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3.
Ann Nucl Med ; 33(7): 449-458, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30929200

RESUMO

OBJECTIVE: Mantle cell lymphoma (MCL) is an aggressive lymphoma sub-type with poor prognosis and high 18F-FDG avidity at PET/CT; nowadays, no validated criteria for PET/CT in treatment response evaluation and prediction of outcome are present. The aim of study was to investigate whether the metabolic PET/CT features may predict treatment evaluation and prognosis in MCL. METHODS: We retrospectively enrolled 87 patients who underwent baseline 18F-FDG PET/CT and 85 end-of-treatment (eot) PET/CT. The baseline PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), lesion-to-liver SUVmax ratio (L-L SUV R), lesion-to-blood pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). EotPET/CT was visually interpreted according to the criteria of the Deauville 5-point scale (DC). Survival curves were plotted according to the Kaplan-Meier method. RESULTS: At a median follow-up of 40 months, relapse/progression occurred in 47 and death in 23 patients. Median PFS and OS were 30 and 41 months. Baseline MTV and TLG were significantly higher in patients with progressive metabolic response compared to complete/partial response group. EotPET/CT results using DC significantly correlated with PFS, not with OS. MTV and TLG were demonstrated to be independent prognostic factors for PFS; instead the other metabolic parameters were not related to outcome survival. Considering OS, no variable was significantly associated. CONCLUSIONS: EotPET/CT results (using DC), MTV and TLG were significantly correlated with response to treatment and PFS.


Assuntos
Fluordesoxiglucose F18 , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
4.
J Cutan Pathol ; 46(7): 538-541, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30957249

RESUMO

Secondary cutaneous involvement by mantle cell lymphoma (MCL), an uncommon aggressive B-cell malignancy, predominantly involves the dermis, with few reports of pannicular involvement. Lymphocytic infiltration of subcutaneous tissue is associated with inflammatory panniculitides and certain T-cell lymphomas, primarily subcutaneous panniculitis-like T-Cell lymphoma (SPTCL), which is characterized by rimming of adipocytes by tumor cells. We report the case of a 69-year-old man with a history of systemic nodal MCL who presented with subcutaneous nodules on his lower extremities after receiving multi-agent chemotherapy. Biopsies showed a dense infiltrate of atypical, mitotically active, monomorphic, medium-sized lymphoid cells in the subcutaneous fat with prominent rimming of the adipocytes by the tumor cells. These features were not morphologically typical of MCL. Immunohistochemistry showed these cells to be CD20+, CD5+ B-cells with strong cyclin D1 expression; fluorescence in situ hybridization (FISH) analysis was positive for t(11;14)(q13;32), confirming the diagnosis of secondary cutaneous involvement of MCL. This represents an exceptional report of cutaneous MCL presenting clinically and histologically with a panniculitis-type pattern and adipocyte rimming, histomorphologically mimicking SPTCL. Noteworthy examples, such as this report, support the practice of utilizing clinical correlation, immunohistochemistry, and/or molecular cytogenetics to confirm the diagnosis of any case suspicious for cutaneous lymphoma.


Assuntos
Linfoma de Célula do Manto , Linfoma de Células T , Paniculite , Neoplasias Cutâneas , Idoso , Antígenos CD20/genética , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Antígenos CD5/genética , Antígenos CD5/metabolismo , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/metabolismo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Diagnóstico Diferencial , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Paniculite/diagnóstico , Paniculite/genética , Paniculite/metabolismo , Paniculite/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Translocação Genética
5.
Acta Haematol ; 141(4): 209-213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943468

RESUMO

A 37-year-old male was admitted with an atypical presentation of central nervous system (CNS) aspergillosis while on ibrutinib therapy for a CNS relapse of mantle cell lymphoma. This case highlights the importance of a high clinical suspicion of opportunistic infections in patients receiving small-molecule kinase inhibitors. This report includes a review of reported cases of Aspergillus infections in patients receiving ibrutinib and the shared features of these cases.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Neuroaspergilose/induzido quimicamente , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adulto , Humanos , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/metabolismo , Masculino , Neuroaspergilose/diagnóstico por imagem , Neuroaspergilose/metabolismo , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Recidiva
6.
Hum Pathol ; 85: 251-259, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30458196

