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2.
Rinsho Shinkeigaku ; 59(6): 365-370, 2019 Jun 22.
Artigo em Japonês | MEDLINE | ID: mdl-31142712

RESUMO

A 67-year-old male was transferred to our hospital with diplopia, decreased deep tendon reflex and ataxia. He had been suspected Fisher syndrome because of previous upper respiratory tract infection. A cerebrospinal fluid examination showed marked hypoglycorrhachia, pleocytosis and elevated protein, and cytological examination suggested malignant lymphoma. Abdominal computed tomography revealed a left adrenal mass. A biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. He was treated with a combination of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin and prednisolone) and intrathecal administration of methotrexate, cytarabine and prednisolone. Neurological symptoms were gradually improved. Malignancy should be considered in addition to bacterial, fungal or tuberculous meningitis in a case with marked hypoglycorrhachia.


Assuntos
Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/diagnóstico , Glucose/líquido cefalorraquidiano , Linfoma Difuso de Grandes Células B/líquido cefalorraquidiano , Linfoma Difuso de Grandes Células B/diagnóstico , Doenças do Nervo Oculomotor/etiologia , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/patologia , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Diagnóstico por Imagem , Doxorrubicina/administração & dosagem , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Masculino , Metotrexato/administração & dosagem , Prednisolona/administração & dosagem , Prednisona/administração & dosagem , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem
6.
Int J Cancer ; 145(7): 1838-1851, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882895

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC.


Assuntos
Carcinoma Ductal Pancreático/terapia , Imunoconjugados/administração & dosagem , Fatores Imunológicos/administração & dosagem , Neoplasias Pancreáticas/terapia , Animais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Fatores Imunológicos/farmacologia , Camundongos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Neoplasias Pancreáticas/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Fator de Transcrição STAT3/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Radiat Oncol Biol Phys ; 104(3): 522-529, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30858143

RESUMO

PURPOSE: We previously reported that ∼30% of patients with localized follicular lymphoma (FL) staged by 18F-fluorodeoxyglucose positron emission tomography-computed tomography receiving primary radiation therapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed. METHODS AND MATERIALS: We conducted a multicenter, retrospective study of patients aged ≥18 years who received RT ≥ 24 Gy for stage I to II, grade 1 to 3A FL, staged with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier analysis and univariable and multivariable analyses with Cox regression. RESULTS: Of 512 patients with median follow-up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median of 23 months (range, 1-143) after primary RT. Median follow-up was 33 months after relapse. Three-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others-88.7% versus 97.6%, respectively (P = .01)-and remained significantly worse on multivariable analyses (follicular lymphoma international prognostic index-adjusted hazard ratio, 3.61; P = .009). Histology at relapse included 93 indolent (grade 1-3A), 3 FL grade 3B/not otherwise specified, and 18 diffuse large B-cell lymphoma; 35 patients did not undergo biopsy. Of those with follow-up ≥3 months who underwent biopsy (n = 74) or had presumed (n = 23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) had RT, and 4 (4.1%) had systemic therapy + RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n = 59, including 20 initially observed) 3-year FFP was 73.9%. CONCLUSIONS: Prognosis for patients with relapsed FL after primary radiation therapy is excellent, supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival compared with those with longer disease-free interval.


Assuntos
Linfoma Folicular/mortalidade , Linfoma Folicular/radioterapia , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluordesoxiglucose F18 , Humanos , Estimativa de Kaplan-Meier , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prednisona/administração & dosagem , Intervalo Livre de Progressão , Compostos Radiofarmacêuticos , Recidiva , Estudos Retrospectivos , Rituximab/uso terapêutico , Fatores de Tempo , Vincristina/administração & dosagem , Conduta Expectante , Adulto Jovem
8.
Int J Hematol ; 109(6): 723-730, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859398

