RESUMEN
PURPOSE: Despite initial treatment with surgical resection, radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) virtually always recurs. Surgery is sometimes recommended to treat recurrence. In this study, we sought to devise a preoperative scale that predicts survival after surgery for recurrent glioblastoma multiforme. PATIENTS AND METHODS: The preoperative clinical and radiographic data of 34 patients who underwent re-operation of recurrent GBM tumors were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression modeling. The factors associated with decreased postoperative survival (P < .05) were used to devise a prognostic scale which was validated with a separate cohort of 109 patients. RESULTS: The factors associated with poor postoperative survival were: tumor involvement of prespecified eloquent/critical brain regions (P = .021), Karnofsky performance status (KPS) < or = 80 (P = .030), and tumor volume > or = 50 cm(3) (P = .048). An additive scale (range, 0 to 3 points) comprised of these three variables distinguishes patients with good (0 points), intermediate (1 to 2 points), and poor (3 points) postoperative survival (median survival, 10.8, 4.5, and 1.0 months, respectively; P < .001). The scale identified three statistically distinct groups within the validation cohort as well (median survival, 9.2, 6.3, and 1.9 months, respectively; P < .001). CONCLUSION: We devised and validated a preoperative scale that identifies patients likely to have poor, intermediate, and good relative outcomes after surgical resection of a recurrent GBM tumor. Application of this simple scale may be useful in counseling patients regarding their treatment options and in designing clinical trials.
Asunto(s)
Glioblastoma/mortalidad , Glioblastoma/patología , Encuestas y Cuestionarios , Adulto , Anciano , Femenino , Glioblastoma/cirugía , Humanos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Reoperación , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Carga TumoralRESUMEN
We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and celecoxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O(6)-methylguanine-DNA methyltransferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29-78) and median KPS score was 90 (range, 70-100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2-8.0) and 4-month PFS was 63% (95% CI: 46%-75%). Median OS was 12.6 months (95% CI: 8.5-16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p=0.07) and PFS (p=0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Neoplasias Encefálicas/sangre , Celecoxib , Metilación de ADN/efectos de los fármacos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Endostatinas/sangre , Endostatinas/efectos de los fármacos , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Factor 2 de Crecimiento de Fibroblastos/efectos de los fármacos , Glioblastoma/sangre , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , O(6)-Metilguanina-ADN Metiltransferasa/genética , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genética , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Temozolomida , Talidomida/administración & dosificación , Talidomida/efectos adversos , Trombospondinas/sangre , Trombospondinas/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacosRESUMEN
We report a case of hypertrophic olivary degeneration due to cerebellar surgery for a low-grade tumor. A 27-year-old female presented with right-sided paresthesias and intermittent leg paresis following a right cerebellar resection of a tumor 2 weeks prior. One month later, her symptoms remained stable while her neurological examination demonstrated slight right hemi-body hypoesthesia and subtle appendicular ataxia in her right upper extremity. An MRI scan revealed a hypertrophied left anterolateral medulla with increased T2 signal and no diffusion abnormality. The T2 hyperintensity and hypertrophy slowly resolved and she clinically improved without further intervention. Hypertrophic olivary degeneration may be mistaken for tumor progression, post-operative vasculopathy or granulation tissue and should be considered in patients undergoing cerebellar surgery.
Asunto(s)
Astrocitoma/cirugía , Neoplasias Cerebelosas/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Núcleo Olivar/patología , Adulto , Ataxia/etiología , Diagnóstico Diferencial , Femenino , Humanos , Hipertrofia , Hipoestesia/etiología , Imagen por Resonancia Magnética , Recurrencia Local de Neoplasia/patologíaRESUMEN
We present software engineering methods to provide free open-source software for MR-guided therapy. We report that graphical representation of the surgical tools, interconnectively with the tracking device, patient-to-image registration, and MRI-based thermal mapping are crucial components of MR-guided therapy in sharing such software. Software process includes a network-based distribution mechanism by multi-platform compiling tool CMake, CVS, quality assurance software DART. We developed six procedures in four separate clinical sites using proposed software engineering and process, and found the proposed method is feasible to facilitate multicenter clinical trial of MR-guided therapies. Our future studies include use of the software in non-MR-guided therapies.