RESUMO

Cortactin is a cytoskeletal-remodeling adaptor protein, playing an oncogenic role in solid tumors. Little is known on cortactin expression in non-Hodgkin B-cell lymphomas (B-NHLs). The present study aimed to characterize cortactin expression in B-NHLs and to assess its role in the differential diagnosis of such entities. Cortactin protein expression was first assessed by immunohistochemistry in a series of 131 B-NHLs, including B-cell chronic lymphocytic leukemia (CLL; n = 17), mantle cell lymphoma (MCL; n = 16), follicular lymphoma (FL; n = 25), marginal zone lymphoma (MZL; n = 30), hairy cell leukemia (HCL; n = 10), splenic diffuse red pulp small B-cell lymphomas (SDRPBL; n = 3), and diffuse large B-cell lymphoma (DLBCL; n = 30) cases. Cortactin was expressed in 14 of 17 CLLs, 10 of 10 HCLs, and 22 of 30 DLBCLs. MCLs, SDRPBLs, most FLs, and MZLs were cortactin negative. The immunohistochemical results were in keeping with in silico gene expression data. In CLL, cortactin positivity did correlate with LEF1 and CD200 expression, and the combined positivity for ≥2 markers strongly predicted CLL diagnosis. Such preliminary data suggested a role for cortactin in the differential diagnosis between CLL and MCL. This hypothesis was confirmed in a large validation set of 112 CLLs (n = 55) and MCLs (n = 57), which also disclosed rare cortactin-expressing MCLs. The immunohistochemical and gene expression results were sustained by flow cytometry and Western blot analysis on CLL and MCL cell lines. In conclusion, cortactin is mainly expressed in subsets of CLL and DLBCL and in HCL. Cortactin may represent a novel marker for the differential diagnosis between CLL and MCL.


Assuntos
Cortactina/metabolismo , Leucemia Linfocítica Crônica de Células B/diagnóstico , Linfoma de Célula do Manto/diagnóstico , Linfoma não Hodgkin/diagnóstico , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Estudos Retrospectivos
7.
Br J Haematol ; 184(4): 616-624, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30095158

RESUMO

Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki-67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression-based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki-67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk-adapted prospective clinical trials in the future.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
8.
Leukemia ; 33(1): 148-158, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29955130

RESUMO

The predominant usage of VH4-34 and V3-21 and reports of stereotyped CDR3s suggest a shared antigenic target of B-cell receptors (BCR) from mantle cell lymphomas (MCL). To identify the target antigens of MCL-BCRs, BCRs from 21 patients and seven MCL cell lines were recombinantly expressed and used for antigen screening. The BCRs from 8/21 patients and 2/7 MCL cell lines reacted specifically with the autoantigen low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1). High-titered and light chain-restricted anti-LRPAP1 serum antibodies were found in MCL patients, but not in controls. LRPAP1 induced proliferation by BCR pathway activation, while an LRPAP1-ETA' toxin-conjugate specifically killed MCL cells with LRPAP1-specific BCRs. Our results suggest a role of LRPAP1 in lymphomagenesis and maintenance of a considerable proportion of MCL cases by chronic autoantigenic stimulation, likely evolving from a chronic autoreactive B-cell response. Importantly, LRPAP1 can be used for a novel therapeutic approach that targets MCL with LRPAP1-reactive BCRs with high specificity.


Assuntos
Autoantígenos/imunologia , Linfócitos B/imunologia , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/imunologia , Linfoma de Célula do Manto/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Autoantígenos/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Proliferação de Células , Humanos , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Receptores de Antígenos de Linfócitos B/metabolismo , Células Tumorais Cultivadas
9.
Br J Haematol ; 184(2): 223-231, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203425

RESUMO

Bendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m2 and bendamustine 90 mg/m2 every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3-4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Erupção por Droga , Interleucina-2 , Linfoma de Célula do Manto , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Erupção por Droga/genética , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Feminino , Seguimentos , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Rituximab/administração & dosagem , Rituximab/efeitos adversos
10.
Asian Pac J Cancer Prev ; 19(12): 3383-3392, 2018 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-30583344

