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1.
Medicine (Baltimore) ; 98(41): e17567, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593142

RESUMO

RATIONALE: Pediatric-type follicular lymphoma (PTFL) is a rare neoplasm with features that differ from those of adult-type follicular lymphoma. Compared to patients with adult-type follicular lymphoma, PTFL patients often show an excellent response. Preoperative diagnosis is challenging and, therefore, an accurate diagnosis is based on the findings of postoperative pathological examination and immunohistochemistry. PATIENT CONCERNS: A 13-year-old boy presented with a slow-growing mass on the right side of his neck. DIAGNOSES: The patient was diagnosed with PTFL based on the findings of histopathological examination and immunohistochemistry. INTERVENTION: The mass was completely resected. OUTCOMES: After 12 months of postoperative follow-up, the patient achieved good recovery without recurrence. LESSONS: The optimal treatment for PTFL has not yet been defined. However, patients with PTFL always show satisfactory prognoses, regardless of treatment strategy (targeted radiotherapy, multiagent chemotherapy, or "watch and wait" strategy). Clinically, pathological and immunohistochemical analyses are necessary in the diagnoses of PTFL cases, especially for distinguishing PTFL from reactive follicular hyperplasia, to avoid unnecessary treatment.


Assuntos
Linfoma de Células B/patologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Pescoço/patologia , Adolescente , Assistência ao Convalescente , Humanos , Imuno-Histoquímica/métodos , Linfoma de Células B/diagnóstico , Linfoma de Células B/imunologia , Linfoma de Células B/cirurgia , Linfoma Folicular/diagnóstico , Linfoma Folicular/cirurgia , Masculino , Pescoço/diagnóstico por imagem , Pescoço/cirurgia , Resultado do Tratamento , Ultrassonografia
2.
Adv Clin Exp Med ; 28(10): 1359-1365, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31518494

RESUMO

BACKGROUND: High-grade B-cell lymphomas (HGBLs) comprise a new entity in the revised 2016/2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. The diagnosis of HGBL encompasses histopathology and immunohistochemistry, with additional molecular examination of the BCL2/MYC or BCL6/MYC rearrangement status. OBJECTIVES: The aim of the study was to summarize our experience in the histopathological and immunohistochemical diagnosis of patients with aggressive B-cell lymphomas according to the revised 2016/2017 WHO classifications. MATERIAL AND METHODS: We reviewed our single-institution experience with accurate diagnoses of HGBL and diffuse large B-cell lymphoma (DLBCL) using the available histopathological and immunohistochemical tools. The timeframe was from January 1, 2017 to April 18, 2018. RESULTS: Out of 265 patients, 217 (81.9%) were diagnosed with DLBCL, 43 (16.2%) with HGBL/DLBCL and 5 (1.9%) with not otherwise specified HGBL (HGBL-NOS). Regarding concurrent expression of MYC and BCL2 and/or BCL6 (double expressors (DE) and triple expressors (TE)), more DE and TE cases were found in the HGBL/DLBCL group than in the DLBCL group (25.53% vs 8.47%, p < 0.001, for DE cases and 55.32% vs 6.21%, p < 0.001, for TE cases). All 48 (100.00%) of the HGBL-NOS and HGBL/DLBCL patients, and 26 (11.98%) of the DLBCL-DE/TE cases were recommended for molecular analysis. CONCLUSIONS: Our findings show that a comprehensive histopathological and immunohistochemical examination may identify potential HGBL cases. This study emphasizes the need to introduce a suitable molecular examination for patients with HGBL morphology and/or double/triple expression of BCL2/BCL6/MYC proteins.


Assuntos
Linfoma de Células B/classificação , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/patologia , Humanos , Imuno-Histoquímica , Estudos Retrospectivos , Organização Mundial da Saúde
3.
Hautarzt ; 70(10): 815-830, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31511903

RESUMO

Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral T­cell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous B­cell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large B­cell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.