Asunto(s)
Algoritmos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Lenguajes de Programación , Programas Informáticos , Cirugía Asistida por Computador/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/+ malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. METHODS: We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. RESULTS: Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [CI] = 0 to 90 months), 17 months (95% CI = 10.6 to 23.4 months), and 6 months (95% CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. CONCLUSIONS: Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.
Asunto(s)
Neoplasias Encefálicas/genética , Cromosomas Humanos Par 1 , Resistencia a Antineoplásicos , Glioma/genética , Compuestos de Nitrosourea/uso terapéutico , Oligodendroglioma/genética , Estatmina/genética , Antineoplásicos/uso terapéutico , Secuencia de Bases , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Mapeo Cromosómico , Cartilla de ADN , ADN de Neoplasias/genética , Electroforesis en Gel Bidimensional , Glioma/tratamiento farmacológico , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Oligodendroglioma/tratamiento farmacológico , ARN Neoplásico/genética , Estatmina/aislamiento & purificaciónRESUMEN
Preclinical evidence suggests that continuous low-dose daily (metronomic) chemotherapy may inhibit tumor endothelial cell proliferation (angiogenesis) and prevent tumor growth. This phase II study evaluated the feasibility of this antiangiogenic chemotherapy regimen in adults with recurrent malignant gliomas. The regimen consisted of low-dose etoposide (35 mg/m2 [maximum, 100 mg/day] daily for 21 days), alternating every 21 days with cyclophosphamide (2 mg/kg [maximum, 100 mg/day] daily for 21 days), in combination with daily thalidomide and celecoxib, in adult patients with recurrent malignant gliomas. Serum and urine samples were collected for measurement of angiogenic peptides. Forty-eight patients were enrolled (15 female, 33 male). Twenty-eight patients had glioblastoma multiforme (GBMs), and 20 had anaplastic gliomas (AGs). Median age was 53 years (range, 33-74 years), and median KPS was 70 (range, 60-100). Therapy was reasonably well tolerated in this heavily pretreated population. Two percent of patients had partial response, 9% had a minor response, 59% had stable disease, and 30% had progressive disease. For GBM patients, median progression-free survival (PFS) was 11 weeks, six-month PFS (6M-PFS) was 9%, and median overall survival (OS) was 21 weeks. For AG patients, median PFS was 14 weeks, 6M-PFS was 26%, and median OS was 41.5 weeks. In a limited subset of patients, serum and urine angiogenic peptides did not correlate with response or survival (p > 0.05). Although there were some responders, this four-drug, oral metronomic regimen did not significantly improve OS in this heavily pretreated group of patients who were generally not eligible for conventional protocols. While metronomic chemotherapy may not be useful in patients with advanced disease, further studies using metronomic chemotherapy combined with more potent antiangiogenic agents in patients with less advanced disease may be warranted.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Celecoxib , Ciclofosfamida/administración & dosificación , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Talidomida/administración & dosificaciónRESUMEN
Using brain proton magnetic resonance spectroscopic imaging (MRSI) in children with central nervous system (CNS) tumors, we tested the hypothesis that combining information from biologically important metabolites, at diagnosis and prior to treatment, would improve prediction of survival. We evaluated brain proton MRSI exams in 76 children (median age at diagnosis: 74 months) with brain tumors. Important biomarkers, choline-containing compounds (Cho), N-acetylaspartate (NAA), total creatine (tCr), lipids and/or lactate (L), were measured at the "highest Cho region" and normalized to the tCr of surrounding healthy tissue. Neuropathological grading was performed using World Health Organization (WHO) criteria. Fifty-eight of 76 (76%) patients were alive at the end of the study period. The mean survival time for all subjects was 52 months. Univariate analysis demonstrated that Cho, L, Cho/NAA and tumor grade differed significantly between survivors and non-survivors (P< or =0.05). Multiple logistic regression and stepwise multivariate Cox regression indicated that Cho + 0.1L was the only independent predictor of survival (likelihood ratio test = 10.27, P<0.001; Cox regression, P=0.004). The combined index Cho + 0.1L was more accurate and more specific predictor than Cho or Cho/NAA. Accuracy and specificity for Cho + 0.1L were 80% and 86%, respectively. We conclude that brain proton MRSI biomarkers predict survival of children with CNS tumors better than does standard histopathology. More accurate prediction using this non-invasive technique represents an important advance and may suggest more appropriate therapy, especially when diagnostic biopsy is not feasible.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias del Sistema Nervioso Central/mortalidad , Espectroscopía de Resonancia Magnética/métodos , Adolescente , Algoritmos , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Modelos de Riesgos Proporcionales , Protones , Análisis de Regresión , Resultado del TratamientoRESUMEN
