RESUMO
High-dose intravenous methotrexate (HD-MTX) CNS prophylaxis in high-risk diffuse large B cell lymphoma (DLBCL) remains controversial. We describe real-world CNS relapse incidence following baseline cerebrospinal fluid (CSF) analysis to exclude asymptomatic leptomeningeal involvement in newly diagnosed high-risk DLBCL patients with versus without single-route HD-MTX CNS prophylaxis. Consecutively diagnosed high-risk systemic DLBCL patients without leptomeningeal involvement by CSF analysis (noCNS) were identified retrospectively. Five-year CNS relapse incidence and survival outcomes were examined, as stratified by receipt of HD-MTX prophylaxis. Secondary analysis of survival outcomes in patients with synchronous leptomeningeal involvement (CNSinv) by CSF analysis at diagnosis were compared with the noCNS group. No significant difference in 5-year CNS relapse incidence was observed following HD-MTX prophylaxis versus no prophylaxis (total n = 445) despite similar CNS-IPI risk; 6.2% versus 5.6%, adjusted HR 1.08 (95% CI 0.41-2.85), p = .88; nor in 5-year progression free survival (PFS) or overall survival (OS) risk. Of CNSinv patients, 93.3% had ≥1 extranodal site. Increased CNS relapse/progression risk (5-year risk; HR 10.7 [95% CI 5.35-21.37], p < .0001) and inferior PFS and OS were observed in CNSinv versus all noCNS patients. The CNSinv group had superior OS compared with noCNS patients who later experienced CNS relapse (HR 0.55, p = .052). HD-MTX prophylaxis does not reduce CNS relapse risk in high-risk systemic DLBCL without leptomeningeal involvement by CSF analysis at diagnosis. Asymptomatic patients with synchronous leptomeningeal involvement on baseline CSF examination are at increased risk of further CNS disease events and inferior survival compared to patients without CSF involvement.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Humanos , Metotrexato , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
Assuntos
Adenina/análogos & derivados , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma/tratamento farmacológico , Linfoma/mortalidade , Piperidinas/administração & dosagem , Adenina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.
Assuntos
Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adenina/análogos & derivados , Adulto , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Piperidinas , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Síndrome , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnóstico por imagem , Macroglobulinemia de Waldenstrom/patologiaRESUMO
INTRODUCTION: To assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients. METHODS: In the HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable. RESULTS: In univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01-1.08; OS 1.06 (95% CI 1.02-1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02-2.35); OS 1.68 (1.05-2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value. CONCLUSION: Neurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old.
Assuntos
Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma/complicações , Linfoma/mortalidade , Testes de Estado Mental e Demência , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Quimiorradioterapia Adjuvante/métodos , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Linfoma/terapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Prognóstico , Fatores de Risco , Rituximab/administração & dosagemRESUMO
BACKGROUND: The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma. METHODS: This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18-70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group-WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m2 on days 1 and 15, intravenous carmustine 100 mg per m2 on day 4, intravenous teniposide 100 mg per m2 on days 2 and 3, and oral prednisone 60 mg per m2 on days 1-5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m2 on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing. FINDINGS: Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55-67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9-51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39-58) in the MBVP group (no rituximab) and 52% (42-61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70-1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes. INTERPRETATION: We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma. FUNDING: Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Metotrexato/administração & dosagem , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The CD-20 antibody rituximab is a standard component of treatment of non-Hodgkin B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial-level random-effects meta-analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression-free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment-related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52-1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression-free survival (HR 0.65; 95% CI, 0.45-0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment-related mortality (RR 0.53; 95% CI, 0.20-1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate-based chemotherapy may improve progression-free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/patologia , Ensaios Clínicos Controlados como Assunto , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Viés de Publicação , Qualidade de Vida , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Resultado do TratamentoRESUMO
For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologiaRESUMO
The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 ≤10%, ≤1%, and ≤0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 ≤0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404.