RESUMO

Follicular lymphoma (FL) is an indolent lymphoma that often transforms into a high-grade lymphoma, mostly diffuse large B-cell lymphoma. A case of FL suggested to transform into plasmablastic lymphoma is presented. A 59-year-old man was admitted to our hospital because of right lower abdominal pain and vomiting. Computed tomography showed a mass in the ileocecum. Colonoscopy showed a mass with an ulcer in the ascending colon, and surgery was performed. Immunohistochemical staining of the biopsied mass showed infiltrated lymphocytes that were positive for CD38, CD45, CD138, and λ chain, and negative for CD4, CD5, CD8, CD10, CD20, CD56, and κ chain. Flow cytometric analysis of the ascites showed similar results. FISH analyses performed using lymph node biopsy specimens, ascite fluid and pleural effusion fluid identified the presence of an IGH/BCL2 translocation. FL was suggested to transform into PBL. Although the patient received three courses of R-CHOP chemotherapy and salvage chemotherapy, the patient died because of lymphoma progression less than 6 months after the diagnosis of PBL. Transformation of FL to PBL is highly unusual. The lack of a standard treatment for PBL results in the poor outcome of this entity. Novel therapeutic approaches are needed.


Assuntos
Linfoma Folicular/patologia , Linfoma Plasmablástico/patologia , Anticorpos Monoclonais Murinos/administração & dosagem , Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Evolução Fatal , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/terapia , Masculino , Pessoa de Meia-Idade , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/terapia , Prednisona/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/genética , Rituximab , Terapia de Salvação , Tomografia Computadorizada por Raios X , Translocação Genética , Vincristina/administração & dosagem
9.
BioDrugs ; 33(2): 221-228, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30747341

RESUMO

BACKGROUND: CT-P10 is the first biosimilar of the anti-CD20 monoclonal antibody, rituximab. CT-P10 is currently available in over 51 countries worldwide, where it is approved in the same indications as its reference product rituximab. In-use stability studies are conducted for biologics to determine how conditions (e.g., temperature, light, humidity, length of time stored) affect drug quality following dilution and storage in infusion bags. OBJECTIVE: We evaluated the in-use stability of CT-P10 for intravenous infusion stored diluted in infusion bags over longer periods than currently recommended by manufacturer guidelines. METHODS: CT-P10, within the final month of its 36-month shelf life, was diluted to 1.0 or 4.0 mg/mL and stored at 2-8 °C in polyethylene or polyvinylchloride infusion bags for 2, 4, and 6 weeks. CT-P10 infusion bags were incubated at room temperature for 24 h before analysis. Analyses included detection of sub-visible particles, formation of impurities and determination of charge variants, and heavy- and light-chain content. Cell-based CD20 binding affinity and complement-dependent cytotoxicity were also assessed. RESULTS: Diluted CT-P10 solutions remained clear, colorless, and free of visible particles irrespective of type of infusion bag, target concentration, or timepoint. Protein concentrations, sub-visible particles, pH, osmolality, and molecular weight and charge variants were stable across all timepoints and variables. The binding affinity and potency of CT-P10 remained unchanged, indicating that the efficacy of the antibody was maintained following in-use preparation. CONCLUSIONS: We demonstrated that CT-P10 was stable after refrigerated storage for up to 6 weeks followed by incubation at room temperature.


Assuntos
Anticorpos Monoclonais Murinos/química , Medicamentos Biossimilares/química , Rituximab/química , Animais , Anticorpos Monoclonais Murinos/administração & dosagem , Medicamentos Biossimilares/administração & dosagem , Células CHO , Cricetulus , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Infusões Intravenosas , Rituximab/administração & dosagem , Temperatura Ambiente , Testes de Toxicidade
10.
Int J Radiat Oncol Biol Phys ; 104(2): 447-455, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30769175

