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OPINION STATEMENT: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.
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Neoplasias Encefálicas , Epilepsia , Humanos , Anticonvulsivantes/efeitos adversos , Levetiracetam/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Convulsões/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.
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Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Guias de Prática Clínica como Assunto , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Metástase NeoplásicaRESUMO
Carmustine wafers (CW; Gliadel(®) wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Carmustina/uso terapêutico , Ácidos Decanoicos/uso terapêutico , Glioma/tratamento farmacológico , Poliésteres/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/patologia , Carmustina/efeitos adversos , Ácidos Decanoicos/efeitos adversos , Implantes de Medicamento/efeitos adversos , Implantes de Medicamento/uso terapêutico , Glioma/patologia , Humanos , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Poliésteres/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Oligodendroglioma/tratamento farmacológico , Avaliação de Resultados da Assistência ao Paciente , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Dacarbazina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Oligodendroglioma/genética , Oligodendroglioma/mortalidade , Oligodendroglioma/patologia , Prognóstico , Taxa de Sobrevida , Temozolomida , Adulto JovemRESUMO
The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.
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Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/cirurgia , Humanos , Radiocirurgia/métodosRESUMO
Ayurveda is the traditional medicine system of India, and has been in practice for millennia. It is a traditional approach that uses 1000's of different plant preparations in various combinations for treatment of human ailments, including cancer. Ethnopharmacological and phytochemical analyses are now elucidating the bioactive constituents of the different plant species and herbal formulations, including ashwagandha, curcumin, guduchi, triphala, and others. To provide an overview of: 1) the ethnopharmacology of Ayurveda and several of its most important plant species and formulations, including pharmacological and molecular mechanisms of its anti-cancer effects; 2) review the literature applying Ayurvedic herbs and formulations to brain tumors. A detailed PubMed search was performed that included publications involving Ayurveda, cancer, ethnopharmacology, phytochemical analysis, molecular analysis, and brain tumors. In recent decades, significant research has begun to elucidate the bioactive compounds of ashwagandha, tumeric, guduchi, and triphala, such as withaferin A, withanolides, curcumin, palmatine, and many others. These compounds and extracts are now being applied to brain tumor cells in vitro and in animal models, with positive signs of anti-cancer activity including reduced cell growth, increased apoptosis, cell cycle arrest, increased differentiation, and inhibition of important internal signal transduction pathways. Several Ayurvedic herbs (ashwagandha, curcumin) have bioactive compounds with significant anti-cancer activity, and are effective in early pre-clinical testing against brain tumor cells in vitro and in animal models. Further pre-clinical testing is warranted, along with advancement into phase I and phase II clinical trials of patients with glioblastoma and other brain tumors.
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Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.
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Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/terapia , HumanosRESUMO
PURPOSE: To use directed biopsy sampling to determine whether microvascular assessment within gliomas, by means of ultrahigh-field-strength high-spatial-resolution gradient-echo (GRE) magnetic resonance (MR) imaging at 8 T, correlates with histopathologic assessment of microvascularity. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. Informed consent was obtained. Thirty-five subjects with gliomas underwent 8-T and 80-cm MR imaging by using a GRE sequence (repetition time, 600-750 msec; echo time, 10 msec; in-plane resolution, 196 mm). Haphazardly arranged serpentine low-signal-intensity structures, often associated with areas of low signal intensity within the tumor bed ("tumoral pseudoblush") at MR imaging, were presumed to be related to tumoral microvascularity. Microvessel density (MVD) and microvessel size (MVS) ranked with a semiquantitative three-tier scale (high, medium, and low) relative to cortical penetrating veins were assessed from regions of interest identified at MR imaging and were compared with a similar assessment of stereotactic biopsy specimens by using Kendall τb. Tumor grade (high vs low) was compared with ultrahigh-field-strength high-resolution GRE MR analysis by using Pearson χ2. Discrepancies between 8-T and histopathologic assessment were identified and analyzed. RESULTS: Ultrahigh-field-strength high-resolution GRE MR imaging and histopathologic assessment concurred for MVS (P<.0001) and MVD (P<.0001). World Health Organization classification tumor grade was associated with number (P<.0005) and size (P<.0005) of foci of microvascularity within the tumor bed at 8-T MR imaging. Radiation-induced microvessel hyalinosis mimicked tumor microvascularity at 8-T MR imaging. Potential confounders could result from radiofrequency inhomogeneity and displaced normal microvasculature. CONCLUSION: Microvascularity identified as a tumoral pseudoblush at ultrahigh-field-strength high-resolution GRE MR imaging without contrast material shows promise as a marker for increased tumoral microvascularity.
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Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/diagnóstico , Adulto , Idoso , Biópsia , Distribuição de Qui-Quadrado , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR-TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR-TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition.