Assuntos
Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Feminino , Proteínas de Fusão bcr-abl/análise , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/induzido quimicamente , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/efeitos adversos , Parestesia/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vômito/induzido quimicamenteRESUMO
Metastasis is a phenomenon of crucial importance in defining prognosis in patients with cancer and is often responsible for cancer-related mortality. It is known that several steps are necessary for clonal cells to disseminate from their primary tumor site and colonize distant tissues, thus originating metastatic lesions. Therefore, investigating the molecular actors regulating this process may provide helpful insights in the development of efficient therapeutic responses. Recent evidences have indicated the role of microRNAs (miRNAs) in modulating the metastatic process in solid tumors. miRNAs are small regulatory non-coding RNAs that bind to specific target mRNAs, leading to translational repression. miRNAs are known to act as negative regulators of gene expression and are involved in the regulation of biological processes, including cell growth, differentiation and apoptosis, both in physiological conditions and during diseases, such as tumors. In the specific field of tumorigenesis, miRNAs play an important role in mediating oncogenesis and favoring tumor progression, as a result of their ability to modulate epithelial-to-mesenchymal transition (EMT) and other series of events facilitating the formation of metastasis. The role of miRNAs in cancer development has been widely studied and has helped elucidate events such as the change in expression of oncogenes, tumor-suppressors and cancer-related proteins. This review focuses on the mechanisms underlying the role of miRNAs as part of the metastatic process.
Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Metástase Neoplásica/genética , Apoptose/genética , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Metástase Neoplásica/patologia , PrognósticoRESUMO
Four series of carbazole derivatives, including N-substituted-hydroxycarbazoles, oxazinocarbazoles, isoxazolocarbazolequinones, and pyridocarbazolequinones, were studied using diverse biological test methods such as a CE-based assay for CK2 activity measurement, a cytotoxicity assay with IPC-81 cell line, determination of MIC of carbazole derivatives as antibacterial agents, a Plasmodium falciparum susceptibility assay, and an ABCG2-mediated mitoxantrone assay. Two oxazinocarbazoles Ib and Ig showed CK2 inhibition with IC50 = 8.7 and 14.0 µM, respectively. Further chemical syntheses were realized and the 7-isopropyl oxazinocarbazole derivative 2 displayed a stronger activity against CK2 (IC50 = 1.40 µM). Oxazinocarbazoles Ib, Ig, and 2 were then tested against IPC-81 leukemia cells and showed the ability to induce leukemia cell death with IC50 values between 57 and 62 µM. Further investigations were also reported on antibacterial and antiplasmodial activities. No significant inhibitory activity on ABCG2 efflux pump was detected.
Assuntos
Antibacterianos/síntese química , Antimaláricos/síntese química , Antineoplásicos/síntese química , Carbazóis/síntese química , Oxazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazinas/química , Oxazinas/farmacologia , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months. METHODS: One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients agedâ ≤â 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. RESULTS: For event-free survival, the hazard ratio was 0.85, 95% CI 0.61-1.18, Pâ =â .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term. CONCLUSIONS: Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Humanos , Metotrexato/uso terapêutico , Rituximab/uso terapêutico , Teniposídeo/uso terapêutico , Carmustina/uso terapêutico , Linfoma/terapia , Prednisolona/uso terapêutico , Qualidade de Vida , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/patologia , Citarabina/uso terapêuticoRESUMO
Autologous stem cell transplantation has greatly improved the prognosis of systemic recurrent non-Hodgkin's lymphoma. However, no prospective data are available concerning the feasibility and efficacy of this strategy for systemic lymphoma relapsing in the central nervous system. We, therefore, we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centers in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World Health Organization performance status of 2, of whom 76% had diffuse large B-cell histology. The majority (79%) of these patients were treated with systemic chemotherapy with or without intravenous rituximab. Twenty-seven patients (29%) were transplanted; age and insufficient response to induction chemotherapy were the main reasons for not being transplanted in the remaining 65 patients. The median overall survival was 7 months (95% confidence interval 2.6-11.4), being 8 months (95% confidence interval 3.8-5.2) for patients ≤ 65 years old. The 1-year survival rate was 34.8%; of the 27 transplanted patients 62% survived more than 1 year. The Memorial Sloan Kettering Prognostic Index for primary central nervous system lymphoma was prognostic for both undergoing transplantation and survival. In conclusion, despite the availability of autologous stem cell transplantation for patients with central nervous system progression or relapse of systemic lymphoma, prognosis is still poor. Long-term survival is, however, possible and more likely in patients able to undergo stem cell transplantation.