Linfoma de Células T/radioterapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Estudos de Casos e Controles , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Vincristina/uso terapêutico
6.
Int J Hematol ; 110(4): 389-392, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468320

RESUMO

CCR4 is expressed on tumor cells of most patients with adult T-cell leukemia/lymphoma (ATL). Gain-of-function mutations of the CCR4 gene in ATL patients may be associated with alterations at the carboxyl terminus, a finding which led to a high efficacy anti-CCR4 antibody, mogamulizumab. Only a few studies have reported CCR4 protein expression and genomic CCR4 mutations in non-ATL T/NK-cell lymphomas. Furthermore, an association between CCR4 protein expression, genomic CCR4 mutations, and transcript CCR4 mutations has not been well analyzed. The T/NK-cell lymphomas (n = 226) enrolled in this study were examined for CCR4 expression by immunohistochemistry. CCR4 mutations in the codons 322-348 were detected by direct sequencing and a SNaPshot Multiplex assay. CCR4 protein expression was positive in 48/52 (92%) and 58/174 (33%) of ATL and non-ATL cases, respectively, and genomic CCR4 mutations were detected in 17/52 (33%) and 6/174 (3.4%), respectively. While all 17 ATL cases with genomic CCR4 mutations were positive for CCR4 protein expression, five of six mutated non-ATL cases were negative for CCR4 protein expression and transcript CCR4 mutations. This study suggests that frequencies of CCR4 expression and genomic CCR4 mutations and an association between the two may be considerably different between ATL cases and non-ATL T/NK-cell lymphomas.


Assuntos
Mutação com Ganho de Função , Leucemia-Linfoma de Células T do Adulto/genética , Linfoma de Células T/genética , Receptores CCR4/genética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Códon/genética , Expressão Gênica , Humanos , Linfoma de Células T/tratamento farmacológico , Terapia de Alvo Molecular , Receptores CCR4/imunologia , Receptores CCR4/metabolismo
7.
Eur J Med Chem ; 181: 111545, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400706

RESUMO

Abnormal activation of B-cell receptor (BCR) signaling plays a key role in the development of lymphoid malignancies, and could be reverted by the simultaneous inhibition of Lyn, Fyn and Blk, three members of the Src family kinase (SFK). Fyn and Blk are also promising targets for the treatment of some forms of T-cell non-Hodgkin lymphoma which point to the druggability of SFKs for the treatment of these cancers. We recently identified Si308 as a potent Fyn inhibitor, while preliminary data showed that it might also inhibit Lyn and Blk. Here, molecular modelling studies were coupled with enzymatic assays to further investigate the effect of Si308 on Lyn and Blk. A small library of pyrazolo[3,4-d]pyrimidines structurally related to Si308 was synthesized and tested on human lymphoma cell lines. Compound 2h emerged as a new multitarget inhibitor of Lyn, Fyn and Blk endowed with remarkable antiproliferative effects on human B and T lymphoma cell lines. Its favorable ADME properties make the compound suitable for further developments.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Células T/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Quinases da Família src/metabolismo
8.
Aust Vet J ; 97(9): 308-315, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31328256

RESUMO

Multi-agent chemotherapy (vincristine, epirubicin and prednisolone) including either cyclophosphamide (CEOP) or lomustine (LEOP) was given as first-line chemotherapy to treatment-naïve canine lymphoma patients with measurable, high grade T-cell lymphoma (HGTCL). All patients responded to either CEOP or LEOP. Toxicity was typical of multi-agent chemotherapy protocols and 25% of dogs receiving lomustine exhibited mild-to-moderate ALT elevation and 29% grade 3 or 4 neutropenia. Median progression-free survival (100 versus 269 days) and overall survival (155 versus 327 days) were significantly higher in patients receiving LEOP compared to CEOP. Overall survival was improved for patients receiving LEOP compared to those receiving CEOP followed by lomustine-based rescue therapy. The results of this retrospective study support further evaluation of lomustine as part of first-line, multi-agent therapy for patients with HGTCL.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/farmacologia , Doenças do Cão/tratamento farmacológico , Lomustina/farmacologia , Linfoma de Células T/veterinária , Animais , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Intervalo Livre de Doença , Cães , Epirubicina/uso terapêutico , Feminino , Linfoma de Células T/tratamento farmacológico , Masculino , Neutropenia/induzido quimicamente , Prednisolona/uso terapêutico , Estudos Retrospectivos , Reino Unido , Vincristina/uso terapêutico
10.
Oncol Rep ; 41(6): 3219-3232, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002364