OBJECTIVE: The purpose of the present study was to analyze the outcomes after craniotomies for brain metastases in a modern series using image-guided technologies either in the regular operating room or in the intraoperative magnetic resonance imaging unit. METHODS: Neurosurgical outcomes were analyzed for 49 patients who underwent 55 image-guided craniotomies for excision of brain metastases during a 5-year period. Tumors were located in critical and noncritical function regions of the brain. A total of 23 craniotomies for tumors in critical brain were performed using intravenous sedation anesthesia; craniotomies for noncritical function brain regions were completed under general anesthesia. The patients were also divided into Radiation Therapy Oncology Group recursive partitioning analysis (RPA) classes on the basis of age, Karnofsky Performance Scale scores, state of primary disease, and presence or absence of extracranial metastases. RESULTS: There was no perioperative mortality. Gross total resection, as verified by postoperative contrast-enhanced computed tomography or magnetic resonance imaging, was achieved in 96% of patients. The median anesthesia time was 4.25 hours, and the median length of hospital stay was 3 days. In 51 symptomatic cases, there was complete resolution of symptoms in 70% (n = 36), improvement in 14% (n = 7), and no change in 12% (n = 6) postoperatively. No patient who was neurologically intact preoperatively deteriorated after surgery, and 93% of patients maintained or improved their functional status. Only two patients (3.6%) with significant preoperative deficits had increased long-term deficits postoperatively. The mean follow-up was 1 year, and the local recurrence rate was 16%. The median survival of the entire group was 16.23 months (17.5 mo in RPA Class I, 22.9 mo in RPA Class II, and 9.8 mo in RPA Class III). CONCLUSION: Gross total resection of brain metastases, including those involving critical function areas, can be safely achieved with a low morbidity rate using contemporary image-guided systems. RPA Class I and II patients with controlled primary disease benefit from aggressive treatment by surgery and radiation.
RESUMEN
Glioblastoma is classified into two subtypes on the basis of clinical history: "primary glioblastoma" arising de novo without detectable antecedent disease and "secondary glioblastoma" evolving from a low-grade astrocytoma. Despite their distinctive clinical courses, they arrive at an indistinguishable clinical and pathologic end point highlighted by widespread invasion and resistance to therapy and, as such, are managed clinically as if they are one disease entity. Because the life history of a cancer cell is often reflected in the pattern of genomic alterations, we sought to determine whether primary and secondary glioblastomas evolve through similar or different molecular pathogenetic routes. Clinically annotated primary and secondary glioblastoma samples were subjected to high-resolution copy number analysis using oligonucleotide-based array comparative genomic hybridization. Unsupervised classification using genomic nonnegative matrix factorization methods identified three distinct genomic subclasses. Whereas one corresponded to clinically defined primary glioblastomas, the remaining two stratified secondary glioblastoma into two genetically distinct cohorts. Thus, this global genomic analysis showed wide-scale differences between primary and secondary glioblastomas that were previously unappreciated, and has shown for the first time that secondary glioblastoma is heterogeneous in its molecular pathogenesis. Consistent with these findings, analysis of regional recurrent copy number alterations revealed many more events unique to these subclasses than shared. The pathobiological significance of these shared and subtype-specific copy number alterations is reinforced by their frequent occurrence, resident genes with clear links to cancer, recurrence in diverse cancer types, and apparent association with clinical outcome. We conclude that glioblastoma is composed of at least three distinct molecular subtypes, including novel subgroups of secondary glioblastoma, which may benefit from different therapeutic strategies.
