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1.
Lancet Oncol ; 14(10): e396-406, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23993384

RESUMEN

Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.


Asunto(s)
Neoplasias Encefálicas/secundario , Ensayos Clínicos como Asunto , Neoplasias Encefálicas/terapia , Supervivencia sin Enfermedad , Humanos , Imagen por Resonancia Magnética
2.
Epilepsia ; 54(8): 1376-80, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23663063

RESUMEN

PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.


Asunto(s)
Trastornos de la Percepción/etiología , Complicaciones Posoperatorias/etiología , Radiocirugia/efectos adversos , Campos Visuales/fisiología , Relación Dosis-Respuesta en la Radiación , Electroencefalografía , Epilepsia del Lóbulo Temporal/complicaciones , Epilepsia del Lóbulo Temporal/cirugía , Estudios de Seguimiento , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Esclerosis/complicaciones , Esclerosis/patología , Estadísticas no Paramétricas , Grabación en Video , Pruebas del Campo Visual
3.
Nat Genet ; 32(3): 453-8, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12355068

RESUMEN

Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.


Asunto(s)
Alelos , Silenciador del Gen , Neoplasias/genética , Northern Blotting , Islas de CpG , Metilación de ADN , Regulación hacia Abajo , Eliminación de Gen , Técnicas Genéticas , Genoma Humano , Humanos , Repeticiones de Microsatélite/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfitos/farmacología , Regulación hacia Arriba
4.
J Neurooncol ; 106(1): 147-53, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21739168

RESUMEN

Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvß3 and αvß5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Venenos de Serpiente/uso terapéutico , Adulto , Anciano , Neoplasias Encefálicas/cirugía , Terapia Combinada , Supervivencia sin Enfermedad , Determinación de Punto Final , Femenino , Glioblastoma/cirugía , Humanos , Inmunoterapia , Integrinas/fisiología , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Recurrencia , Venenos de Serpiente/efectos adversos , Venenos de Serpiente/farmacocinética
5.
J Neurooncol ; 108(1): 133-9, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22350375

RESUMEN

The purpose of this study is to evaluate the roles of resection extent and adjuvant radiation in the treatment of craniopharyngiomas. We reviewed the records of 122 patients ages 11-52 years who received primary treatment for craniopharyngioma between 1980 and 2009 at the University of California, San Francisco (UCSF). Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were development of panhypopituitarism, diabetes insipidus (DI), and visual field defects. Of 122 patients, 30 (24%) were treated with gross total resection (GTR) without radiation therapy (RT), 3 (3%) with GTR + RT, 41 (33.6%) with subtotal resection (STR) without RT, and 48 (39.3%) with STR + RT. Median age at diagnosis was 30 years, with 46 patients 18 years or younger. Median follow-up for all patients was 56.4 months (interquartile range 18.9-144.2 months) and 47 months (interquartile range 12.3-121.8 months) for the 60 patients without progression. Fifty six patients progressed, 10 have died, 6 without progression. Median PFS was 61.1 months for all patients. PFS rate at 2 years was 61.5% (95% CI: 52.1-70.9). OS rate at 10 years was 91.1% (95% CI 84.3-97.9). There was no significant difference in PFS and OS between patients treated with GTR vs. STR + XRT (PFS; p = 0.544, OS; p = 0.735), but STR alone resulted in significantly shortened PFS compared to STR + RT or GTR (p < 0.001 for both). STR was associated with significantly shortened OS compared to STR + RT (p = 0.050) and trended to shorter OS compared to GTR (p = 0.066). GTR was associated with significantly greater risk of developing DI (56.3 vs. 13.3% with STR + XRT, p < 0.001) and panhypopituitarism (54.8 vs. 26.7% with STR + XRT, p = 0.014). In conclusion, for patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection.


