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1.
Medicine (Baltimore) ; 99(33): e21736, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872060

RESUMO

RATIONALE: Pilot studies have reported that patients with systemic lupus erythematosus (SLE) appear more likely to develop into neoplasia, especially lymphatic hyperplasia diseases. To our knowledge, this is the first case report of the concomitant onset of SLE and primary breast diffuse large B-cell lymphoma (PB-DLBCL). PATIENT CONCERNS: We reported an unusual case of the occurrence of primary breast diffuse large B-cell lymphoma in a 25-year-old female patient who had been diagnosed with SLE and treated with immunosuppressive drugs for about 4 years. She presented a 7-week history of a painless mass above the left breast and no history suggestive of any nipple discharge, fever, and weight loss. DIAGNOSIS: Ultrasonography of the breast showed that there was 1 mass in the left breast. After breast mass surgical resection, histopathological examinations were performed and revealed that it was primary breast diffuse large B-cell lymphoma. INTERVENTIONS: Treatment strategy with vincristine and dexamethasone was used to improve symptoms. However, the patient's renal function deteriorated and the blood potassium rose continuously and she and their family members refused the follow-up treatments. OUTCOMES: The patient died 8 months after she was discharged from the hospital. LESSONS: PB-DLBCL is a rare occurrence in SLE patients. Therefore, a careful examination is very important in SLE cohort, as activity of the disease and malignancy may mimic each other. Meanwhile, when symptoms cannot be explained or insensitive to treatment, the occurrence of malignant tumors must be highly considered.


Assuntos
Neoplasias da Mama/complicações , Mama/patologia , Falência Renal Crônica/etiologia , Lúpus Eritematoso Sistêmico/complicações , Linfoma Difuso de Grandes Células B/complicações , Adulto , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Evolução Fatal , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Radiografia , Ultrassonografia
2.
Medicine (Baltimore) ; 99(35): e21704, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871888

RESUMO

To explore the relationship between C3435T polymorphism of multi-drug resistance gene (MDR1) gene and susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of diffuse large B-cell lymphoma (DLBCL) in XinJiang.The peripheral venous blood samples of 54 patients with DLBCL and 60 healthy controls were collected. The alleles and genotypes of MDR1 gene C3435T were detected by DNA direct extraction with PCR technique, and the frequency of C3435T allele and genotypes were detected by the chi-square test. The relationship between the allele and genotype distribution of C3435T locus and the susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of DLBCL were analyzed.1 the frequency of CT heterozygote and CC homozygote mutation was significantly higher in the case group (46.3% in CT genotype and 42.6% in CC genotype) compared to the control group (P < 0.05). The frequency of CC genotype mutation in the case group was 42.6%, which was significantly higher than that in the control group (P < 0.05, OR 3.209, 95% CI: 1.288-7.997). 2 the genotypes of C3435T locus of MDR1 gene were distributed in age, sex, nationality, pathological characteristics, clinical-stage, IPI index, B symptoms, infection with EB virus, clinicopathological characteristics and clinical efficacy of hepatitis B in patients with DLBCL. There was no significant difference in myelosuppression (P > 0.05).The homozygous mutation genotype of CC is the risk genotype of DLBCL. The alleles and genotypes are not associated with the clinicopathological characteristics, efficacy and myelosuppression toxicity of DLBCL.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , China , Feminino , Heterozigoto , Homozigoto , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
3.
Anticancer Res ; 40(10): 5423-5426, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988863

RESUMO

BACKGROUND/AIM: Exposure to pesticides has been reportedly associated with several types of cancer. MATERIALS AND METHODS: In this study, we used data from The United States Geological Survey (USGS), United States Census, and the Surveillance, Epidemiology, and End Results (SEER) database to analyze the association between the area density of specific agricultural pesticides and the county level annual incidence of diffuse large B-cell lymphoma (DLBCL). RESULTS: Incidence of DLBCL was significantly associated with an area density of 14 of the pesticides reported by USGS. CONCLUSION: This highlights the need for further investigation into the safety of the use of these pesticides. The importance of this study comes not only from the significant association it shows between pesticides and the incidence of cancer, but also from the fact that it included all compounds reported to USGS as being used in agriculture. This helps in prioritizing pesticides for further evaluation.