Asunto(s)
Astrocitoma/genética , Regulación Neoplásica de la Expresión Génica/genética , Genoma Humano/genética , Glioblastoma/genética , Astrocitoma/patología , Aberraciones Cromosómicas , Análisis por Conglomerados , Progresión de la Enfermedad , Eliminación de Gen , Perfilación de la Expresión Génica , Genómica/métodos , Glioblastoma/clasificación , Glioblastoma/patología , Humanos , Hibridación de Ácido Nucleico/métodos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
PURPOSE: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells. EXPERIMENTAL DESIGN: Using a panel of four primary human glioblastoma cell lines with heterogeneous O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide. RESULTS: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O(6)-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O(6)-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings. CONCLUSIONS: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O(6)-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.
Asunto(s)
Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Terapia Combinada , Daño del ADN , Dacarbazina/administración & dosificación , Dacarbazina/farmacología , Modelos Animales de Enfermedad , Guanina/administración & dosificación , Guanina/análogos & derivados , Guanina/farmacología , Humanos , Metilación , Ratones , Ratones Desnudos , O(6)-Metilguanina-ADN Metiltransferasa/efectos de los fármacos , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , O(6)-Metilguanina-ADN Metiltransferasa/efectos de la radiación , Relación Estructura-Actividad , Temozolomida , Trasplante Heterólogo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A major obstacle in the treatment of gliomas is the invasive capacity of the tumor cells. Previous studies have demonstrated the capability of neural stem cells (NSCs) to target these disseminated tumor cells and to serve as therapeutic delivery vehicles. Less is known about the factors involved in brain tumor tropism of NSCs and their interactions within the tumor environment. As gliomas progress and invade, an extensive modulation of the extracellular matrix (ECM) occurs. Tumor-ECM derived from six glioblastoma cell lines, ECM produced by normal human astrocytes and purified ECM compounds known to be upregulated in the glioma environment were analyzed for their effects on NSCs motility in vitro. We found that tumor-produced ECM was highly permissive for NSC migration. Laminin was the most permissive substrate for human NSC migration, and tenascin-C the strongest inducer of a directed human NSC migration (haptotaxis). A positive correlation between the degree of adhesion and migration of NSCs on different ECM compounds exists, as for glioma cells. Our in vitro data suggest that the ECM of malignant gliomas is a modulator of NSC migration. ECM proteins preferentially expressed in areas of glioma cell invasion may provide a permissive environment for NSC tropism to disseminated tumor cells.
Asunto(s)
Neoplasias Encefálicas/patología , Movimiento Celular/fisiología , Matriz Extracelular/metabolismo , Glioma/patología , Células Madre/citología , Tropismo/fisiología , Antígenos de Neoplasias , Factores Biológicos/metabolismo , Factores Biológicos/farmacología , Neoplasias Encefálicas/metabolismo , Adhesión Celular/fisiología , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiotaxis/fisiología , Medios de Cultivo Condicionados/farmacología , Matriz Extracelular/fisiología , Glioma/metabolismo , Humanos , Laminina/fisiología , Modelos Lineales , Invasividad Neoplásica , Proteínas del Tejido Nervioso , Antígeno Ventral Neuro-Oncológico , Neuronas/citología , Proteínas de Unión al ARN , Células Madre/efectos de los fármacosRESUMEN
OBJECTIVE: There are no currently accepted evidence-based guidelines for the diagnosis and management of the normal-pressure hydrocephalus (NPH) patient. As a result, an independent study group was assembled to address this issue and determine the feasibility of developing standardized guidelines, which would be acceptable in the United States and abroad and would be based on the available scientific evidence. The guidelines were to encompass value of clinical presentation, value of supplementary diagnostic tests, surgical management, and outcome assessment. METHODS: Initially, a series of 10 questions were formulated in the areas of pathophysiology, diagnosis, and treatment to obtain a consensus by panels of experts (see Acknowledgments) assembled in San Antonio, TX, in September 2000. This workshop provided significant insight into the difficulties in developing NPH guidelines, and a consensus was reached as to those questions involving expert opinion. Subsequently, evidentiary tables were developed on the basis of the available evidence. Only those studies with 20 or more idiopathic NPH (INPH) patients were included. RESULTS: Sensitivity, specificity, and positive and negative predictive values for INPH diagnostic criteria were assessed, and guidelines were developed on the basis of the available evidence. Recommendations for classification of INPH and additional studies were documented. CONCLUSION: The development of the guidelines was made difficult because systematic studies of INPH and patient numbers were few. It was decided to maintain the classification of NPH into two major categories, INPH and those of known cause (secondary NPH). Many studies "mixed" these classifications, and as a result, they could not be used in the evidentiary tables. Despite these problems, evidence-based guidelines were developed, and it is hoped that they will be useful in guiding clinical management of the INPH patient.