Assuntos
Linfoma de Células B/terapia , Linfoma não Hodgkin/terapia , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Linfoma , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Linfoma Cutâneo de Células T/mortalidade , Micose Fungoide/mortalidade , Síndrome de Sézary/mortalidade , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida
4.
Presse Med ; 48(7-8 Pt 1): 816-824, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31439443

RESUMO

Diagnosis of mature B cell malignancies is highly multidisciplinary. Biological tools provide diagnostic, prognostic and theranostic information. Biological hematology allows considering mature B cell diseases from two perspectives : cellular and molecular approaches. Cytomorphology and flow cytometry are tools from cell hematology. Conventional cytogenetics, FISH and molecular biology are tools from molecular hematology. NGS is a new technique that could dramatically change diagnostic and therapeutic management of B cell malignancies in the near future. Integration of clinical, pathological and biological data allows for personalized management of these diseases.


Assuntos
Técnicas de Laboratório Clínico/métodos , Leucemia de Células B/diagnóstico , Linfoma de Células B/diagnóstico , Integração de Sistemas , Hibridização Genômica Comparativa/métodos , Citodiagnóstico/métodos , Análise Citogenética/métodos , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunofenotipagem/métodos , Hibridização in Situ Fluorescente/métodos , Leucemia de Células B/genética , Leucemia de Células B/patologia , Linfoma de Células B/genética , Linfoma de Células B/patologia , Técnicas de Diagnóstico Molecular/métodos , Imagem Multimodal/métodos , Imagem Multimodal/tendências
5.
Hematol Oncol ; 37(4): 483-486, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408541

RESUMO

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.


Assuntos
Eritema Infeccioso/complicações , Doença de Hodgkin/etiologia , Linfoma de Células B/etiologia , Neoplasias Primárias Múltiplas/etiologia , Viremia/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Medula Óssea/patologia , Medula Óssea/virologia , Criança , Eritema Infeccioso/sangue , Eritema Infeccioso/patologia , Eritema Infeccioso/virologia , Doença de Hodgkin/patologia , Humanos , Linfoma de Células B/patologia , Masculino , Neoplasias Primárias Múltiplas/patologia , Pancitopenia/etiologia , Pseudolinfoma/etiologia , Indução de Remissão , Rituximab/administração & dosagem , Linfócitos T/patologia , Sequenciamento Completo do Exoma
6.
Ann Hematol ; 98(9): 2025-2033, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312929

RESUMO

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Mitoxantrona/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Terapia de Salvação/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vincristina/uso terapêutico
7.
Lancet Haematol ; 6(8): e429-e437, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296423

RESUMO

BACKGROUND: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. METHODS: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual. FINDINGS: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. INTERPRETATION: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. FUNDING: Lymphoma Academic Research Organisation, and Celgene and Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
8.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146399

RESUMO

Flow cytometry is helpful in differentiating between B-cell lymphoma (BCL) and reactive lymphocytic proliferation (RLP) in FNA biopsies. However; the presence of inconclusive surface immunoglobulin light chains (sIg LC) poses a problem. We investigated the usefulness of additional tests; namely Bcl-2 expression and expression of cytoplasmic Ig LC (cIg LC), mainly on samples with inconclusive sIg LC. Both tests were performed on 232 FNA samples from lymph nodes. Bcl-2 alone was determined qualitatively and quantitatively on 315 samples. The quantitative test was correctly positive in 76% of cases and falsely negative in 24%. The correctly positive results of the qualitative test were 11% points lower. cIg LC correctly identified 65% of BCL with dual positive sIg LC; 36% of BCL with difficult to interpret sIg LC and only 7% of BCL with negative sIg LC. The best results in differentiating between BCL and RLP were obtained when all three tests were used together. In samples with inconclusive sIg LC and additional monoclonal or polyclonal populations the κ:λ ratios did not differentiate between RLP and BCL. We propose that in case of inconclusive sIg LC Bcl-2 test is used first. The addition of cIg LC test is sensible only in cases with dual positive and difficult to interpret sIg LC.


Assuntos
Biomarcadores Tumorais/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biópsia por Agulha Fina , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Cadeias Leves de Imunoglobulina/genética , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/genética
9.
J Stroke Cerebrovasc Dis ; 28(9): e132-e134, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31239223

RESUMO

Intravascular lymphomatosis (IVL) is a rare subtype of large B-cell lymphoma that follows an aggressive course with rapidly progressive neurological involvement and potentially fatal outcome.1 We report on a 64-year-old man with progressive myelopathy at T6-T7 and recurrent cerebral infarctions. This case is illustrative of the clinical course that is seen in IVL. It aims to present a timeline of imaging findings that demonstrate the progression of disease and characteristic pathology findings. We emphasize the importance of IVL on the differential diagnosis of spinal cord infarction.