Assuntos
Exposição Ambiental/efeitos adversos , Linfoma de Células B/epidemiologia , Linfoma Difuso de Grandes Células B/epidemiologia , Praguicidas/efeitos adversos , Humanos , Linfoma de Células B/induzido quimicamente , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/induzido quimicamente , Linfoma Difuso de Grandes Células B/patologia , Estados Unidos/epidemiologia
4.
Lancet ; 396(10254): 839-852, 2020 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-32888407

RESUMO

BACKGROUND: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. METHODS: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. FINDINGS: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. INTERPRETATION: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.


Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Idoso , Idoso de 80 Anos ou mais , Anemia/epidemiologia , Antígenos CD19/administração & dosagem , Antígenos CD19/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Síndrome da Liberação de Citocina/epidemiologia , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese/métodos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Doenças do Sistema Nervoso/epidemiologia , Neutropenia/epidemiologia , Recidiva , Segurança , Análise de Sobrevida , Trombocitopenia/epidemiologia , Resultado do Tratamento
5.
Cardiovasc Pathol ; 49: 107264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32805552

RESUMO

We report a 60-year-old male with fibrin-associated diffuse large B-cell lymphoma (fa-DLBCL) in left atrial myxoma. Echocardiography showed a mass (63 mm × 33 mm) in the left atrium. Histological inspection indicated fa-DLBCL on the surface of atrial myxoma incidentally, together with extensive fibrinous like exudation on myxoma surface. Malignant cells were localized in solid sheets and nests at the peripheral area of the fibrinous exudation which were positive for B-lineage markers (CD20+, CD79a+, PAX-5+) and in situ hybridization of EBV-encoded RNA (EBER). PCR amplification showed clonal rearrangement of immunoglobulin heavy chain (IgH) genes. The patient was still alive with no recurrence in the 35-month follow-up after surgery. We also did a detailed clinicopathological analysis and literature review, which indicated that fa-DLBCL was a heterogeneous entity.


Assuntos
Biomarcadores Tumorais/análise , Fibrina/análise , Neoplasias Cardíacas/patologia , Linfoma Difuso de Grandes Células B/patologia , Mixoma/patologia , Biomarcadores Tumorais/genética , Genes de Cadeia Pesada de Imunoglobulina , Neoplasias Cardíacas/química , Neoplasias Cardíacas/cirurgia , Herpesvirus Humano 4/genética , Humanos , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/cirurgia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Mixoma/química , Mixoma/cirurgia , RNA Viral/genética , Resultado do Tratamento
6.
Lancet Haematol ; 7(9): e649-e659, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32758434

RESUMO

BACKGROUND: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma. METHODS: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing. FINDINGS: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation. INTERPRETATION: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting. FUNDING: Celgene Corporation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Piperidonas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/patologia , Piperidonas/efeitos adversos , Piperidonas/farmacocinética , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Recidiva , Índice de Gravidade de Doença , Trombocitopenia/etiologia , Trombocitopenia/patologia , Resultado do Tratamento
7.
Nat Commun ; 11(1): 3651, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686676

RESUMO

Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles - such as cellular senescence - remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomas - with and without defined genetic lesions - recapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)-methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss- and gain-of-function genetics, and an unbiased clinical trial-like approach. A mouse-derived senescence-indicating gene signature, termed "SUVARness", as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic.


Assuntos
Senescência Celular , Histona Metiltransferases , Linfoma Difuso de Grandes Células B , Células 3T3 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Transgênicos , Prognóstico
8.
Brain Tumor Pathol ; 37(4): 127-135, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32627089