Asunto(s)
Hidrocéfalo Normotenso/diagnóstico , Hidrocéfalo Normotenso/terapia , Guías de Práctica Clínica como Asunto , Medicina Basada en la Evidencia , Humanos , Hidrocéfalo Normotenso/clasificación , Hidrocéfalo Normotenso/etiología , Terminología como AsuntoRESUMEN
OBJECTIVE: The precise incidence and prevalence of idiopathic normal-pressure hydrocephalus (INPH) is not known, and evidence-based clinical diagnostic criteria have not been developed previously. This report contains evidence-based guidelines for clinical diagnosis of INPH that are intended to facilitate future epidemiological studies of INPH, promote earlier and more accurate diagnosis, and ultimately improve treatment outcome. METHODS: The criteria for the diagnosis of INPH are based on evidence from the medical literature, supplemented as necessary by expert opinion. From 1966 to 2003, 653 publications on "normal-pressure hydrocephalus" were cited in MEDLINE, including 29 articles that met the more stringent criteria of including "idiopathic normal-pressure hydrocephalus" in their title. Additional studies were considered that explicitly identified INPH cases and/or specified the criteria for a diagnosis of INPH. Studies were graded according to the class of evidence and results summarized in evidentiary tables. For issues of clinical relevance that lacked substantive evidence from the medical literature, the opinions of consulting experts were considered and contributed to "Options." RESULTS: Evidence-based guidelines for the clinical diagnosis of INPH have been developed. A detailed understanding of the range of clinical manifestations of this disorder and adherence to practice guidelines should improve the timely and accurate recognition of this disorder. CONCLUSION: It is recommended that INPH be classified into probable, possible, and unlikely categories. We hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH.
Asunto(s)
Medicina Basada en la Evidencia , Hidrocéfalo Normotenso/diagnóstico , Síntomas Conductuales , Presión del Líquido Cefalorraquídeo , Derivaciones del Líquido Cefalorraquídeo , Trastornos del Conocimiento/etiología , Diagnóstico por Imagen , Humanos , Hidrocéfalo Normotenso/complicaciones , Hidrocéfalo Normotenso/psicología , Hidrocéfalo Normotenso/cirugía , Trastornos Mentales/etiología , Trastornos del Movimiento/etiologíaRESUMEN
OBJECTIVE: The diagnosis and management of idiopathic normal-pressure hydrocephalus (INPH) remains unclear. Moreover, the value of supplementary tests to predict which patients would benefit from placement of a shunt has not been established. This report develops evidence-based guidelines for the use of supplementary tests as an aid in prognosis. METHODS: MEDLINE searches from 1966 to the present were undertaken by use of the query NPH, normal-pressure hydrocephalus, lumbar drain, CSF [cerebrospinal fluid] tap test, and external CSF drainage in humans. This resulted in 242 articles. To provide a scientific, evidence-based review, we have chosen to restrict our analysis to clinically relevant studies usually consisting of large numbers of shunted NPH patients. Studies that did not specify INPH or secondary NPH were considered in a separate evidentiary table. RESULTS: Evidence-based guidelines for use in supplementary tests have been developed. A positive response to a 40- to 50-ml tap test has a higher degree of certainty for a favorable response to shunt placement than can be obtained by clinical examination. However, the tap test cannot be used as an exclusionary test because of its low sensitivity (26-61%). Determination of the CSF outflow resistance via an infusion test carries a higher sensitivity (57-100%) compared with the tap test and a similar positive predictive value of 75 to 92%. Prolonged external lumbar drainage in excess of 300 ml is associated with high sensitivity (50-100%) and high positive predictive value (80-100%). CONCLUSION: To date, a single standard for the prognostic evaluation of INPH patients is lacking. However, supplemental tests can increase predictive accuracy for prognosis to greater than 90%. Additional multicenter prospective randomized clinical trials are needed.