Assuntos
Isquemia Encefálica/etiologia , Infarto/etiologia , Linfoma de Células B/complicações , Medula Espinal/irrigação sanguínea , Acidente Vascular Cerebral/etiologia , Neoplasias Vasculares/complicações , Biópsia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Evolução Fatal , Humanos , Infarto/diagnóstico por imagem , Infarto/patologia , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/patologia
10.
Crit Rev Oncol Hematol ; 138: 156-171, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31092372

RESUMO

The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.


Assuntos
Hepatite C/complicações , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma de Células B/virologia , Linfócitos B/imunologia , Linfócitos B/virologia , Carcinogênese/genética , Carcinogênese/patologia , Hepacivirus , Humanos
11.
Int J Mol Sci ; 20(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109083

RESUMO

Chimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. In this study, we aimed to exploit increased ROS levels in the tumor microenvironment with prodrugs of ROS accelerators, which are specifically activated in cancer cells. Upon activation, ROS accelerators induce further generation of ROS. This leads to an accumulation of ROS in tumor cells. We hypothesized that the latter cells will be more susceptible to CARTs. CD19-specific CARTs were generated with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Cytotoxicity was determined by chromium-51 release assay. Influence of the ROS accelerators on viability and phenotype of CARTs was determined by flow cytometry. The combination of CARTs with the ROS accelerator PipFcB significantly increased their cytotoxicity in the Burkitt lymphoma cell lines Raji and Daudi, as well as primary chronic lymphocytic leukemia cells. Exposure of CARTs to PipFcB for 48 h did not influence T cell exhaustion, viability, or T cell subpopulations. In summary, the combination of CARTs with ROS accelerators may improve adoptive immunotherapy and help to overcome tumor microenvironment-mediated treatment resistance.


Assuntos
Leucemia de Células B/imunologia , Leucemia de Células B/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Degranulação Celular , Linhagem Celular Tumoral , Citocinas/biossíntese , Citotoxicidade Imunológica , Humanos , Leucemia de Células B/patologia , Leucemia de Células B/terapia , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Estresse Oxidativo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética
12.
Zhonghua Bing Li Xue Za Zhi ; 48(5): 364-368, 2019 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-31104675

RESUMO

Objective: To investigate the clinical presentation pathological diagnostic features and molecular genetics of paediatric-type follicular lymphoma (PTFL). Methods: Eight cases of PTFL at Fujian Cancer Hospital between January 2003 and May 2018 were analyzed by hematoxylin-eosin stain, immunohistochemistry, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH). The relevant literature review was performed. Results: All patients were male with age ranging from 12 to 27 years (median age of 18 years and average age of 19 years). Clinical manifestations included painless lymph adenopathy, primarily involving head and neck lymph nodes (6/8). According to Ann Arbor stage, there were 7 patients at stage Ⅰ A and 1 patient at stage Ⅱ A. Histologically, the structure of the lymph nodes was effaced with pushing borders visible at the tumor periphery. The lesions consisted of expanding, irregular follicles that were arranged in back to back fashion along with thinning or disappearing sleeves. The starry sky phenomenon in the follicle was prominent with loss of polarity. Under high power magnification, the follicles were composed of uniform, medium-sized blastic cells in 5 cases or centroblast in 3 cases. The neoplastic cells were positive for B cell markers and germinal center markers primarily confined to the germinal center. Bcl-2 was negative in 7 cases and 1 case showed weak bcl-2 staining. MUM1 was negative in all cases. Ki-67 demonstrated a high proliferation index of great than 70% in 7 of 8 cases. Eight cases showed Ig clonal rearrangement. No bcl-2, bcl-6, and IRF4/MUM1 gene rearrangements by FISH were detected in all cases. One patient was treated with 6 cycles of CHOP after surgical resection. Other patients underwent only simple surgical resection. All patients were alive upon clinical follow-up. Conclusion: PTFL is a rare subtype of B cell lymphoma with unique clinical and pathological features. It should be distinguished from reactive follicular hyperplasia, nodal marginal lymphoma in children, large B-cell lymphoma with IRF4 rearrangement and usual follicular lymphoma.


