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BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.
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Antineoplásicos , Glioblastoma , Glioma , Adulto , Feminino , Humanos , Masculino , Quimiorradioterapia , Terapia Genética , Glioblastoma/genética , Glioblastoma/terapia , Glioma/genética , Glioma/terapia , Adolescente , Pessoa de Meia-Idade , IdosoRESUMO
Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Mutação , Glioma/genética , Glioma/metabolismo , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismoRESUMO
The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Adulto , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Sistema Nervoso Central , MutaçãoRESUMO
Background: There is no consensus on the treatment of central nervous system (CNS) lymphoma refractory to first-line methotrexate-based chemotherapy. Whole brain radiotherapy (WBRT) is sometimes used but may result in unacceptable neurocognitive dysfunction. We examined the efficacy and toxicities of WBRT with or without concurrent temozolomide in CNS lymphoma treatment. Methods: This single-institution IRB-approved retrospective study included adults with CNS lymphoma who received WBRT, either consolidative low-dose WBRT alone or low-dose WBRT with a focal boost to residual disease and were previously treated with high-dose methotrexate. The relationships between the WBRT regimen, concurrent temozolomide, and clinical outcomes and toxicities were assessed using proportional hazards and logistic regression models. Results: A total of 45 patients with a median age of 64 years (range 24-74) treated from 2004 to 2019 were included. In total, 20 patients received concurrent temozolomide. In the WBRT + Boost cohort (n = 32), concurrent temozolomide resulted in better 2-year overall survival (OS) and progression free survival (PFS) (73% OS and 66% PFS) compared to patients treated without concurrent temozolomide (44% OS and 24% PFS). On multivariate analysis, concurrent temozolomide was associated with significantly better PFS (HR 0.28, P = .02). There were no significant differences between the two radiation groups or between those treated with or without concurrent temozolomide, with respect to significant acute hematologic, non-hematologic, and long-term neurocognitive toxicities (P > .05). Conclusions: In this study, concurrent temozolomide with radiotherapy in CNS lymphoma was associated with better PFS and was well tolerated. Low-dose WBRT with a boost is a safe and reasonable treatment approach for focal refractory disease. Prospective research that includes rigorous neurocognitive assessments is now warranted.
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Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.
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COVID-19/epidemiologia , Mudança Climática , Epilepsia/epidemiologia , Saúde Global/tendências , Saúde Pública/tendências , Animais , COVID-19/prevenção & controle , Morte Súbita , Epilepsia/terapia , Temperatura Alta/efeitos adversos , Humanos , Umidade/efeitos adversos , Privação do Sono/epidemiologia , Privação do Sono/terapia , Tempo (Meteorologia)RESUMO
PURPOSE: We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TVHCV) and hyperperfused (TVCBV) tumor volumes would improve outcomes in patients with glioblastoma. METHODS AND MATERIALS: This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TVHCV/TVCBV >1 cm3, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TVHCV/TVCBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TVHCV/TVCBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative 11C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised. RESULTS: Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TVHCV alone, and 13 patients were boosted to both TVHCV/TVCBV. Gross or subtotal resection was performed in 87% of patients; 22% were O6-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TVHCV/TVCBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TVHCV/TVCBV decreased to less than the median volume (3 cm3) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the 11C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy. CONCLUSIONS: Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.
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Glioblastoma/terapia , Doses de Radiação , Adulto , Idoso , Quimiorradioterapia , Feminino , Glioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Dosagem RadioterapêuticaRESUMO
Differentiating pseudoprogression from true tumor progression has become a significant challenge in follow-up of diffuse infiltrating gliomas, particularly high grade, which leads to a potential treatment delay for patients with early glioma recurrence. In this study, we proposed to use a multiparametric MRI data as a sequence input for the convolutional neural network with the recurrent neural network based deep learning structure to discriminate between pseudoprogression and true tumor progression. In this study, 43 biopsy-proven patient data identified as diffuse infiltrating glioma patients whose disease progressed/recurred were used. The dataset consists of five original MRI sequences; pre-contrast T1-weighted, post-contrast T1-weighted, T2-weighted, FLAIR, and ADC images as well as two engineered sequences; T1post-T1pre and T2-FLAIR. Next, we used three CNN-LSTM models with a different set of sequences as input sequences to pass through CNN-LSTM layers. We performed threefold cross-validation in the training dataset and generated the boxplot, accuracy, and ROC curve, AUC from each trained model with the test dataset to evaluate models. The mean accuracy for VGG16 models ranged from 0.44 to 0.60 and the mean AUC ranged from 0.47 to 0.59. For CNN-LSTM model, the mean accuracy ranged from 0.62 to 0.75 and the mean AUC ranged from 0.64 to 0.81. The performance of the proposed CNN-LSTM with multiparametric sequence data was found to outperform the popular convolutional CNN with a single MRI sequence. In conclusion, incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression.