Asunto(s)
Craneofaringioma/radioterapia , Craneofaringioma/cirugía , Neoplasias Hipofisarias/radioterapia , Neoplasias Hipofisarias/cirugía , Adolescente , Adulto , Niño , Terapia Combinada , Craneofaringioma/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/mortalidad , Radioterapia Adyuvante/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
6.
Ann Neurol ; 65(2): 167-75, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19243009

RESUMEN

OBJECTIVE: The safety, efficacy, and morbidity of radiosurgery (RS) must be established before it can be offered as an alternative to open surgery for unilateral mesial temporal lobe epilepsy. We report the 3-year outcomes of a multicenter, prospective pilot study of RS. METHODS: RS was randomized to 20 or 24Gy targeting the amygdala, hippocampus, and parahippocampal gyrus. Seizure diaries evaluated the final seizure remission between months 24 and 36. Verbal memory was evaluated at baseline and 24m with the Wechsler Memory Scale-Revised (WMS-R) and California Verbal Learning Test (CVLT). Patients were classified as having "significant improvement," "no change," and "significant impairment" based on relative change indices. RESULTS: Thirteen high-dose and 17 low-dose patients were treated. Both groups showed significant reductions in seizures by 1 year after treatment. At the 36-month follow-up evaluation, 67% of patients were free of seizures for the prior 12 months (high dose: 10/13, 76.9%; low dose: 10/17, 58.8%). Use of steroids, headaches, and visual field defects did not differ by dose or seizure remission. The prevalence of verbal memory impairment was 15% (4/26 patients); none declined on more than one measure. The prevalence of significant verbal memory improvements was 12% (3/26). INTERPRETATION: RS for unilateral mesial temporal lobe epilepsy offers seizure remission rates comparable with those reported previously for open surgery. There were no major safety concerns with high-dose RS compared with low-dose RS. Additional research is required to determine whether RS may be a treatment option for some patients with mesial temporal lobe epilepsy.


Asunto(s)
Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/cirugía , Memoria/fisiología , Radiocirugia/métodos , Aprendizaje Verbal/fisiología , Adulto , Relación Dosis-Respuesta en la Radiación , Femenino , Cefalea/etiología , Humanos , Masculino , Pruebas Neuropsicológicas , Proyectos Piloto , Estudios Prospectivos , Radiocirugia/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Campos Visuales
7.
J Neurooncol ; 97(1): 33-40, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19705067

RESUMEN

Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway. Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 5'-promoter region of PTEN using methylation-specific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma.


Asunto(s)
Neoplasias Encefálicas/mortalidad , Glioma/mortalidad , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Adulto , Neoplasias Encefálicas/tratamiento farmacológico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/tratamiento farmacológico , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Estadísticas no Paramétricas , Sulfitos/farmacología , Sulfitos/uso terapéutico , Serina-Treonina Quinasas TOR , Adulto Joven
8.
J Neurooncol ; 96(2): 211-7, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19562255

RESUMEN

There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29-81) and median Karnofsky performance status (KPS) score 90 (range 60-100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.


Asunto(s)
Neoplasias Meníngeas/tratamiento farmacológico , Meningioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Clorhidrato de Erlotinib , Femenino , Estudios de Seguimiento , Gefitinib , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Tomografía Computarizada por Rayos X
9.
Neurooncol Adv ; 2(1): vdaa124, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33235994

RESUMEN

BACKGROUND: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs. METHODS: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6). RESULTS: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated. CONCLUSION: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.