RESUMO

The inactivation of tumor suppressor gene positive regulatory domain containing I (PRDM1) and activation of signal transducer and activator of transcription 3 (STAT3) have been detected in the majority of extranodal NK/T­cell lymphoma, nasal type (EN­NK/T­NT) cases. In the present study, their association with and effects on the clinicopathologic features of EN­NK/T­NT are described. PRDM1 was revealed to be expressed in 19 out of 58 patients (32.8%) with EN­NK/T­NT, and phosphorylated STAT3 was overexpressed in 42 out of 58 (72.4%). Oncogenic pathways were investigated by NanoString encounter technology in 5 PRDM1(+) and 5 PRDM1(­) EN­NK/T­NT specimens. Multiple oncogenic pathways involved in cell apoptosis, cellcycle (CC) and angiogenesis were discriminately activated in EN­NK/T­NT cases, and in PRDM1(+) cases in particular. The sustained activation of the Janus kinase 3 (JAK)/STAT3 pathway was more pronounced. In addition, missense mutations in the SRC homology 2 domain of STAT3 were detected in 7 out of 37 EN­NK/T­NT cases (18.92%), and the acquired mutation was related to the activation of the JAK3/STAT3 pathway. The downregulation of PRDM1 and upregulation of phospho­STAT3 (Tyr705) were associated with angiocentric infiltration of EN­NK/T­NT (P=0.039). Notably, the prognosis of patients in the PRDM1(+)/STAT3 [mutated (mut­)] group was considerably improved than that of patients in the STAT3(mut+)/PRDM(­) group (P=0.037). In addition, the inhibition of NK/T cell lymphoma cell lines by Stattic and tofacitinib could suppress cell proliferation by inducing cell apoptosis or arresting the CC. The present results revealed that the JAK3/STAT3 oncogenic pathway and PRDM1 expression could stratify clinicopathologic features of EN­NK/T­NT. The inhibition of the JAK3/STAT3 pathway may serve as a treatment option for EN­NK/T­NT.


Assuntos
Janus Quinase 3/genética , Linfoma de Células T/tratamento farmacológico , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator de Transcrição STAT3/genética , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia
11.
Acta Haematol ; 141(4): 216-221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943470

RESUMO

BACKGROUND: The treatment of relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) is limited to a few agents. Romidepsin, a histone deacetylase inhibitor, was approved for PTCL treatment as a single agent in the R/R setting, yet with partial efficacy. Several attempts to combine romidepsin with other chemotherapy regimens have been reported, however, with significant toxicity. OBJECTIVES: To study the romidepsin-bendamustine combination in PTCL in an attempt to maximize efficacy while minimizing toxicity. METHODS: We report on a series of 7 heavily pretreated PTCL patients (2-5 previous lines of therapy) treated with a romidepsin-bendamustine combination. RESULTS: Four patients were not previously exposed to either drug. Of these, 2 achieved complete remission. Interestingly, 1 patient continued treatment with a prolonged progression-free survival of more than 4 years. Toxicity was minimal and no treatment-related deaths or discontinuation were noted. Significant nausea and vomiting were reported in over 50% of patients. Hematological toxicity was mild and lower than that reported for other romidepsin-chemotherapy combinations and was correlated with bone marrow involvement by lymphoma. CONCLUSIONS: Although reporting a small number of patients, our data suggest that the combination of romidepsin and bendamustine may be a feasible therapeutic option in R/R PTCL patients and merits further study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma de Células T/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfoma de Células T/mortalidade , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida
13.
Int J Med Sci ; 16(3): 424-442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911277