RESUMO

In recent years, the features of lymphomas associated with chronic inflammation, referred to as diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation (DLBCL-CI), have been elucidated. DLBCL-CI is an aggressive lymphoma occurring in the context of long-standing chronic inflammation and showing an association with Epstein-Barr virus. Fibrin-associated diffuse large B-cell lymphoma (F-DLBCL) was suggested as a new and unusual form of DLBCL-CI in the most recent version of the World Health Organization classification. From the perspective of genetics, DLBCL-CI was associated with frequent TP53 mutation, MYC amplification and complex karyotypes, but cases of F-DLBCL behaved indolently and showed a relatively lower genetic complexity. In the central nervous system (CNS), several examples of DLBCL-CI and F-DLBCL have been reported. As with DLBCL-CI outside the CNS, DLBCL-CI in the CNS is an aggressive lymphoma. However, the clinical outcome of F-DLBCL in the CNS is good. Immunohistochemistry for p53 and c-Myc in DLBCL-CI and F-DLBCL in the CNS showed similar findings of those outside the CNS. However, one aggressive case showed transitional genetics and morphology between F-DLBCL and DLBCL-CI. These findings suggest that some cases of F-DLBCL in the CNS might have the potential to progress to DLBCL-CI.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Progressão da Doença , Fibrina , Humanos , Inflamação , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Mutação , Proteínas Proto-Oncogênicas c-myc/genética , Proteína Supressora de Tumor p53/genética
9.
PLoS One ; 15(7): e0235786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639975

RESUMO

In front-line treatment of diffuse large B-cell lymphoma (DLBCL), prior studies suggest that concordant but not discordant involvement of the bone marrow (BM) portends a poor prognosis. The prognostic impact of bone marrow infiltration (BMI) in recurrent or refractory DLBCL (r/rDLBCL) and transformed indolent lymphoma (r/rTRIL) patients is less clear. Thus, we examined the prognostic significance of the infiltration of bone marrow (BMI) by concordant, large B-cells (conBMI) and discordant, small B-cells (disBMI) in this patient group. We performed a single center retrospective analysis of the prognostic impact of BMI diagnosed before start of second-line treatment as well as multiple clinicopathologic variables in 82 patients with r/rDLBCL or r/rTRIL intended to treat with autologous SCT. Twenty-five of 82 patients (30.5%) had BMI. Out of these, 19 (76%) had conBMI and 6 (24%) had disBMI. In patients with conBMI but not disBMI, uni- and multivariate analysis revealed inferior progression free survival (PFS) and overall survival (OS) compared to patients without BMI (median PFS, 9.2 vs 17.45 months, log rank: p = 0.049; Hazard Ratio, 2.34 (Confidence Interval, 1.24-4.44), p = 0.009; median OS 14.72 vs 28.91 months, log rank: p = 0.017; Hazard Ratio, 2.76 (Confidence Interval, 1.43-5.31), p = 0.002). ConBMI was strongly associated with nonGCB subtype as classified by the Hans algorithm (82.4% vs 17.6%, p = 0.01). ConBMI comprised an independent predictor of poor prognosis in primary and secondary r/rDLBCL. Incorporating conBMI in the pretherapeutic risk assessment for r/rDLBCL and r/rTRIL patients may be useful for prognostication, for stratification in clinical trials, and to assess new therapies for this high-risk patient subset that might not benefit from SCT in second-line treatment.


Assuntos
Medula Óssea/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Linfócitos B/patologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
10.
Medicine (Baltimore) ; 99(28): e20938, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664092

RESUMO

RATIONALE: Primary adrenal lymphoma (PAL) is an extremely rare and highly invasive malignant disease. Imaging examination usually shows bilateral adrenal involvement with large tumor masses and local infiltration. However, it is unclear how lymphoma dynamically develops into huge tumor masses in the adrenal glands. The overall survival rate of PAL is generally poor, and the underlying mechanism might be related to prooncogenic mutation but not fully elucidated. PATIENT CONCERNS: A 52-year-old woman complaining of a large mass in the left adrenal region for 1 month was admitted to our department. DIAGNOSIS: Computed tomography firstly showed a huge mass (8.9 × 7.5 cm) in the left adrenal gland and diffusely enlarged right adrenal gland. A month later, the mass in the left adrenal gland further enlarged (9.5x7.5 cm) with infiltration of the left renal artery and retroperitoneal lymphadenopathy, and the right adrenal gland rapidly progressed into a huge mass (8.0x4.7 cm). Additionally, her chest computed tomography revealed mediastinal and bilateral hilar lymphadenopathy. Then an adrenal biopsy confirmed the diagnosis of diffuse large B-cell lymphoma, nongerminal center B-cell type, stage IV by Ann Arbor staging system. Immunohistochemistry showed positivity for Ki-67 (approximately 90%), BCL2 (approximately 80%) and MYC (approximately 70%) double-expressor lymphoma. INTERVENTIONS: The patient's condition progressed rapidly, there was no opportunity to use pathology-based chemotherapy. Dexamethasone was given intravenously by thoracic and intraperitoneal injection; antibiotics and supporting treatment were also given. OUTCOMES: The patient's condition progressed rapidly, with the development of malignant chest and abdominal cavity fluid and lung infection, and eventually developed septic shock and respiratory failure. She responded poorly to treatment regimens, and eventually died 8 days after the diagnosis of PAL. LESSONS: PAL grows progressively throughout the adrenal glands, high Ki-67 positivity and BCL2/ MYC co-expression predict rapid progress and poor prognosis.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Linfoma Difuso de Grandes Células B/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica
11.
Lancet Oncol ; 21(7): 978-988, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32511983