Assuntos
Linfoma de Células B , Linfoma Folicular , Adolescente , Adulto , Criança , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-6 , Adulto Jovem
13.
Nat Med ; 25(5): 814-824, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962585

RESUMO

Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8+ T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial ( NCT01976585 ). Non-responding patients developed a population of PD1+CD8+ T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.


Assuntos
Linfoma de Células B/terapia , Adulto , Idoso , Animais , Apresentação do Antígeno , Linfócitos T CD8-Positivos/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Carboximetilcelulose Sódica/uso terapêutico , Linhagem Celular Tumoral , Terapia Combinada , Células Dendríticas/imunologia , Feminino , Humanos , Imunoterapia Adotiva , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Poli I-C/uso terapêutico , Polilisina/análogos & derivados , Polilisina/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor 3 Toll-Like/agonistas , Vacinação
14.
J Cancer Res Ther ; 15(2): 350-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964110

RESUMO

Background: We assessed the frequency of epigenetic lesions, including lymphoid-specific helicase (LSH), 5-hydroxymethylcytosine (5-hmC) and E2F1, and the possible correlations among molecular findings, phenotype, clinical features, and outcome. Methods: We investigated 181 paraffin-embedded B-cell lymphoma samples using immunohistochemistry and in situ hybridization. Results: The levels of Ki67, LSH, 5-hmC, and E2F1 were all increased in germinal center B-cell lymphomas when compared with those in normal lymph nodes, and LSH was highly expressed in diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) that were positive for Epstein-Barr virus (EBV) infection, indicating that LSH is linked to EBV infection in DLBCL and BL. Interestingly, LSH was mainly localized in the germinal centers of lymph nodes whereas 5-hmC staining localized to areas surrounding the germinal centers. Conclusions: These findings indicate a critical role for LSH as a biomarker and therapeutic target in follicular germinal center B-cell lymphoma.


Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Centro Germinativo/patologia , Herpesvirus Humano 4 , Linfoma de Células B/etiologia , Linfoma de Células B/patologia , Biomarcadores , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica
15.
Pediatr Hematol Oncol ; 36(2): 113-121, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31002269

RESUMO

OBJECTIVES: To assess the impact of second-look biopsy of residual mass during or after chemotherapy in pediatric mature B-cell NHL. METHODS: Patients with mature B-cell non-Hodgkin lymphoma (NHL) who were suspicious of radiological residual mass at mid or end of treatment and subjected to second biopsy were treated at our center between January 2001 and December 2015. Their clinical characteristics, imaging findings, pathological changes, management, and prognosis were reviewed retrospectively. RESULTS: A total of 31 children were included (13 boys and 18 girls, median age at diagnosis 6.1 years). The median time from diagnosis to second biopsy was 3.15 months (range 2.3-18 months). Biopsy confirmed the presence of viable tumor in eight patients. The specificity and positive predictive value of conventional imaging in detecting residual detectable by biopsy were at 9 and 28.6%, while sensitivity and negative predictive value of this approach were both 100%. Three of the histologic positive patients experienced progressive disease or relapse while the others achieved complete remission (CR) and 21 patients achieved long-time CR at median follow-up of 3.2 years. The median progression-free survival (PFS) time of all 31 was 28 months and 5-year PFS rate was 90.0%. Five-year PFS rate of negative-biopsy and positive-biopsy group were 100 and 62.5%, respectively (p = 0.002). CONCLUSION: Conventional imaging has very high sensitivity but very low specificity for the accurate determination of residual disease in pediatric NHL. Second-look biopsy is necessary to differentiate viable tumor from necrosis or fibrosis and is solid evidence-based foundation of subsequent treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Linfoma de Células B/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Neoplasia Residual , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Indução de Remissão , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
16.
Int J Hematol ; 109(5): 593-602, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830578