10.
Neuro Oncol ; 11(1): 59-68, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18713953

RESUMEN

The purpose of this study was to describe the quality of life (QOL) of low-grade glioma (LGG) patients at baseline prior to chemotherapy and through 12 cycles of temozolomide (TMZ) chemotherapy. Patients with histologically confirmed LGG with only prior surgery were given TMZ for 12 cycles. QOL assessments by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) were obtained at baseline prior to chemotherapy and at 2-month intervals while receiving TMZ. Patients with LGG at baseline prior to chemotherapy had higher reported social well-being scores (mean difference = 5.0; p < 0.01) but had lower reported emotional well-being scores (mean difference = 2.2; p < 0.01) compared to a normal population. Compared to patients with left hemisphere tumors, patients with right hemisphere tumors reported higher physical well-being scores (p = 0.01): 44% could not drive, 26% did not feel independent, and 26% were afraid of having a seizure. Difficulty with work was noted in 24%. Mean change scores at each chemotherapy cycle compared to baseline for all QOL subscales showed either no significant change or were significantly positive (p < 0.01). Patients with LGG on TMZ at baseline prior to chemotherapy reported QOL comparable to a normal population with the exception of social and emotional well-being, and those with right hemisphere tumors reported higher physical well-being scores compared to those with left hemisphere tumors. While remaining on therapy, LGG patients were able to maintain their QOL in all realms. LGG patients' QOL may be further improved by addressing their emotional well-being and their loss of independence in terms of driving or working.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Oligodendroglioma/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Calidad de Vida , Adulto , Anciano , Astrocitoma/patología , Astrocitoma/psicología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/psicología , Dacarbazina/uso terapéutico , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oligodendroglioma/patología , Oligodendroglioma/psicología , Pronóstico , Estudios Prospectivos , Perfil de Impacto de Enfermedad , Temozolomida , Resultado del Tratamiento , Adulto Joven
11.
NMR Biomed ; 22(4): 449-55, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19125391

RESUMEN

Distinguishing between low-grade oligodendrogliomas (ODs) and astrocytomas (AC) is of interest for defining prognosis and stratifying patients to specific treatment regimens. The purpose of this study was to determine if the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion imaging can help to differentiate between newly diagnosed grade II OD and AC subtypes and to evaluate the ADC and FA values for the mixed population of oligoastrocytomas (OA). Fifty-three patients with newly diagnosed grade II gliomas were studied using a 1.5T whole body scanner (23 ODs, 16 ACs, and 14 OAs). The imaging protocol included post-gadolinium T1-weighted images, T2-weighted images, and either three and/or six directional diffusion imaging sequence with b = 1000 s/mm(2). Diffusion-weighted images were analyzed using in-house software to calculate maps of ADC and for six directional acquisitions, FA. The intensity values were normalized by values from normal appearing white matter (NAWM) to generate maps of normalized apparent diffusion coefficient (nADC) and normalized fractional anisotropy (nFA). The hyperintense region in the T2 weighted image was defined as the T2All region. A Mann-Whitney rank-sum test was performed on the 25th, median, and 75th nADC and nFA among the three subtypes. Logistic regression was performed to determine how well the nADC and nFA predict subtype. Lesions diagnosed as being OD had significantly lower nADC and significantly higher nFA, compared to AC. The nADC and nFA values individually classified the data with an accuracy of 87%. Combining the two did not enhance the classification. The patients with OA had nADC and nFA values between those of OD and AC. This suggests that ADC and FA may be helpful in directing tissue sampling to the most appropriate regions for taking biopsies in order to make a definitive diagnosis.


Asunto(s)
Imagen de Difusión por Resonancia Magnética , Glioma/diagnóstico , Adulto , Anciano , Anisotropía , Femenino , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad
12.
J Neurooncol ; 93(1): 151-6, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19430892