RESUMO

BACKGROUND: Patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for autologous stem-cell transplantation have poor outcomes and few treatment options. Tafasitamab (MOR208) is an Fc-enhanced, humanised, anti-CD19 monoclonal antibody that has shown preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies. Preclinical data suggested that tafasitamab might act synergistically with lenalidomide. We aimed to assess the antitumour activity and safety of tafasitamab plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for autologous stem-cell transplantation. METHODS: In this multicentre, open-label, single-arm, phase 2 study (L-MIND), patients older than 18 years with histologically confirmed diffuse large B-cell lymphoma, who relapsed or had refractory disease after previous treatment with one to three systemic regimens (with at least one anti-CD20 therapy), were not candidates for high-dose chemotherapy and subsequent autologous stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, and had measurable disease at baseline were recruited from 35 academic and community hospitals in ten countries. Patients received coadministered intravenous tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy (in patients with stable disease or better) until disease progression. The primary endpoint was the proportion of patients with an objective response (centrally assessed), defined as a complete or partial response according to the 2007 International Working Group response criteria for malignant lymphoma. Antitumour activity analyses are based on all patients who received at least one dose of both tafasitamab and lenalidomide; safety analyses are based on all patients who received at least one dose of either study medication. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, NCT02399085. FINDINGS: Between Jan 18, 2016, and Nov 15, 2017, 156 patients were screened: 81 were enrolled and received at least one dose of either study medication, and 80 received at least one dose of both tafasitamab and lenalidomide. Median follow-up was 13·2 months (IQR 7·3-20·4) as of data cutoff on Nov 30, 2018. 48 (60%; 95% CI 48-71) of 80 patients who received tafasitamab plus lenalidomide had an objective response: 34 (43%; 32-54) had a complete response and 14 (18%; 10-28) had a partial response. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (39 [48%] of 81 patients), thrombocytopenia (14 [17%]), and febrile neutropenia (ten [12%]). Serious adverse events occurred in 41 (51%) of 81 patients. The most frequently reported serious adverse events (in two or more patients) were pneumonia (five [6%]), febrile neutropenia (five [6%]), pulmonary embolism (three [4%]), bronchitis (two [2%]), atrial fibrillation (two [2%]), and congestive cardiac failure (two [2%]). INTERPRETATION: Tafasitamab in combination with lenalidomide was well tolerated and resulted in a high proportion of patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation having a complete response, and might represent a new therapeutic option in this setting. FUNDING: MorphoSys.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
12.
PLoS Pathog ; 16(6): e1008590, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542010