Asunto(s)
Derivaciones del Líquido Cefalorraquídeo , Hidrocéfalo Normotenso/diagnóstico , Hidrocéfalo Normotenso/cirugía , Cuidados Preoperatorios , Medicina Basada en la Evidencia , Humanos , Guías de Práctica Clínica como Asunto , Valor Predictivo de las Pruebas , PronósticoRESUMEN
OBJECTIVE: To develop evidence-based guidelines for surgical management of idiopathic normal-pressure hydrocephalus (INPH). Compared with the diagnostic phase, the surgical management of INPH has received less scientific attention. The quality of much of the literature concerning the surgical management has been limited by many factors. These include retrospective analysis, small patient numbers, analysis of a mixed NPH population, and sometimes a lack of detail as to what type of shunt system was used. Many earlier studies predated our current understanding of the hydrodynamics of cerebrospinal fluid shunts, and therefore, the conclusions drawn may no longer be valid. METHODS: A MEDLINE and PubMed search from 1966 to the present was conducted using the following key terms: normal-pressure hydrocephalus and idiopathic adult-onset hydrocephalus. Only English-language literature in peer-reviewed journals was reviewed. The search was further limited to articles that described the method of treatment and outcome selectively for INPH patients. Finally, only studies that included 20 or more INPH patients were considered with respect to formulating the recommendations in these Guidelines (27 articles). RESULTS: For practical reasons, it is important to identify probable shunt responders diagnosed with INPH. If the patient is an acceptable candidate for anesthesia, then an INPH-specific risk-benefit analysis should be determined. In general, patients exhibiting negligible symptoms may not be suitable candidates for surgical management, given the known risks and complications associated with shunting INPH. The choice of valve type and setting should be based on empirical reasoning and a basic understanding of shunt hydrodynamics. The most conservative choice is a valve incorporating an antisiphon device, with the understanding that underdrainage (despite a low opening pressure) may occur in a small percentage of patients because of the antisiphon device. On the basis of retrospective studies, the use of an adjustable valve seems to be beneficial in the management of INPH. CONCLUSION: The treatment of INPH should not be considered lightly, given the seriousness of the potential complications. Within these limitations and the available evidence, guidelines for surgical management were developed.
Asunto(s)
Derivaciones del Líquido Cefalorraquídeo , Hidrocéfalo Normotenso/cirugía , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Diseño de Equipo , Medicina Basada en la Evidencia , Humanos , Selección de Paciente , Guías de Práctica Clínica como Asunto , Medición de RiesgoRESUMEN
OBJECTIVE: To develop guidelines for assessing shunt outcome in patients with idiopathic normal-pressure hydrocephalus (INPH). To date, the literature available on this topic has been marked by disparate definitions of clinical improvement, varying postoperative follow-up protocols and periods, and substantial differences in the postoperative management. Because specific criteria for defining clinical improvement are seldom reported, conclusions drawn about shunt outcome may be subjective. METHODS: A MEDLINE search back to 1966 was undertaken using the query NPH, normal-pressure hydrocephalus, shunting, shunt treatment, shunt response, outcome, and clinical outcome. The criteria for selection were studies that included INPH from 1966 to the present in which the outcome of INPH was reported in patient groups of 20 or more. RESULTS: To date, there is no standard for outcome assessment of shunt treatment in INPH. The variable improvement rates reported are not only because of different criteria for selection of patients but also because of different postoperative assessment procedures and follow-up intervals. CONCLUSION: Studies that have established fixed protocols for follow-up have shown that short- and long-term periods after shunting are determined by many factors. Whereas short-term results were more likely to be influenced by shunt-associated risks, long-term results were independent of factors inherent to the shunt procedure and shunt complications, i.e., death and morbidity related to concomitant cerebrovascular and vascular diseases. Studies have shown that beyond 1 year after surgery, these factors definitely influence the clinical effect of shunting, making the 1-year postshunt period a potential determinant of the shunt outcome. Guidelines for outcome assessment were developed on the basis of the available evidence and consensus of expert opinion.
Asunto(s)
Derivaciones del Líquido Cefalorraquídeo , Hidrocéfalo Normotenso/cirugía , Evaluación de Resultado en la Atención de Salud/normas , Guías como Asunto , Humanos , Resultado del TratamientoRESUMEN
The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor-upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.