RESUMO

PURPOSE: In patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, the standard radiation therapy (RT) dose is ≥30 Gy. We report the outcome of patients treated with reduced dose 24 Gy compared with those treated with ≥30 Gy. METHODS AND MATERIALS: We reviewed results from 32 patients who received a diagnosis of gastric MALT lymphoma between 2007 and 2017 who were treated with involved site RT using intensity modulated radiation therapy (IMRT). Response to therapy was based on post-RT endoscopic biopsy. Freedom from local treatment failure (FFLTF), freedom from treatment failure (FFTF), and overall survival (OS) outcomes were determined. RESULTS: The median age of patients at diagnosis was 58 years. Therapy for MALT was given prior to RT in 14 patients with residual biopsy proven disease documented in all cases (anti-microbial, n=11; rituximab, n=2; rituximab, cyclophosphamide, doxorubicin, vincristine, n=1). One patient received RT (36 Gy) and concurrent rituximab. The median RT dose was 30 Gy; it was 30 to 36 Gy in 66% of patients (n = 21) and 24 Gy in 34% of patients (n = 11). Post-RT biopsy documented a complete response in all patients. Failures occurred in the stomach and duodenum, respectively, at 3.6 and 4.5 years, after 30 Gy. At a median follow-up of 55.2 months (73.8 for ≥30 Gy compared with 28.7 for 24 Gy; P < .001), the 2-year FFLTF, FFTF, and OS were 100%, 100%, and 97%, respectively. No association was found between the lower (24-Gy) dose and FFLTF (P = .819), FFTF (P = .819), or OS (P = .469). CONCLUSIONS: Contemporary RT with involved site targeting using IMRT is associated with high complete response rates for patients with gastric MALT lymphoma, even using reduced doses of 24 Gy. Additional follow-up and increased patient numbers are required to confirm equivalent disease control.


Assuntos
Mucosa Gástrica , Linfoma de Zona Marginal Tipo Células B/radioterapia , Radioterapia de Intensidade Modulada/métodos , Neoplasias Gástricas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Dosagem Radioterapêutica , Estudos Retrospectivos , Rituximab/administração & dosagem , Neoplasias Gástricas/mortalidade , Resultado do Tratamento , Vincristina/administração & dosagem
11.
BioDrugs ; 33(1): 79-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30719632

RESUMO

OBJECTIVE: The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks. METHODS: In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed. RESULTS: Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (- 2.7 and - 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles. CONCLUSION: CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. CLINICALTRIALS. GOV IDENTIFIER: NCT02149121.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/administração & dosagem , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Sedimentação Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Rituximab/efeitos adversos , Adulto Jovem
12.
Nephrology (Carlton) ; 24(2): 272, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30697886

Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Neutropenia Febril Induzida por Quimioterapia , Glomerulonefrite por IGA/complicações , Falência Renal Crônica , Neoplasias Renais , Transplante de Rim , Linfoma Difuso de Grandes Células B , Complicações Pós-Operatórias , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Neutropenia Febril Induzida por Quimioterapia/diagnóstico , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Neutropenia Febril Induzida por Quimioterapia/etiologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Evolução Fatal , Humanos , Imunossupressão/métodos , Rim/diagnóstico por imagem , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/fisiopatologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Reoperação/métodos , Rituximab , Vincristina/administração & dosagem , Vincristina/efeitos adversos
13.
Int J Cancer ; 145(7): 1798-1808, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30680712

RESUMO

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.


Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/efeitos adversos , Animais , Anticorpos Monoclonais Murinos/efeitos adversos , Esquema de Medicação , Efrina-A4/metabolismo , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Camundongos , Pessoa de Meia-Idade , Neoplasias/metabolismo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
15.
J Clin Oncol ; 37(3): 190-201, 2019 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-30523716

RESUMO

PURPOSE: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. PATIENTS AND METHODS: We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. RESULTS: We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested. CONCLUSION: We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.


Assuntos
Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Rearranjo Gênico , Centro Germinativo/patologia , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Neoplásico/genética , Rituximab/administração & dosagem , Transcriptoma , Vincristina/administração & dosagem , Adulto Jovem
16.
J Clin Oncol ; 37(3): 202-212, 2019 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-30523719

RESUMO

PURPOSE: Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. PATIENTS AND METHODS: We defined a molecular high-grade (MHG) group by applying a gene expression-based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. RESULTS: The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases. CONCLUSION: MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Bases de Dados Genéticas , Doxorrubicina/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prednisona/administração & dosagem , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Rituximab/administração & dosagem , Transcriptoma , Vincristina/administração & dosagem
17.
J Cancer Res Clin Oncol ; 145(1): 117-127, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30327941