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/mortalidade , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Treatment of non-Hodgkin lymphoma (NHL) with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) is known to be associated with a significant risk of febrile neutropenia (FN) of up to 50% [Osby et al. 2003 Blood 101(10): 3840-3848; Lyman and Delgado 2003 Cancer 98(11): 2402-2409]. This study sought to examine the impact of primary granulocyte colony-stimulating factor (GCSF) prophylaxis on the incidence of FN, quality of life and overall cost. METHODS: In this retrospective cohort study, a group of 65 consecutive patients who received CHOP chemotherapy for NHL between December 2006 and October 2009 was studied. Patients either received filgrastim (300 mcg, average of seven doses), pegylated filgrastim (6 mg, single dose), or no GCSF prophylaxis. In addition, 19 patients were asked to complete Functional Assessment of Cancer Therapy: General quality-of-life questionnaires. RESULTS: Overall, patients who received primary GCSF prophylaxis had significantly fewer FN compared to those who did not (5 vs. 60%, p < 0.0001; numbers needed to treat of 1.8; 95% confidence interval, 1.6-2.9). Cost-benefit analysis showed that the GCSF prophylaxis was associated with only a small increase in direct financial cost ($238 NZD [US$189] more to give primary GCSF prophylaxis per patient vs. no prophylaxis). The quality of life assessment showed that the patients' quality of life scores were similar to the published data from the validation study population (466 patients with mixed cancers) for Functional Assessment of Cancer Therapy. CONCLUSIONS: Our study shows that primary GCSF prophylaxis is effective in preventing FN in patients receiving CHOP chemotherapy for NHL without adversely affecting their quality of life, and is cost effective.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Análise Custo-Benefício , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Febre/induzido quimicamente , Febre/epidemiologia , Febre/prevenção & controle , Filgrastim , Fator Estimulador de Colônias de Granulócitos/economia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neutropenia/prevenção & controle , Polietilenoglicóis , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Qualidade de Vida , Proteínas Recombinantes/economia , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Inquéritos e Questionários , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Adulto JovemRESUMO
The normal umbilical cord is a crucial component during pregnancy, but sometimes it could become compromised due to some abnormalities such as excessive long umbilical cord, and though they usually end up with a healthy baby, they may lead to severe consequences. Excessive long umbilical cords are found in 4% of pregnancies and represent a risk factor for nuchal cords and true knots. We report a case of a 37-year-old Syrian pregnant woman who presented to the hospital at 37 weeks of gestation asking for a C-section for a fear of ambiguous ultrasound findings that have been interpreted as fetal malformation. At delivery, a healthy baby was born with a 150-cm umbilical cord, a true knot, and double-looped nuchal cords; the formation of the loops and the knot had been attributed to the elongated cord. Besides, ultrasound imaging could sometimes be deceptive and lead to unnecessary interventions; therefore, cord anomalies should always be kept in mind because they do not always represent a justification for a C-section.
RESUMO
Primaquine is an important antimalarial drug for malaria transmission blocking and radical cure, but it is not currently available in child-friendly formulations in appropriate doses. Adult-strength tablets are often crushed and dissolved in water to obtain the required dose, which exposes the drug's bitter taste. As part of the developing paediatric primaquine (DPP) project, this study adopted a responsive sensory pharmaceutics approach by integrating real-time formulation development and pre-clinical taste assessment to develop palatable, flavour-infused primaquine tablets. A design of experiment (DoE) approach was used to screen different taste-masking agents and excipient blends with trained, expert sensory assessors, with quinine hydrochloride as a model bitter tastant. The taste-masking efficacy of selected prototype formulation blends was validated with naïve assessors using the highest 15 mg primaquine dose. The mean bitterness intensity rating, measured on a discrete 11-point scale, was halved from 7.04 for the unflavoured control to 2.74-3.70 for the formulation blends. Sucralose had the biggest impact on bitterness suppression and improving palatability. Two different flavouring systems have been developed, and their acceptability in paediatric patients will be assessed as part of upcoming validation field clinical trials in Africa.