RESUMEN

Patients with brain tumors including intracranial meningiomas are at increased risk for developing deep vein thrombosis (DVTs) and suffering thromboembolic events (VTEs). Many surgeons are concerned that early use of low dose enoxaparin may increase the risk of intracranial hemorrhage which outweighs the benefit of DVT/VTE reduction. We aimed to address concerns around the use of enoxaparin after meningioma resection in the development of postoperative intracranial hemorrhages and DVT/VTEs. This is a retrospective review of 86 patients with intracranial meningiomas who underwent craniectomy and surgical resection of the mass, treated by one attending surgeon at UCSF Medical Center between 2000 and 2005. Within 48 h after surgery patients treated 2003-2005 routinely received enoxaparin therapy unless there was documented intracranial hemorrhage, lumbar subarachnoid drain, enoxaparin hypersensitivity, or thrombocytopenia (n = 24). These were compared to a cohort treated 2000-2002 who did not receive the drug (n = 62). Exclusion criteria were prior VTEs or coagulopathies. The groups were similar in tumor and surgical characteristics. Enoxaparin therapy did not increase the incidence of intracranial hemorrhage following surgical meningioma resection and the incidence of DVTs/VTEs was 0% (n = 0) versus 4.8% (n = 3) in the non-enoxaparin group. Results did not reach statistical significance. In this retrospective study, postoperative administration of enoxaparin following meningioma resection does not increase the risk of intracranial hematoma though enoxaparin administration may slightly decrease the incidence of post-surgical thromboembolic events. Due to study design and power, we were not able to demonstrate DVT/VTE reduction with statistical significance.


Asunto(s)
Anticoagulantes/uso terapéutico , Enoxaparina/uso terapéutico , Neoplasias Meníngeas/complicaciones , Meningioma/complicaciones , Complicaciones Posoperatorias/prevención & control , Trombosis/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Femenino , Humanos , Incidencia , Hemorragias Intracraneales/epidemiología , Masculino , Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos , Estudios Retrospectivos , Trombosis/etiología
13.
J Neurooncol ; 93(3): 349-54, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19169651

RESUMEN

Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Neoplasias Encefálicas/complicaciones , Glioma/complicaciones , Fenitoína/uso terapéutico , Piracetam/análogos & derivados , Convulsiones/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/cirugía , Craneotomía/efectos adversos , Femenino , Glioma/cirugía , Humanos , Levetiracetam , Masculino , Persona de Mediana Edad , Proyectos Piloto , Piracetam/uso terapéutico , Convulsiones/etiología
14.
J Neurooncol ; 91(3): 337-51, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19009235

RESUMEN

Glioblastoma Multiforme (GBM) are heterogeneous lesions, both in terms of their appearance on anatomic images and their response to therapy. The goal of this study was to evaluate the prognostic value of parameters derived from physiological and metabolic images of these lesions. Fifty-six patients with GBM were scanned immediately before surgical resection using conventional anatomical MR imaging and, where possible, perfusion-weighted imaging, diffusion-weighted imaging, and proton MR spectroscopic imaging. The median survival time was 517 days, with 15 patients censored. Absolute anatomic lesion volumes were not associated with survival but patients for whom the combined volume of contrast enhancement and necrosis was a large percentage of the T2 hyperintense lesion had relatively poor survival. Other volumetric parameters linked with less favorable survival were the volume of the region with elevated choline to N-acetylaspartate index (CNI) and the volume within the T2 lesion that had apparent diffusion coefficient (ADC) less than 1.5 times that in white matter. Intensity parameters associated with survival were the maximum and the sum of levels of lactate and of lipid within the CNI lesion, as well as the magnitude of the 10th percentile of the normalized ADC within the contrast-enhancing lesion. Patients whose imaging parameters indicating that lesions with a relatively large percentage with breakdown of the blood brain barrier or necrosis, large regions with abnormal metabolism or areas with restricted diffusion have relatively poor survival. These parameters may provide useful information for predicting outcome and for the stratification of patients into high or low risk groups for clinical trials.


Asunto(s)
Glioblastoma/metabolismo , Glioblastoma/patología , Imagen por Resonancia Magnética , Adulto , Anciano , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Mapeo Encefálico , Neoplasias Encefálicas , Colina/metabolismo , Creatina/metabolismo , Diagnóstico Diferencial , Imagen de Difusión por Resonancia Magnética , Femenino , Glioblastoma/diagnóstico por imagen , Glioblastoma/mortalidad , Humanos , Aumento de la Imagen , Procesamiento de Imagen Asistido por Computador , Estimación de Kaplan-Meier , Ácido Láctico/metabolismo , Lípidos/análisis , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Protones , Cintigrafía , Estudios Retrospectivos
15.
Neuro Oncol ; 10(2): 112-20, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18287341