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Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Aprendizado Profundo , Progressão da Doença , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Oligodendroglioma/diagnóstico por imagem , Adulto , Idoso , Área Sob a Curva , Astrocitoma/patologia , Biópsia , Neoplasias Encefálicas/patologia , Confiabilidade dos Dados , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Oligodendroglioma/patologia , Curva ROC , Estudos RetrospectivosRESUMO
The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Adulto , Astrocitoma/diagnóstico , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , Glioma/diagnóstico , Glioma/terapia , Humanos , Guias de Prática Clínica como AssuntoRESUMO
PURPOSE: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. METHODS AND MATERIALS: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. RESULTS: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). CONCLUSIONS: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response.
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Azetidinas/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Nitrocompostos/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Irradiação Craniana , Feminino , Humanos , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiossensibilizantes/uso terapêuticoRESUMO
PURPOSE: To evaluate whether response assessment of newly diagnosed glioblastoma at 3 months using 11C-methionine-positron emission tomography (MET-PET) is better associated with patient outcome compared with baseline MET-PET or anatomic magnetic resonance imaging alone. METHODS AND MATERIALS: Patients included were participants in a phase I/II trial of dose-escalated chemoradiation based on anatomic magnetic resonance imaging. Automated segmentation of metabolic tumor volume (MTV) was performed at a threshold of 1.5 times mean cerebellar uptake. Progression-free (PFS) and overall survival were estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariate analysis for PFS and overall survival was performed using Cox proportional hazards, and spatial overlap between imaging and recurrence volumes were analyzed. RESULTS: Among 37 patients, 15 had gross total resection, of whom 10 (67%) had residual MTV, 16 subtotal resection, and 6 biopsy alone. Median radiation therapy dose was 75 Gy (range, 66-81). Median baseline T1 Gd-enhanced tumor volume (GTV-Gd) was 38.0 cm3 (range, 8.0-81.5). Median pre-CRT MTV was 4.9 cm3 (range, 0-43.8). Among 25 patients with 3-month MET-PET, MTV was only 2.4 cm3 (range, 0.004-18.0) in patients with uptake. Patients with MTV = 0 cm3 at 3 months had superior PFS (18.2 vs 10.1 months, P = .03). On multivariate analysis, larger 3-month MTV (hazard ratio [HR] 2.4, 95% confidence interval [CI], 1.4-4.3, P = .03), persistent MET-PET subvolume (overlap of pre-CRT and 3 month MTV; HR 2.0, 95% CI, 1.2-3.4, P = .06), and increase in MTV (HR 1.8, 95% CI, 1.1-3.1, P = .09) were the only imaging factors significant for worse PFS. GTV-Gd at recurrence encompassed 97% of the persistent MET-PET subvolume (interquartile range 72%-100%), versus 71% (interquartile range 39%-93%) of baseline MTV, 54% of baseline GTV-Gd (18%-87%), and 78% of 3-month MTV (47%-95%). CONCLUSIONS: The majority of patients with apparent gross total resection of glioblastoma have measurable postoperative MTV. Total and persisting MTV 3 months post-CRT were significant predictors of PFS, and persistent MET-PET subvolume was the strongest predictor for localizing tumor recurrence.
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BACKGROUND AND PURPOSE: We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era. MATERIALS AND METHODS: Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66-81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression. RESULTS: Median follow-up was 23 months (95% CI 4-124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3-11.0) and OS was 18.7 months (95% CI 13.1-25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93-0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16-0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16-0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09-0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival. CONCLUSION: Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.
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Neoplasias Encefálicas/mortalidade , Quimiorradioterapia/mortalidade , Glioblastoma/mortalidade , Terapia de Salvação , Temozolomida/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Glioblastoma/diagnóstico , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.
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Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , DNA Tumoral Circulante/análise , Biópsia Líquida/métodos , Células Neoplásicas Circulantes/patologia , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/terapia , DNA Tumoral Circulante/genética , Tomada de Decisão Clínica , Humanos , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , PrognósticoRESUMO
We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.
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Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Glioblastoma/diagnóstico por imagem , Humanos , Avaliação de Estado de Karnofsky , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Intervalo Livre de Progressão , Estudos Retrospectivos , Temozolomida/uso terapêuticoRESUMO
For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Sistema Nervoso Central/diagnóstico , Glioma/diagnóstico , Sistema Nervoso/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada/métodos , Terapia Combinada/normas , Glioma/classificação , Glioma/patologia , Glioma/terapia , Humanos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Gradação de Tumores , Prognóstico , Radioterapia/métodos , Radioterapia/normasRESUMO
Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.