RESUMO
BACKGROUND: In primary central nervous system lymphoma (PCNSL), small enhancing lesions can persist after treatment. It is unknown whether a difference in response category (complete response [CR], complete response unconfirmed [CRu], or partial response [PR]) reflects survival. We aimed to determine the value of a central radiology review on response assessment and whether the extent of response influenced progression-free and/or overall survival. METHODS: All patients in the HOVON 105/ALLG NHL 24 study with at least a baseline MRI and one MRI made for response evaluation available for central review were included. Tumor measurements were done by 2 independent central reviewers, disagreements were adjudicated by a third reviewer. Crude agreement and interobserver agreement (Cohen's kappa) were calculated. Differences in progression-free and overall survival between different categories of response at the end-of-protocol-treatment were assessed by the log-rank test in a landmark survival-analysis. RESULTS: Agreement between the central reviewers was 61.7% and between local and central response assessment was 63.0%. Cohen's kappa's, which corrects for expected agreement, were 0.44 and 0.46 (moderate), respectively. Progression agreement or not was 93.3% (kappa 0.87) between local and central response assessment. There were no significant differences in progression-free and overall survival between patients with CR, CRu, or PR at the end-of-protocol-treatment, according to both local and central response assessment. CONCLUSIONS: Reliability of response assessment (CR/CRu/PR) is moderate even by central radiology review and these response categories do not reliably predict survival. Therefore, primary outcome in PCNSL studies should be survival rather than CR or CR/CRu-rate.
RESUMO
BACKGROUND: To analyze the effect of treatment on neurocognitive functioning and the association of neurocognition with radiological abnormalities in primary central nervous system lymphoma (PCNSL). METHODS: One hundred and ninety-nine patients from a phase III trial (HOVON 105/ALLG NHL 24), randomized to standard chemotherapy with or without rituximab, followed in patients ≤60 years old by 30-Gy whole-brain radiotherapy (WBRT), were asked to participate in a neuropsychological evaluation before and during treatment, and up to 2 years posttreatment. Scores were transformed into a standardized z-score; clinically relevant changes were defined as a change in z-score of ≥1 SD. The effect of WBRT was analyzed in irradiated patients. All MRIs were centrally assessed for white matter abnormalities and cerebral atrophy, and their relation with neurocognitive scores over time in each domain was calculated. RESULTS: 125/199 patients consented to neurocognitive evaluation. Statistically significant improvements in neurocognition were seen in all domains. A clinically relevant improvement was seen only in the motor speed domain, without differences between the arms. In the follow-up of irradiated patients (n = 43), no change was observed in any domain score, compared to after WBRT. Small but significant inverse correlations were found between neurocognitive scores over time and changes in white matter abnormalities (regression coefficients: -0.048 to -0.347) and cerebral atrophy (-0.212 to -1.774). CONCLUSIONS: Addition of rituximab to standard treatment in PCNSL patients did not impact neurocognitive functioning up to 2 years posttreatment, nor did treatment with 30-Gy WBRT in patients ≤60 years old. Increased white matter abnormalities and brain atrophy showed weak associations with neurocognition.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma não Hodgkin , Linfoma , Humanos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Pessoa de Meia-Idade , Testes Neuropsicológicos , Rituximab/uso terapêuticoRESUMO
Bing-Neel syndrome (BNS) is characterised by infiltration of the central nervous system by lymphoplasmacytic lymphoma (LPL) cells and is traditionally regarded as a complication of pre-existing systemic Waldenström's macroglobulinaemia (WM). We describe the case of a 49â¯year old woman with leptomeningeal LPL who did not fulfil diagnostic criteria for concomitant systemic WM at presentation, and who failed to respond to conventional chemotherapy treatment (including high dose methotrexate) but did respond to the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib. This highlights an important variation in the typical natural history of this rare disease and also further supplements emerging evidence regarding efficacy of ibrutinib in its treatment.