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Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Bevacizumab , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
N-methyl-D-aspartate receptor (NMDA-R) antibody encephalitis is an immune-mediated disorder characterized by the presence of anti-NMDA antibody in serum and cerebrospinal fluid, with a characteristic combination of psychological and neurological signs and symptoms. The scientific knowledge pertaining to the management of anti-NMDA-R encephalitis is growing. It is important that neuroscience nurses be aware of treatments as well as the newest novel treatment options available. Early aggressive intervention is imperative to recovery. The first line of treatment often includes high-dose steroids, intravenous immunoglobulin, and therapeutic plasma exchange. Second-line therapy for refractory NMDA-R encephalitis includes intravenous rituximab and cyclophosphamide. Even with these treatments, up to 25% of patients may be left with severe deficits or have a fatal outcome. It is well known that penetration of monoclonal anti-CD20 antibody therapy (rituximab) into the cerebrospinal fluid is 0.1% of that in the serum. Therefore, efficacy of rituximab in the treatment of NMDA encephalitis may be improved by intrathecal administration in selected cases with a poor response to intravenous rituximab. We present a case of anti-NMDA-R encephalitis that was refractory to first- and second-line therapies, who responded to intrathecal rituximab, to highlight a novel treatment that may be able to prevent long-term disability and improve clinical outcomes.
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Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Injeções Espinhais , Rituximab/uso terapêutico , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/líquido cefalorraquidiano , Ciclofosfamida/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Imunossupressores/uso terapêutico , Enfermagem em Neurociência , Convulsões , Adulto JovemRESUMO
Therapies targeting glioma cells that diffusely infiltrate normal brain are highly sought after. Our aim was to identify novel approaches to this problem using glioma spheroid migration assays. Lithium, a currently approved drug for the treatment of bipolar illnesses, has not been previously examined in the context of glioma migration. We found that lithium treatment potently blocked glioma cell migration in spheroid, wound-healing, and brain slice assays. The effects observed were dose dependent and reversible, and worked using every glioma cell line tested. In addition, there was little effect on cell viability at lithium concentrations that inhibit migration, showing that this is a specific effect. Lithium treatment was associated with a marked change in cell morphology, with cells retracting the long extensions at their leading edge. Examination of known targets of lithium showed that inositol monophosphatase inhibition had no effect on glioma migration, whereas inhibition of glycogen synthase kinase-3 (GSK-3) did. This suggested that the effects of lithium on glioma cell migration could possibly be mediated through GSK-3. Specific pharmacologic GSK-3 inhibitors and siRNA knockdown of GSK-3alpha or GSK-3beta isoforms both reduced cell motility. These data outline previously unidentified pathways and inhibitors that may be useful for the development of novel anti-invasive therapeutics for the treatment of brain tumors.
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Antineoplásicos/farmacologia , Neoplasias Encefálicas/enzimologia , Movimento Celular/efeitos dos fármacos , Glioma/enzimologia , Quinase 3 da Glicogênio Sintase/metabolismo , Cloreto de Lítio/farmacologia , Animais , Western Blotting , Neoplasias Encefálicas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Glioma/patologia , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Humanos , Camundongos , Invasividade Neoplásica/fisiopatologia , Neurônios/efeitos dos fármacos , Técnicas de Cultura de ÓrgãosRESUMO
High-grade primary brain tumors remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of these malignant tumors and identify oncogenic pathways that might be amenable to small-molecule and antibody 'targeted' therapy. Growth factor signaling pathways are often upregulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation include Raf, MEK, PI3K, Akt (protein kinase B), and mTOR (mammalian target of rapamycin). In addition, overactivity of VEGF and other effectors leads to neoplastic angiogenesis. 'Targeted' therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (eg, imatinib and erlotinib) and farnesyltransferase inhibitors (eg, tipifarnib). Molecular therapeutic small molecules specific to Raf, PI3K, and mTOR include sorafenib, LY-294002, and temsirolimus, respectively. 'Targeted' anti-angiogenesis approaches include mAbs to VEGF (eg, bevacizumab) and VEGF receptor tyrosine kinase inhibitors (eg, vatalanib and sunitinib). Further development of 'targeted' therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality-of-life for patients with malignant brain tumors.
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Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/química , Receptores ErbB/classificação , Receptores ErbB/efeitos dos fármacos , Previsões , Genes ras , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Estrutura Molecular , Neovascularização Patológica/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sirolimo/uso terapêutico , Resultado do TratamentoRESUMO
The focus of care for patients with brain metastases will always be on therapeutic options such as surgery, radiotherapy, and chemotherapy. However, proper symptom management and supportive care of non-therapeutic issues will be equally as important, including treatment of seizures, use of anticonvulsants, corticosteroids, and gastric acid inhibitors, assessment of swallowing dysfunction, treatment of thromboembolic events, appropriate use, and safe application of anticoagulation, and evaluation of psychiatric issues. Appropriate management of these supportive aspects of patient care will improve overall quality of life and allow the patient and family to more easily concentrate on treatment.