RESUMO

Chromosomal microdeletions frequently cause loss of prognostically relevant tumor suppressor genes in hematologic malignancies; however, detection of minute deletions by conventional methods for chromosomal analysis, such as G-banding and fluorescence in situ hybridization (FISH), is difficult due to their low resolution. Here, we describe a new diagnostic modality that enables detection of chromosomal microdeletions, using CDKN2A gene deletion in B cell lymphomas (BCLs) as an example. In this method, which we refer to as amplified-FISH (AM-FISH), a 31-kb fluorescein isothiocyanate (FITC)-conjugated DNA probe encoding only CDKN2A was first hybridized with the chromosome, and then labeled with Alexa Fluor 488-conjugated anti-FITC secondary antibody to increase sensitivity. CDKN2A signals were equally identifiable by AM-FISH and conventional FISH in normal mononuclear blood cells. In contrast, when two BCL cell lines lacking CDKN2A were analyzed, CDKN2A signals were not detected by AM-FISH, whereas conventional FISH yielded false signals. Furthermore, AM-FISH detected CDKN2A deletions in two BCL patients with 9p21 microdeletions, which were not detected by conventional FISH. These results suggest that AM-FISH is a highly sensitive, specific, and simple method for diagnosis of chromosomal microdeletions.


Assuntos
Deleção Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Hibridização in Situ Fluorescente/métodos , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Linfoma de Células B/patologia
17.
Eur J Med Chem ; 170: 112-125, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878826

RESUMO

A series of 24 benzothiadiazine derivatives with structural novelty were designed, synthesized and biologically evaluated as PI3Kδ-selective inhibitors. As a consequence of the structure-activity relationship (SAR) study, compounds 63 and 71 were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. In subsequent biological evaluation, S-63 (IC50: 4.6 nM) and S-71 (IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, respectively, to that of idelalisib. Additionally, both S-63 (GI50: 33.2 nM) and S-71 (GI50: 15.9 nM) exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib. Moreover, both S-63 and S-71 exhibited excellent PI3Kδ selectivity. In the further in vivo pharmacokinetic (PK) study, S-63 displayed a good plasma exposure and an acceptable oral bioavailability of 29.2%. By virtue of its biological performance, S-63 merits further development as a potential therapeutic agent for battling B-cell-mediated malignancies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/patologia , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenho de Drogas , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
18.
Nat Commun ; 10(1): 1415, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926791

RESUMO

B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.


Assuntos
Elementos de DNA Transponíveis/genética , Testes Genéticos/métodos , Linfoma de Células B/genética , Animais , Sistemas CRISPR-Cas/genética , Células Clonais , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Genes Supressores de Tumor , Estudos de Associação Genética , Humanos , Perda de Heterozigosidade , Linfoma de Células B/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos B/metabolismo , Reprodutibilidade dos Testes
19.
Intern Med ; 58(14): 2073-2077, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918199

RESUMO

Primary chest wall lymphoma is rare and typically associated with chronic pleural inflammation. Double-hit lymphoma (DHL), which is defined as aggressive mature B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, is a highly aggressive malignancy that tends to have extranodal involvement and is resistant to standard immunochemotherapy. We herein report a 55-year-old man with no history of chronic pleural inflammation, diagnosed with primary chest wall DHL with MYC/BCL6 rearrangement, and harboring a unique BCL6 translocation, t (3;7) (q27;p12). After six courses of intensive chemotherapy, he has achieved complete remission. To our knowledge, this is the first case report of primary chest wall DHL.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Parede Torácica/patologia , Translocação Genética , Humanos , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Ann Biol Clin (Paris) ; 77(2): 191-195, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30907360

RESUMO

We report the case of an 83-year-old woman admitted to the accident and emergency unit for pneumopathy. The blood cell count on the DXH automaton (Coulter® ™ UniCel® DxH) found a normochromic and normocytic anemia, anormal platelet count and subnormal leukocyte formula. The only alarm raised by the automaton was the presence of a basocytosis. A control of the leucocyte count by flow cytometry and blood smear has been done. It revealed there was no basocytosis, but showed the presence of an atypical monomorphic lymphocytes B population (T/B < 1 ratio in flow cytometry), around which platelets aggregated. The lymphocytic immunophenotyping allowed us to highlight the presence of a CD5+ B clonal subpopulation.


Assuntos
Plaquetas/patologia , Linfócitos/patologia , Linfoma de Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , Diagnóstico Diferencial , Feminino , Humanos , Imunofenotipagem , Linfoma de Células B/sangue , Linfoma de Células B/patologia , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/patologia
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