RESUMO

T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Linfoma de Células T/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/fisiologia , Citocinas/metabolismo , Depsipeptídeos/administração & dosagem , Depsipeptídeos/farmacologia , Epigênese Genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Linfoma de Células T/enzimologia , Sulfonamidas/administração & dosagem , Vorinostat/farmacologia
14.
World Neurosurg ; 125: 339-342, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30797915

RESUMO

BACKGROUND: We describe a patient affected by a T-cell primary central nervous system lymphoma (PCNSL) with highly aberrant specific B-cell markers (CD79a and CD20). An unusual imaging presentation leads us to misdiagnose this lesion for a meningioma and perform surgical resection. CASE DESCRIPTION: We think that this infrequent anatomic presentation might be due to the aberrant specific B-cell markers (CD79a and CD20) genotype expression. We believe this case to be relevant in order to appreciate the diagnosis of cerebral lymphomas according to various presentations. We wonder whether it was not the aberrant genotype that contributed to this quirky presentation and ultimately if surgery in PCNSL should not be discussed? CONCLUSIONS: Furthermore, this case calls attention to the complexity of lineage assignment, imaging diagnosis, and treatment strategy in PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma de Células T/diagnóstico , Meningioma/diagnóstico , Idoso , Antígenos CD20/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Antígenos CD79/metabolismo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/cirurgia , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/cirurgia , Imagem por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
16.
Curr Top Med Chem ; 19(3): 223-241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30674261

RESUMO

The state of histone acetylation plays a very crucial role in carcinogenesis and its development by chromatin remodeling and thus altering transcription of oncogenes and tumor suppressor genes. Such epigenetic regulation was controlled by zinc-dependent histone deacetylases (HDACs), one of the major regulators. Due to the therapeutic potential of HDACs as one of the promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. Notably, there are five HDAC inhibitors already approved to the market. Vorinostat (SAHA), Belinostat (PXD-101) and Romidepsin (FK228) have been approved by Food and Drug Administration (FDA) in USA for treating cutaneous T-cell lymphoma (CTCL) or peripheral T cell lymphoma (PTCL) while Panbinostat (LBH-589) has also been approved by the FDA for the treatment of multiple myeloma. Recently, Chidamide was approved by China Food and Drug Administration (CFDA) for the treatment of PTCL. The structural feature of almost all HDAC inhibitors consists of Cap group, linker, and zinc-binding group (ZBG). The binding of ZBG groups to zinc ion plays a decisive role in the inhibition of HDAC. Therefore, we will summarize the developed HDAC inhibitors according to different ZBG groups and discuss their binding mode with zinc ion.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Zinco/química , Acilação , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , China , Aprovação de Drogas/legislação & jurisprudência , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Humanos , Linfoma de Células T/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration
17.
Cancer Treat Res ; 176: 195-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30596220

RESUMO

There are a number of rare T-cell lymphoma subtypes that may be encountered in clinical practice. In recent years, improved immunohistochemical techniques and molecular tumor profiling have permitted refinement of some of the diagnostic categories in this group, as well as the recognition of distinct conditions not previously well elucidated. In this chapter, we cover the diagnostic and clinical features of some of the more common of these conditions, including subcutaneous panniculitis-like T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, CD4-positive small/medium T-cell lymphoproliferative disorder, and acral CD8-positive T-cell lymphoma. Given the rarity of these conditions, optimal treatments approaches are not always well established, not least as data from large-scale clinical trials are lacking. In this chapter, we aim to provide a summation of current thinking around best treatment, as well as highlighting some controversies in the management of these diagnoses.