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Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Antineoplásicos/uso terapêutico , Humanos , Cuidados Paliativos , Qualidade de Vida , RadiocirurgiaRESUMO
Meningiomas are slow growing, extraaxial tumors that derive from the arachnoidal cap cells of the meninges. Resection remains the main modality of treatment and can be curative in some cases. External-beam radiotherapy and radiosurgery can benefit selected patients. The role of chemotherapy continues to be defined, but should be considered for patients with inoperable or frequently recurring meningiomas. Hydroxyurea, an inhibitor of ribonucleotide reductase, is one of the most active agents and is known to induce apoptosis in meningioma cells in vitro and in mouse xenografts. Results of preliminary clinical studies suggest that hydroxyurea has modest activity against recurrent and inoperable meningiomas, and can induce long term stabilization in some patients. However, the results are conflicting and a few clinical trials did not show positive results. Further clinical trials with larger patient cohorts and longer follow-up periods will be necessary to confirm the activity of hydroxyurea.
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Antineoplásicos/uso terapêutico , Hidroxiureia/uso terapêutico , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Antineoplásicos/farmacologia , Humanos , Hidroxiureia/farmacologia , Neoplasias Meníngeas/patologia , Meningioma/patologiaRESUMO
Brain tumors remain a significant cause of morbidity and mortality and are often refractory to treatment. Neuroimaging, in particular magnetic resonance imaging (MRI) and associated techniques, has become an important tool for the neuro-oncologist in the management of brain tumors. Magnetic resonance imaging is the most sensitive method to demonstrate the presence of a mass in the brain and can often narrow the differential diagnosis with nonneoplastic lesions such as cerebral abscess and subacute infarction. Once the diagnosis has been confirmed, MRI is essential for initial treatment planning, including surgical resection and radiation therapy. In selected patients, serial MRI will also be necessary to evaluate for response during adjuvant chemotherapy and to monitor for treatment-induced toxicity. New magnetic resonance techniques such as magnetic resonance spectroscopy, diffusion-weighted imaging, and perfusion-based imaging methods will also be discussed where applicable.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Procedimentos Neurocirúrgicos/tendências , Planejamento de Assistência ao Paciente , Abscesso Encefálico/diagnóstico , Neoplasias Encefálicas/classificação , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância MagnéticaRESUMO
BACKGROUND: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00589875.
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Neoplasias Encefálicas/tratamento farmacológico , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Glioma/tratamento farmacológico , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Aciclovir/efeitos adversos , Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Adenoviridae , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Neoplasias Encefálicas/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Vetores Genéticos/uso terapêutico , Glioma/cirurgia , Humanos , Pessoa de Meia-Idade , Simplexvirus/genética , Análise de Sobrevida , Timidina Quinase/genética , Resultado do Tratamento , Valaciclovir , Valina/efeitos adversos , Valina/análogos & derivados , Valina/uso terapêuticoRESUMO
PURPOSE: This phase III Eastern Cooperative Oncology Group-Southwest Oncology Group intergroup study was conducted to determine whether three 72-hour infusions of carmustine (BiCNU) and cisplatin administered monthly before external-beam radiotherapy would improve the survival of patients with newly diagnosed glioblastoma multiforme. The control arm consisted of radiation with standard adjuvant BiCNU. PATIENTS AND METHODS: A total of 223 patients were accrued from 1996 to 1999. Of these, 219 patients were eligible; 109 were randomly assigned to the experimental arm, and 110 were randomly assigned to the control arm. Randomization was stratified by age, performance status, and extent of resection. RESULTS: The median age of the patients was 55 years; 55% were male, 93% were white, 26% had a biopsy only, and 84% were ambulatory. Treatment arms were well balanced with respect to baseline characteristics. Median follow-up time of the 15 patients still alive at the time of analysis was 3.3 years (range, 2 to 5 years). Median survival times for the standard and experimental arms were 11.2 and 11.0 months (P =.33, two-sided log-rank test), and survival at 1 year was 45% versus 44%, respectively. Fifty-six percent of patients received all three cycles of BiCNU/cisplatin, 12% received two cycles, and 31% received only one cycle. Toxicity was primarily hematologic and was more common in the experimental arm (P <.01). CONCLUSION: This study demonstrates that 72-hour infusions of BiCNU and cisplatin followed by radiation do not improve median survival, survival at 1 year, or time to progression. Furthermore, this treatment requires more time in the hospital and is associated with more serious toxicities than standard therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Neoplasias Supratentoriais/tratamento farmacológico , Neoplasias Supratentoriais/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carmustina/administração & dosagem , Quimioterapia Adjuvante/efeitos adversos , Cisplatino/administração & dosagem , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Radioterapia Adjuvante/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
We used 8-T high-spatial-resolution gradient-echo MR imaging to directly visualize microvascularity in pathologically proved glioblastoma multiforme. Images were compared with 1.5-T high-spatial-resolution fast spin-echo T2-weighted images and digital subtraction angiograms. Preliminary data indicate that 8-T high-spatial-resolution MR imaging may enable the identification of areas of abnormal microvascularity in glioblastoma multiforme that are not visible with other routine clinical techniques.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Glioblastoma/irrigação sanguínea , Imageamento por Ressonância Magnética/métodos , Adulto , Angiografia Digital , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico , Glioblastoma/diagnóstico por imagem , Humanos , Masculino , Microcirculação/patologia , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/diagnóstico por imagemRESUMO
Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.