RESUMEN

The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-->P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 microl drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Glioma/tratamiento farmacológico , Oligonucleótidos/administración & dosificación , Telomerasa/antagonistas & inhibidores , Administración Intranasal , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratas , Ratas Desnudas , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Neuro Oncol ; 10(2): 162-70, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18356283

RESUMEN

The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Glioma/tratamiento farmacológico , Glioma/mortalidad , Adulto , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
17.
Neuro Oncol ; 10(4): 631-42, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18559968

RESUMEN

The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.


Asunto(s)
Neoplasias Encefálicas/terapia , Ensayos Clínicos Fase I como Asunto/normas , Ensayos Clínicos Fase II como Asunto/normas , Proyectos de Investigación/normas , Humanos
18.
Radiat Res ; 169(6): 626-32, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18494546

RESUMEN

Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. In the central nervous system (CNS), loss of critical cellular components may lead to performance decrements that could ultimately compromise mission goals and long-term quality of life. Hippocampal-dependent cognitive impairments occur after exposure to ionizing radiation, and while the pathogenesis of this effect is not yet clear, it may involve the production of newly born neurons (neurogenesis) in the hippocampal dentate gyrus. We irradiated mice with 0.5-4 Gy of (56)Fe ions and 2 months later quantified neurogenesis and numbers of activated microglia as a measure of neuroinflammation in the dentate gyrus. Results showed that there were few changes after 0.5 Gy, but that there was a dose-related decrease in hippocampal neurogenesis and a dose-related increase in numbers of newly born activated microglia from 0.5-4.0 Gy. While those findings were similar to what was reported after X irradiation, there were also some differences, particularly in the response of newly born glia. Overall, this study showed that hippocampal neurogenesis was sensitive to relatively low doses of (56)Fe particles, and that those effects were associated with neuroinflammation. Whether these changes will result in functional impairments or if/how they can be managed are topics for further investigation.


Asunto(s)
Encéfalo/patología , Hipocampo/metabolismo , Hierro/química , Animales , Encéfalo/metabolismo , Encéfalo/efectos de la radiación , Sistema Nervioso Central/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Hipocampo/efectos de la radiación , Inflamación , Iones , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/efectos de la radiación , Neuronas/metabolismo , Fenotipo , Rayos X
19.
J Neurosurg ; 108(4): 736-45, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18377253

RESUMEN

OBJECT: Long-term outcomes following surgery for nonfunctional pituitary adenomas (NFPAs) are unclear. The role of adjuvant radiation therapy is therefore controversial because it is associated with higher tumor control but also carries known long-term morbidity. The authors' aim was to determine predictors of recurrence and overall survival and to define patient subgroups that may benefit from radiotherapy. METHODS: The authors performed a retrospective cohort analysis of 663 patients who underwent surgery between 1975 and 1995 for treatment of primary NFPAs. The main outcome measures were disease progression after surgery, defined by clinical and/or imaging criteria, and all-cause mortality. RESULTS: Over a median clinical follow-up of 8.4 years, there were 64 (9.7%) recurrences after treatment, with a median time to recurrence of 5.6 years. The 5-, 10-, and 15-year recurrence-free probabilities were 0.93, 0.87, and 0.81, respectively. Multivariate Cox proportional hazard regression analysis identified the following predictors as associated with increased recurrence: cavernous sinus invasion (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.5-6.4; p < 0.001) and subtotal resection (STR) without radiotherapy (HR 3.6, 95% CI 1.4-14; p = 0.01). Using time-to-event estimates to adjust for differences in follow-up between groups, radiotherapy was found to reduce tumor recurrence in only those patients who received an STR (p < 0.001, log-rank test) but not gross-total resection (GTR; p = 0.63, log-rank test). Median follow-up for overall survival was 14.0 years. The 5-, 10-, 15- and 20-year overall survival estimates were 0.91, 0.81, 0.69, and 0.55, respectively. Within the study cohort and in age- and sex-adjusted comparison with the general US population, increased relative mortality was observed in patients who underwent radiotherapy or STR. CONCLUSIONS: Cavernous sinus invasion is an important prognostic variable for long-term control of NFPAs. Radiotherapy results in long-term tumor control for patients who undergo STR but does not affect recurrence rates and may increase the risk of death after GTR. Given the risks associated with radiotherapy, there is no role for its routine application in patients who have undergone GTR of their NFPA. In all patients, long-term monitoring is required.