RESUMO

PURPOSE: This study was to compare DA-EPOCH-R and R-CHOP regimen as first-line therapy in diffuse large B cell lymphoma (DLBCL) patients, retrospectively. METHODS: A total of 252 cases treated with R-CHOP and 146 cases who received DA-EPOCH-R were enrolled into this study. RESULTS: Overall, 162 (64.3%) and 105 patients (71.9%) achieved complete remission, 43 (17.1%) and 14 patients (9.6%) achieved partial remission following R-CHOP and DA-EPOCH-R regimen, respectively. After a median follow-up of 48 months, better progression-free survival (PFS) was seen in DA-EPOCH-R group, but no better overall survival (OS) was found in patients treated with DA-EPOCH-R compared to R-CHOP (P = 0.015 for PFS, P = 0.19 for OS). However, subgroup analysis according to cell of origin, international prognostic index (IPI), and age showed DA-EPOCH-R resulted in significantly better PFS and OS than R-CHOP regimen in patients with germinal center B-cell-like (GCB) phenotype (P = 0.002 for PFS, P = 0.007 for OS), high IPI (P = 0.002 for PFS; P = 0.03 for OS), and with a younger age (P = 0.002 for PFS, P = 0.045 for OS). We also compared two regimens in patients with double expressor lymphoma (DEL). The prognosis of DEL patients was significantly worse than non-DEL patients (P < 0.001 for PFS, P < 0.001 for OS), but DA-EPOCH-R regimen may not overcome the poor prognosis (P = 0.47 for PFS, P = 0.79 for OS). CONCLUSION: GCB DLBCL, younger patients, and high-risk patients, but not DEL patients, may benefit from continuous-infusion DA-EPOCH-R regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Indução de Remissão , Estudos Retrospectivos , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
18.
Ann Hematol ; 98(2): 401-411, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30413902

RESUMO

We evaluated the association between the prognostic nutritional index (PNI) and the clinical features of diffuse large B cell lymphoma (DLBCL) and developed a novel prognostic model using a nomogram including the PNI and other biomarkers for cancer cachexia. A total of 228 DLBCL patients treated with first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) were retrospectively reviewed. PNI was calculated as 10 × serum levels of albumin (g/dL) + 0.005 × absolute lymphocyte count (/mm3). Patients were categorized into low- and high-PNI groups based on a cut-off value of 40. The nomogram for predicting overall survival (OS) was constructed using a Cox regression model. PNI was positively correlated with skeletal muscle index, body mass index, and serum levels of albumin. The low-PNI group had a lower complete response rate (60.3% vs. 87.6%), increased treatment-related toxicity, and more frequent treatment discontinuation (43.5% vs. 8.8%) than the high-PNI group. The median OS was shorter in the low-PNI group than the high-PNI group (15.6 months vs. not reached; p < 0.001). Multivariate Cox regression analyses showed that PNI, sarcopenia, and the international prognostic index (IPI) were independent prognostic factors for OS. The nomogram developed using this regression model showed excellent discriminatory ability for predicting OS (c-index, 0.80) compared to the IPI alone (c-index, 0.75). Low PNI was associated with adverse clinical features of DLBCL. The proposed nomogram supports the clinical impact of cachexia on survival and may contribute to individualized therapy in DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B , Modelos Biológicos , Avaliação Nutricional , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Índice de Massa Corporal , Caquexia/tratamento farmacológico , Caquexia/metabolismo , Caquexia/patologia , Caquexia/fisiopatologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab , Sarcopenia/tratamento farmacológico , Sarcopenia/mortalidade , Sarcopenia/patologia , Sarcopenia/fisiopatologia , Taxa de Sobrevida , Vincristina/administração & dosagem , Vincristina/efeitos adversos
19.
Hematology ; 24(1): 52-59, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30101679

RESUMO

OBJECTIVES: Chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with rituximab (R-CHOP) is currently the first-line therapy for diffuse large B-cell lymphoma (DLBCL). However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them. METHODS: At our institute, for DLBCL patients aged 65-79 and ≥80 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP. RESULTS: Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p < 0.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60-80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups. DISCUSSION AND CONCLUSIONS: Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversos
20.
Br J Haematol ; 183(5): 717-726, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30406945

RESUMO

Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline-containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4·6% after 3-5 cycles of R-CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate.


Assuntos
Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Insuficiência Cardíaca/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Arritmias Cardíacas/mortalidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/mortalidade , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dinamarca/epidemiologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Imunoterapia/efeitos adversos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Rituximab , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
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