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1.
Ann Oncol ; 34(2): 186-199, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36402300

RESUMO

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Humanos , Fosfatidilinositol 3-Quinases/genética , Linfoma Difuso de Grandes Células B/patologia , Mutação , Complexo Repressor Polycomb 2/genética , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia
2.
J Neurooncol ; 148(3): 545-554, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32524392

RESUMO

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/mortalidade , Quimiorradioterapia/mortalidade , Irradiação Craniana/mortalidade , Diagnóstico Tardio/estatística & dados numéricos , Imunocompetência , Linfoma não Hodgkin/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carmustina/administração & dosagem , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/terapia , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/terapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
3.
Acta Oncol ; 57(3): 403-411, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29243538

RESUMO

BACKGROUND: Charcot Marie Tooth (CMT) disease is the most common form of hereditary neuropathy. Due to the high prevalence of mild and undiagnosed forms, patients with CMT disease may be exposed to severe neurotoxicity following the administration of neurotoxic chemotherapies. The aim of this report is to alert oncologists to the potential to precipitate severe irreversible peripheral neuropathies when administering neurotoxic compounds to undiagnosed CMT patients. MATERIAL AND METHODS: A retrospective research in the OncoNeuroTox database was performed (2010-2016), searching for patients with the diagnosis of chemotherapy-induced peripheral neuropathy (CIPN) and CMT disease. A comprehensive literature review for previously published cases was performed using the Pubmed and Cochrane databases (1972-2017). RESULTS: Among 428 patients with CIPN, we identified eight patients with concomitant CMT disease. Seven patients out of the eight had no previous diagnosis of CMT disease, although accurate familial history disclosed mild signs of peripheral neuropathy in five cases. Patients themselves had minor stigmata of long-standing peripheral damage. Patients received chemotherapy regimens based on vinca alkaloids, taxanes or a combination of vinca alkaloids and platinum compounds. In two cases, cumulative doses were below or equal to the expected neurotoxic threshold. Following chemotherapy administration, patients developed severe length-dependent sensory-motor deficits. Despite early drug discontinuation, most patients remained severely disabled. CONCLUSION: A brief checklist to disclose long-standing signs of peripheral neuropathy could be helpful to detect patients with undiagnosed hereditary neuropathies who could be at risk of developing severe irreversible neurotoxicity following the administration of neurotoxic agents.


Assuntos
Antineoplásicos/efeitos adversos , Doença de Charcot-Marie-Tooth/complicações , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
4.
Rev Neurol ; 56(3): 137-42, 2013 Feb 01.
Artigo em Espanhol | MEDLINE | ID: mdl-23359074

RESUMO

INTRODUCTION: Carotid stenosis is a complication of cervical radiotherapy. In these cases carotid angioplasty has been considered as the elective revascularisation treatment. Yet, the indication to treat is under discussion due to the high rate of restenosis and the scarcity of studies conducted on the long-term development. AIMS: To report on a series of patients with carotid stenosis following radiotherapy who were treated by means of angioplasty, the aim being to analyse their long- and short-term development. PATIENTS AND METHODS: Of a series of 426 patients with carotid stenosis treated by endovascular means, 12 of them (2.8%) had previously received radiotherapy in the neck. All of them were submitted to a clinical and imaging follow-up. Data were collected concerning the rate of complications during the first four weeks and in the long term, as well as the rate of restenosis in the follow-up. RESULTS: The mean interval between radiotherapy and the detection of stenosis was 14.7 years. Ten patients (83.3%) were symptomatic. No complications occurred during the first four weeks following the angioplasty. The mean follow-up time was 45.09 months: 16.7% of patients presented a stroke, 8.3% suffered acute myocardial infarction and 33.3% died (16.6% due to cancer). At least six patients (50%) were diagnosed with restenosis, all equal to or greater than 50% and none of them were symptomatic. CONCLUSIONS: Carotid angioplasty is a safe, effective technique in stenosis following radiotherapy, with few short-term complications. The rate of carotid restenosis is high. The main cause of death is cancer.


Assuntos
Angioplastia , Lesões das Artérias Carótidas/etiologia , Estenose das Carótidas/cirurgia , Lesões por Radiação/cirurgia , Radioterapia/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/etiologia , Carcinoma/radioterapia , Estenose das Carótidas/etiologia , Feminino , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Neoplasias Laríngeas/radioterapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Lesões por Radiação/etiologia , Recidiva , Stents
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