RESUMO

EBV transforms B cells in vitro and causes human B-cell lymphomas including classical Hodgkin lymphoma (CHL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). The EBV latency protein, EBNA2, transcriptionally activates the promoters of all latent viral protein-coding genes expressed in type III EBV latency and is essential for EBV's ability to transform B cells in vitro. However, EBNA2 is not expressed in EBV-infected CHLs and BLs in humans. EBV-positive CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV-positive BLs, which usually have type I latency are largely driven by c-Myc translocations, and only express the EBNA1 protein and viral non-coding RNAs. Approximately 15% of human BLs contain naturally occurring EBNA2-deleted viruses that support a form of viral latency known as Wp-restricted (expressing the EBNA-LP, EBNA3A/3B/3C, EBNA1 and BHRF1 proteins), but whether Wp-restricted latency and/or EBNA2-deleted EBV can induce lymphomas in humanized mice, or in the absence of c-Myc translocations, is unknown. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL induces EBV-positive B-cell lymphomas in a subset of infected cord blood-humanized (CBH) mice. Furthermore, we find that P3HR1-infected lymphoma cells support two different viral latency types and phenotypes that are mutually exclusive: 1) Large (often multinucleated), CD30-positive, CD45-negative cells reminiscent of the Reed-Sternberg (RS) cells in CHL that express high levels of LMP1 but not EBNA-LP (consistent with type II viral latency); and 2) smaller monomorphic CD30-negative DLBCL-like cells that express EBNA-LP and EBNA3A but not LMP1 (consistent with Wp-restricted latency). These results reveal that EBNA2 is not absolutely required for EBV to form tumors in CBH mice and suggest that P3HR1 virus can be used to model EBV positive lymphomas with both Wp-restricted and type II latency in vivo.


Assuntos
Infecções por Vírus Epstein-Barr , Antígenos Nucleares do Vírus Epstein-Barr/genética , Deleção de Genes , Herpesvirus Humano 4/fisiologia , Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Proteínas Virais/genética , Latência Viral , Animais , Linhagem Celular , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Camundongos , Proteínas Virais/metabolismo
13.
Ann Hematol ; 99(7): 1583-1594, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32506244

RESUMO

Relapsing diffuse large B cell lymphomas (rDLBCL) represent a heterogeneous disease. This heterogeneity should be recognized and reflected, because it can deform the interpretation of clinical trial results. DLBCL patients with the first relapse and without CNS involvement were identified in the Czech Lymphoma Study Group (CLSG) database. Interval-to-therapy (ITT) was defined as the time between the first manifestation of rDLBCL and the start of any treatment. The overall survival (OS) of different ITT cohorts (< 7 vs. 7-21 vs. > 21 days) was compared. In total, 587 rDLBCLs (51.8% males) progressed with a median of 12.8 months (range 1.6 to 152.3) since the initial diagnosis (2000-2017). At the time of relapse, the median age was 67 years (range 22-95). First-line therapy was administered in 99.3% of the patients; CHOP and anti-CD20 were given to 69.2% and 84.7% of the patients, respectively. The salvage immune/chemotherapy was administered in 88.1% of the patients (39.2% platinum-based regimen). The median ITT was 20 days (range 1-851), but 23.2% of patients initiated therapy within 7 days. The 5-year OS was 17.4% (range 10-24.5%) vs. 20.5% (range 13.5-27.4%) vs. 42.2% (range 35.5-48.8%) for ITT < 7 vs. 7-21 vs. > 21 days (p < 0.001). ITT was associated with B symptoms (p 0.004), ECOG (p < 0.001), stage (p 0.002), bulky disease (p 0.005), elevated LDH (p < 0.001), and IPI (p < 0.001). The ITT mirrors the real clinical behavior of rDLBCL. There are patients (ITT < 7 days) with aggressive disease and a poor outcome. Conversely, there are rDLBCLs with ITT ≥ 21 days who survive for a long time.


Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Ciclofosfamida/uso terapêutico , República Tcheca/epidemiologia , Bases de Dados Factuais , Progressão da Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/estatística & dados numéricos , Prednisona/uso terapêutico , Prognóstico , Recidiva , Estudos Retrospectivos , Rituximab/administração & dosagem , Tempo para o Tratamento/estatística & dados numéricos , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto Jovem
15.
Hematol Oncol ; 38(3): 257-265, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32356913

RESUMO

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida
17.
Virchows Arch ; 477(4): 603-607, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32372222

RESUMO

Three cases of unexpected/sudden death (N = 2) or acute heart failure (N = 1) were investigated in our centre. The first patient died unexpectedly after surgery for cardiac tamponade and constrictive pericarditis; at autopsy, gross features mimicked a pericardial mesothelioma. The second patient died suddenly after recovering from a respiratory insufficiency episode; autopsy revealed an epicardial mass encircling the right coronary artery. The third patient presenting symptoms mimicked a fulminant myocarditis and she underwent endomyocardial biopsy. In all cases, histology disclosed a diffuse large B cell non-Hodgkin lymphoma, localized to the pericardium together with the right ventricle and the conduction system, to the epicardium and the right coronary artery or to the myocardium, respectively. Histology was crucial for the diagnosis, the atypical presentation favouring other diagnostic hypotheses. Although primary cardiac lymphoma is uncommon and usually shows a sub-acute onset, it may also cause unexpected/sudden death or acute heart failure.