Asunto(s)
Adenoma/radioterapia , Adenoma/cirugía , Recurrencia Local de Neoplasia/etiología , Neoplasias Hipofisarias/radioterapia , Neoplasias Hipofisarias/cirugía , Adenoma/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Terapia Combinada , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Hipofisarias/mortalidad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo
20.
J Neurosurg ; 108(2): 227-35, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18240916

RESUMEN

OBJECT: Seizures play an important role in the clinical presentation and postoperative quality of life of patients who undergo surgical resection of low-grade gliomas (LGGs). The aim of this study was to identify factors that influenced perioperative seizure characteristics and postoperative seizure control. METHODS: The authors performed a retrospective chart review of all cases involving adult patients who underwent initial surgery for LGGs at the University of California, San Francisco between 1997 and 2003. RESULTS: Three hundred and thirty-two cases were included for analysis; 269 (81%) of the 332 patients presented with >or=1 seizures (generalized alone, 33%; complex partial alone, 16%; simple partial alone, 22%; and combination, 29%). Cortical location and oligodendroglioma and oligoastrocytoma subtypes were significantly more likely to be associated with seizures compared with deeper midline locations and astrocytoma, respectively (p=0.017 and 0.001, respectively; multivariate analysis). Of the 269 patients with seizures, 132 (49%) had pharmacoresistant seizures before surgery. In these patients, seizures were more likely to be simple partial and to involve the temporal lobe, and the period from seizure onset to surgery was likely to have been longer (p=0.0005, 0.0089, and 0.006, respectively; multivariate analysis). For the cohort of patients that presented with seizures, 12-month outcome after surgery (Engel class) was as follows: seizure free (I), 67%; rare seizures (II), 17%; meaningful seizure improvement (III), 8%; and no improvement or worsening (IV), 9%. Poor seizure control was more common in patients with longer seizure history (p<0.001) and simple partial seizures (p=0.004). With respect to treatment-related variables, seizure control was far more likely to be achieved after gross-total resection than after subtotal resection/biopsy alone (odds ratio 16, 95% confidence interval 2.2-124, p=0.0064). Seizure recurrence after initial postoperative seizure control was associated with tumor progression (p=0.001). CONCLUSIONS: The majority of patients with LGG present with seizures; in approximately half of these patients, the seizures are pharmacoresistant before surgery. Postoperatively, >90% of these patients are seizure free or have meaningful improvement. A shorter history of seizures and gross-total resection appear to be associated with a favorable prognosis for seizure control.


Asunto(s)
Neoplasias Encefálicas/complicaciones , Glioma/complicaciones , Convulsiones/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/uso terapéutico , Neoplasias Encefálicas/cirugía , Estudios de Cohortes , Progresión de la Enfermedad , Epilepsias Parciales/etiología , Epilepsias Parciales/prevención & control , Epilepsia Parcial Compleja/etiología , Epilepsia Parcial Compleja/prevención & control , Femenino , Estudios de Seguimiento , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Oligodendroglioma/complicaciones , Oligodendroglioma/cirugía , Calidad de Vida , Recurrencia , Estudios Retrospectivos , Convulsiones/prevención & control , Lóbulo Temporal/patología , Factores de Tiempo , Resultado del Tratamiento
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