RESUMO

Background: Multiparameter flow cytometry is a useful tool for diagnostic evaluation of mature B-cell neoplasms (MBN). Recently, it has been shown that assessment of CD200 expression may improve the distinction between chronic lymphocytic leukemia (CLL; CD200 positive) and mantle cell lymphoma (MCL; CD200 negative), but any potential as a prognostic marker for CLL remains to be established. Materials and methods: This cross sectional study was conducted on sixty-seven patients newly diagnosed as having mature B-cell lymphoproliferative disorders Levels of CD 200 in lymphoma cells were assessed. Results: CD200 was consistently expressed in CLL and hairy cell leukemia B cells, but not in MCL cells. Heterogeneous expression was noted in other CD5 positive Non-Hodgkin lymphomas. High CD200 expression (≥50%) was associated with a higher CD5, 19 and CD23 expression, older age, higher TLC and absolute lymphocyte count, hepatomegaly, splenomegaly and a higher Rai stage. There were no significant correlations between CD200 expression and response to treatment. Conclusion: CD200 could be of high value in distinguishing CLL, MCL, and atypical CLL. CD200 expression can also be of prognostic and therapeutic value in CLL cases.


Assuntos
Antígenos CD/metabolismo , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma de Células B/diagnóstico , Linfoma de Células B/metabolismo , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores Tumorais/metabolismo , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Imunofenotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Células B/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
BMC Cancer ; 18(1): 1129, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445933

RESUMO

BACKGROUND: Interactions between the protein synthesis inhibitor homoharringtonine (HHT) and the proteasome inhibitor bortezomib were investigated in DLBCL and mantle cell lymphoma cells (MCL). METHODS: Various DLBCL and MCL cells were exposed to HHT and bortezomib alone or together after which apoptosis and signaling pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. RESULTS: HHT and bortezomib co-administration synergistically induced apoptosis in GC-, ABC- and double-hit DLBCL cells. Similar interactions were observed in MCL cells and in primary lymphoma cells. HHT/bortezomib co-administration diminished binding of MCL-1 to both BAK and NOXA. Knock-down of NOXA significantly diminished lethality whereas MCL-1 knock-down or ectopic NOXA expression increased cell death. Notably, HHT/bortezomib lethality was dramatically reduced in BAK knockout or knockdown cells. Finally, HHT/bortezomib co-administration significantly improved survival compared to single agents in GC- and ABC- xenograft models while exhibiting little toxicity. CONCLUSIONS: These findings indicate that HHT and bortezomib cooperate to kill DLBCL and MCL cells through a process involving MCL-1 down-regulation, NOXA up-regulation, and BAK activation. They also suggest that a strategy combining HHT with bortezomib warrants attention in DLBCL and MCL.


Assuntos
Bortezomib/farmacologia , Mepesuccinato de Omacetaxina/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma de Célula do Manto/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Inibidores de Proteassoma/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Blood ; 132(26): 2722-2729, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30385481

RESUMO

Blastoid mantle cell lymphoma is characterized by highly aggressive features and a dismal clinical course. These blastoid and pleomorphic variants are defined by cytomorphological features, but the criteria are somewhat subjective. The diagnosis may be supported by a high cell proliferation based on the Ki-67 labeling index. Recent analyses have shown that the Ki-67 index overrules the prognostic information derived from the cytology subtypes. Nevertheless, genetic analysis suggests that blastoid and pleomorphic variants are distinct from classical mantle cell lymphoma. In clinical cohorts, the frequency of these subsets varies widely but probably represents ∼10% of all cases. Chemotherapy regimens commonly used in mantle cell lymphoma, such as bendamustine, rarely achieve prolonged remissions when given at the dosage developed for classical variants of the disease. Thus, high-dose cytarabine-containing regimens with high-dose consolidation may be generally recommended based on the more aggressive clinical course in these patients. However, even with these intensified regimens, the long-term outcome seems to be impaired. Thus, especially in this patient subset, allogeneic transplantation may be discussed at an early time point in disease management. Accordingly, targeted approaches are warranted in these patients, but clinical data are scarce. Ibrutinib treatment results in high rates of responses, but the median duration of remission is <6 months. Similarly, lenalidomide and temsirolimus result in only short-term remissions. Novel approaches, such as chimeric antigenic receptor T cells, may have the potential to finally improve the dismal long-term outcome of these patients.


Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células , Linfoma de Célula do Manto , Idoso , Feminino , Humanos , Antígeno Ki-67/metabolismo , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Pessoa de Meia-Idade , Prognóstico
13.
Rev Assoc Med Bras (1992) ; 64(6): 525-529, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30304310

RESUMO

OBJECTIVE: Ki-67 is a nuclear protein associated with cellular proliferation in normal or leukemic conditions that can help identify more aggressive diseases and is usually evaluated with immunohistochemistry. The aim of this was to assess Ki-67 expression on mature B-cell neoplasms samples with flow cytometry immunophenotyping. METHOD: After surface staining with CD19 and CD45, intracellular staining for Ki-67 was performed in leukemic mature B-cells. Ki-67 expression was evaluated with flow cytometry. RESULTS: Ki-67 expression was higher in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cases. It was also associated with CD38 mean fluorescence intensity. CONCLUSIONS: Ki-67 expression evaluated by flow cytometry can be a useful tool in the diagnosis of mature B-cell neoplasms. More studies are needed to validate Ki-67 assessment with flow cytometry immunophenotyping.


Assuntos
Linfócitos B/metabolismo , Antígeno Ki-67/metabolismo , Leucemia de Células B/metabolismo , Antígenos CD19 , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem/métodos , Linfoma de Célula do Manto/metabolismo
14.
Clin Lymphoma Myeloma Leuk ; 18(11): 731-736, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30075973

RESUMO

INTRODUCTION: Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma and requires both bone marrow biopsy and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to correctly stage the disease at diagnosis. However, accurate identification of bone marrow involvement by lymphoma on FDG PET/CT scans has not been previously demonstrated. We hypothesized that a voxel-based analysis of the iliac bones on the FDG PET/CT scan might provide insight into bone marrow involvement. PATIENTS AND METHODS: A retrospective cohort study of patients with a diagnosis of MCL who had undergone both single iliac bone marrow biopsy and FDG-PET/CT scan from 1 study site were included in the development phase (n = 10). An additional 12 patients from a second institution were included in the validation phase. Using a semiautomated workflow, a voxel-based data set of FDG uptake within the bilateral iliac bones was captured for each patient. In the development phase, empirical receiver operating characteristic curves for each data set were fit. We then identified the standardized uptake value (SUV) threshold cutpoints at which the sensitivity and specificity were optimized to 100%. In the validation phase, we evaluated the performance of these candidate SUV threshold cutpoints in 15 additional patients from a second institution. RESULTS: We found that 1 cutpoint, > 38% of voxels with activity < 0.95, outperformed all the other candidate cutpoints, correctly classifying all patients except for 1 (overall sensitivity, 100%; specificity, 87.5%). CONCLUSION: The ability to correctly identify bone marrow involvement using FDG PET/CT-based voxel analysis provides promise as a novel noninvasive method of accurate staging.


Assuntos
Medula Óssea/patologia , Fluordesoxiglucose F18/metabolismo , Linfoma de Célula do Manto/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Medula Óssea/diagnóstico por imagem , Medula Óssea/metabolismo , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos
15.
Blood Adv ; 2(16): 2039-2051, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30115641

RESUMO

The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico HSP90/metabolismo , Linfoma de Célula do Manto/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Benzodioxóis/farmacologia , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Purinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Clin Invest ; 128(9): 4132-4147, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29990311

RESUMO

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.


Assuntos
Ciclina D1/genética , Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Código das Histonas , Humanos , Modelos Biológicos , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética
17.
Expert Rev Hematol ; 11(9): 749-756, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30052472

RESUMO

INTRODUCTION: Despite recent prognostic improvements, mantle cell lymphoma (MCL) remains incurable. Bruton tyrosine kinase (BTK) is a key receptor in B-cell tumorigenesis, and the benefits of the first BTK inhibitor, ibrutinib, are becoming clear in MCL. However, off-target activities, which contribute to ibrutinib-related adverse events, suggest potential for further improvement of this drug class. Areas covered: The authors systematically interrogated ClinicalTrials.gov for trials containing keywords for BTK and MCL. Published literature for new and emerging BTK inhibitors being investigated in MCL was then identified (PubMed and Embase), summarized, and placed in the context of treatment guidelines. Expert commentary: Reduced off-target effects of new and emerging covalent, irreversible BTK inhibitors under investigation in patients with MCL offer the potential of improved safety compared with ibrutinib. Efficacy may also be favorable based on trial data for acalabrutinib, which has just been approved in the USA as second-line therapy for MCL. The role of BTK inhibitors in treating MCL will evolve substantially over the coming years as results from a number of trials become available, particularly in relation to potential upfront use and possible synergy with other targeted therapies such as B-cell lymphoma 2, phosphoinositide 3-kinase and checkpoint inhibitors.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Guias de Prática Clínica como Assunto , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
18.
Acta Biochim Biophys Sin (Shanghai) ; 50(8): 782-792, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29961897