Assuntos
Morte Súbita Cardíaca/etiologia , Insuficiência Cardíaca/etiologia , Neoplasias Cardíacas/complicações , Linfoma Difuso de Grandes Células B/complicações , Miocárdio/patologia , Doença Aguda , Idoso , Autopsia , Biomarcadores Tumorais/análise , Biópsia , Causas de Morte , Morte Súbita Cardíaca/patologia , Evolução Fatal , Feminino , Insuficiência Cardíaca/patologia , Neoplasias Cardíacas/imunologia , Neoplasias Cardíacas/patologia , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia
18.
J Cancer Res Ther ; 16(1): 167-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362630

RESUMO

Lymphoproliferative malignancies can involve both nodal- and extra-nodal tissues. The most common extranodal site involved is the gastrointestinal (GI) tract, and it is secondary to the widespread primary nodal disease. However, about 33% of non-Hodgkin's lymphoma primarily arise from tissues other than lymph nodes, spleen, or bone marrow, for example, GI tract, skin, or the central nervous system and are called primary extranodal lymphomas. The most common site of GI localization is stomach (50%-60%) followed by small bowel. Primary colonic lymphoma is seen only in 6% of GI lymphomas and up to 0.5%-1% of all colon malignancies. Hence, primary GI lymphoma is extremely rare, and primary colonic lymphoma is an even rarer occurrence. There is clearly a paucity of cases reported in literature resulting in unclear treatment protocol. Here, we report a case of a 51-year-old man who presented with abdominal pain, weight loss, and bright red blood per rectum. A colonoscopy revealed diffuse bleeding ulcers involving the entire colon. Pathology was consistent with primary diffuse large B-cell lymphoma arising from the colon. The patient was started on treatment with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone.


Assuntos
Neoplasias do Colo/virologia , Infecções por Vírus Epstein-Barr/complicações , Hemorragia Gastrointestinal/virologia , Herpesvirus Humano 4/isolamento & purificação , Linfoma Difuso de Grandes Células B/virologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Infecções por Vírus Epstein-Barr/virologia , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/patologia , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Prognóstico
19.
J Cancer Res Ther ; 16(1): 183-185, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362635

RESUMO

Diffuse large B-cell lymphomas (DLBCL) with MYC translocations combined with translocations involving BCL-2 or BCL-6 are referred to as double-hit lymphomas. These lymphomas are generally refractory to currently available therapies and have a poor prognosis. Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of DLBCL, which shares clinical, pathologic, and genetic similarities with classical Hodgkin's lymphoma. Unlike DLBCL, rearrangements involving MYC, BCL-2, and BCL-6 are typically absent in PMBL. We present a patient with PMBL who had increased gene copy numbers of MYC and BCL-2 along with increased protein expression of BCL-2 (c-Myc expression was about 15%-20% by immunostain). The disease was refractory to standard and salvage chemotherapies. The lymphoma, however, responded to brentuximab vedotin, a CD30-directed chemoimmunoconjugate.


Assuntos
Brentuximab Vedotin/uso terapêutico , Antígeno Ki-1/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética
20.
Clin Nucl Med ; 45(7): 559-560, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32433164

RESUMO

A 36-year-old woman with a history of large B-cell lymphoma was referred for the exploration of sclerotic bone thoracic vertebral metastases discovered on a contrast-enhanced CT examination. F-FDG PET showed no pathological uptake in the affected vertebrae, as well as normal vertebral density on the coupled unenhanced CT. After review of the initial contrast-enhanced CT, a left brachiocephalic vein stenosis was noted, leading to a retrograde contrast filling of the accessory hemiazygos vein and the capillary spaces within the vertebrae, mimicking sclerotic metastases.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Fluordesoxiglucose F18 , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Vértebras Torácicas/diagnóstico por imagem
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