Assuntos
Linfoma Cutâneo de Células T , Linfoma de Células T , Paniculite , Neoplasias Cutâneas , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfócitos T
19.
Br J Ophthalmol ; 103(2): 269-273, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29706604

RESUMO

AIMS: To evaluate the clinical characteristics and treatment outcomes of natural killer/T-cell lymphoma (NKTL) involving the ocular adnexa. METHODS: Retrospective, comparative, observational case series. A total of 350 patients with NKTL, including 27 patients with NKTL involving the ocular adnexa from 1999 to 2016. The patients were grouped into two groups: group 1 comprised patients presenting with ophthalmic symptoms, and group 2 comprised patients presenting with symptoms from other organs but subsequently developed ophthalmic involvement. RESULTS: Group 1 comprised 12 patients (44.4%) and group 2 comprised 15 (55.6%). Mean duration of symptoms in group 1 was 1.8±1.2 months, while the time from diagnosis of NKTL to development of ophthalmic symptoms in group 2 was 45.3±65.6 months. Periorbital swelling was the most common presenting symptom in both groups (83.3% in group 1 and 73.3% in group 2). Symptoms mimicking cellulitis and pseudotumor were present in 50.0% and 16.7% of cases, respectively. The 5-year overall survival rate was 18.5% in group 1 and 26.4% in group 2, while the 5-year progression-free survival rate was 0% and 13.3%, respectively. CONCLUSIONS: Our series is to our knowledge the largest cohort study on NKTL reported to date and demonstrates that ocular adnexal NKTL is a rare but seriously fatal disease. It is characterised by acute inflammatory signs as present in as many as two-thirds of our patients in this series. It should be considered as a differential diagnosis in patients presenting with rapidly progressing proptosis and diagnosed promptly for optimal management.


Assuntos
Células Matadoras Naturais/patologia , Linfoma de Células T/patologia , Neoplasias do Seio Maxilar/patologia , Neoplasias Bucais/patologia , Neoplasias Nasais/patologia , Neoplasias Orbitárias/patologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Masculino , Neoplasias do Seio Maxilar/tratamento farmacológico , Neoplasias do Seio Maxilar/mortalidade , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/mortalidade , Neoplasias Nasais/tratamento farmacológico , Neoplasias Nasais/mortalidade , Neoplasias Orbitárias/tratamento farmacológico , Neoplasias Orbitárias/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
20.
Cancer Res Treat ; 51(1): 150-157, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29621877

RESUMO

PURPOSE: Determine the frequency and prognostic value of circulating Epstein-Barr virus (EBV) DNA copy number in angioimmunoblastic T-cell lymphoma (AITL) patients who were treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) regimens. Materials and Methods: Sixty newly-diagnosed AITL patients were retrospectively enrolled in the present study. All patients were treated with DA-EPOCH regimen. RESULTS: Twenty-two subjects (36.7%) had a EBV DNA-positive test at diagnosis. EBV DNA‒positive patients were associated with lower lymphocyte-monocyte ratio (p=0.024). Median follow-up was 40 months (range, 14 to 100 months). The overall response rate for all the 60 AITL patents were 71.7% (95% confidence interval [CI], 58.6 to 82.5) with 3-year progressive-free survival (PFS) rate of 30.9%±6.1% and overall survival (OS) rate of 60.1%±6.6%. Not only did PFS estimation differ between the EBV DNA‒positive and EBV DNA‒negative group (hazard ratio [HR], 2.24; 95% CI, 1.15 to 4.35; p=0.006), but also worse OS was observed in the pretreatment EBV DNA‒positive group than in the EBV DNA‒negative group (HR, 2.74; 95% CI, 1.22 to 6.19; p=0.006). EBV DNA test positivity was independent prognostic marker for both PFS (HR, 2.17; 95% CI, 1.17 to 4.00; p=0.014) and OS (HR, 3.24; 95% CI, 1.48 to 7.11; p=0.004) after adjusting International Prognostic Index and prognostic index for AITL score. Reduction in EBV copies was significantly associated with therapy-response. CONCLUSION: Circulating EBV DNA level was an important prognostic and monitoring marker for AITL patients who treated with DA-EPOCH regimens which cannot improve outcomes for AITL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Variações do Número de Cópias de DNA/efeitos dos fármacos , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4/genética , Linfoma de Células T/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , DNA Viral/efeitos dos fármacos , DNA Viral/genética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/virologia , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Feminino , Herpesvirus Humano 4/efeitos dos fármacos , Humanos , Contagem de Linfócitos , Linfoma de Células T/sangue , Linfoma de Células T/virologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/farmacologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/farmacologia
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