RESUMO

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Hematol Oncol ; 11(1): 83, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907126

RESUMO

Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone). While initial treatment can facilitate recovery and complete remission in a few patients, many patients experience relapsed or refractory mantle cell lymphoma within 2 to 3 years after initial treatment. Targeted agents such as ibrutinib, an inhibitor of Bruton's tyrosine kinase, which has been approved only in the relapsed setting, can be used to treat patients with relapsed or refractory mantle cell lymphoma. However, mantle cell lymphoma cells often acquire resistance to such targeted agents and continue to survive by activating alternate signaling pathways such as the PI3K-Akt pathway or the NF-κB pathways.NF-κB is a transcription factor family that regulates the growth and survival of B cells; mantle cell lymphoma cells depend on NF-κB signaling for continued growth and proliferation. The NF-κB signaling pathways are categorized into canonical and non-canonical types, wherein the canonical pathway prompts inflammatory responses, immune regulation, and cell proliferation, while the non-canonical leads to B cell maturation and lymphoid organogenesis. Since these pathways upregulate survival genes and tumor-promoting cytokines, they can be activated to overcome the inhibitory effects of targeted agents, thereby having profound effects on tumorigenesis. The NF-κB pathways are also highly targetable in that they are interconnected with numerous other pathways, including B cell receptor signaling, PI3K/Akt/mTOR signaling, and toll-like receptor signaling pathways. Additionally, elements of the non-canonical NF- κB pathway, such as NF-κB-inducing kinase, can be targeted to overcome resistance to targeting of the canonical NF- κB pathway.Targeting the molecular mechanisms of the NF-κB pathways can facilitate the development of novel agents to treat malignancies and overcome drug resistance in patients with relapsed or refractory mantle cell lymphoma.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , NF-kappa B/metabolismo , Transdução de Sinais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Linfoma de Célula do Manto/metabolismo , Terapia de Alvo Molecular/métodos
20.
Int J Oncol ; 53(2): 823-834, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901111

RESUMO

Mantle cell lymphoma (MCL) is a distinct and highly aggressive subtype of B-cell non-Hodgkin lymphoma. Dihydrocelastrol (DHCE) is a dihydro-analog of celastrol, which is isolated from the traditional Chinese medicinal plant Tripterygium wilfordii. The present study aimed to investigate the effects of DHCE treatment on MCL cells, and to determine the mechanism underlying its potent antitumor activity in vitro and in vivo using the Cell Counting kit-8 assay, clonogenic assay, apoptosis assay, cell cycle analysis, immunofluorescence staining, western blotting and tumor xenograft models. The results demonstrated that DHCE treatment exerted minimal cytotoxic effects on normal cells, but markedly suppressed MCL cell proliferation by inducing G0/G1 phase cell cycle arrest, and inhibited MCL cell viability by stimulating apoptosis via extrinsic and intrinsic pathways. In addition, the results revealed that DHCE suppressed cell growth and proliferation by inhibiting mammalian target of rapamycin complex (mTORC)1-mediated phosphorylation of ribosomal protein S6 kinase and eukaryotic initiation factor 4E binding protein. Simultaneously, DHCE induced apoptosis and inhibited cell survival by suppressing mTORC2-mediated phosphorylation of protein kinase B and nuclear factor-κB activity. In addition to in vitro findings, DHCE treatment reduced the MCL tumor burden in a xenograft mouse model, without indications of toxicity. Furthermore, combined treatment with DHCE and bortezomib, a proteasome inhibitor, induced a synergistic cytotoxic effect on MCL cells. These findings indicated that DHCE may have the potential to serve as a novel therapeutic agent for the treatment of MCL through dually inhibiting mTORC1 and mTORC2.


Assuntos
Antineoplásicos/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Triterpenos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/metabolismo , Masculino , Camundongos , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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