Asunto(s)
Neoplasias Encefálicas/patología , Neuronas/citología , Células Madre/citología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Trasplante de Células , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Ensayo de Inmunoadsorción Enzimática , Humanos , Microscopía Fluorescente , Neovascularización Patológica , Reacción en Cadena de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Porcinos , Tropismo , Venas Umbilicales/citología , Regulación hacia Arriba , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: This experimental study assessed the usefulness of a rat model of corneal angiogenesis for assessing the angiogenic activity of cerebrovascular malformations (CVMs) over time. It is the first investigation to have focused on dynamic quantification of angiogenesis related to CVMs (i.e., assessing changes over time as opposed to one point in time) and the first to have compared different CVMs and other tissues in this way. METHODS: The CVM specimens were from 15 randomly selected arteriovenous malformation (AVM) cases, 15 randomly selected cavernous malformation cases, and 2 venous angioma cases. All the samples came from surgical resections performed in the Marmara University Department of Neurosurgery and the Marmara University Institute of Neurological Sciences between January 1998 and January 2003. Glioblastoma multiforme tissues, normal adult brain tissues, and normal brain artery tissues were used as controls. Tissue from each specimen was implanted in one corneal micropocket in each cornea of a single rat, and the level of angiogenic activity in the cornea was graded (low, moderate, or high) at Days 1 through 9 after tissue implantation. Another set of rats was subjected to the same corneal implantation procedure, and two widely accepted indicators of neovascularization, microvessel counts and vascular endothelial growth factor expression, were assessed at Days 3, 5, 7, and 9 after surgery. The tissue-group results for grade of angiogenic activity, microvessel count, and grade of vascular endothelial growth factor expression were compared. RESULTS: Of the three CVM types, the AVMs showed the highest angiogenic activity, cavernous malformations exhibited some degree of angiogenic activity (less than AVMs but more than normal brain artery tissue), and angiogenesis induction by venous angiomas was comparable to that of normal brain artery tissue. Corneas implanted with the AVM samples showed Grade 1 angiogenesis on Day 2, Grade 2 angiogenesis on Day 4, and Grade 2.5 angiogenesis on Day 8. Cavernous malformation samples caused Grade 1 angiogenesis after Day 5, and grading remained less than 1.5. Venous angioma samples resulted in angiogenesis graded less than 1. CONCLUSION: The results showed that this rat model of corneal angiogenesis is of value for assessing the angiogenic potential of CVMs and for evaluating details of the neovascularization process over time. Further investigation of CVMs with this model might yield information about how angiogenesis can be modulated, and this could lead to development of biological treatments that inhibit this process.
Asunto(s)
Malformaciones Arteriovenosas/fisiopatología , Neovascularización de la Córnea/complicaciones , Modelos Biológicos , Neovascularización Patológica , Adolescente , Adulto , Animales , Neovascularización de la Córnea/cirugía , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Distribución Aleatoria , Ratas , Estudios Retrospectivos , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PURPOSE: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases. EXPERIMENTAL DESIGN: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed. RESULTS: In vitro secretion of endostatin by 2.5 x 10(5) cells within 24 hours was 0.12 +/- 0.03 ng, 4.35 +/- 0.4, and 1.18 +/- 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 +/- 2.6 versus 13.3 +/- 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 x 10(5) wild-type cells killed the mice within 24 +/- 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals. CONCLUSION: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.
Asunto(s)
Neoplasias Encefálicas/secundario , Endostatinas/metabolismo , Melanoma/patología , Animales , Apoptosis , Línea Celular Tumoral , Endostatinas/genética , Femenino , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Antígeno Ki-67/análisis , Melanoma/genética , Melanoma/metabolismo , Ratones , Ratones Endogámicos , Trasplante de Neoplasias , Neovascularización Patológica/patología , TransfecciónRESUMEN
OBJECTIVE: This retrospective study examined whether changes in ventricular volume correspond with changes in adjustable valve pressure settings in a cohort of patients who received shunts to treat idiopathic normal pressure hydrocephalus. We also examined whether these pressure-volume curves and other patient variables would co-occur with a positive clinical response to shunting. METHODS: We selected 51 patients diagnosed with idiopathic normal pressure hydrocephalus who had undergone implantation of a Codman Hakim programmable valve (Medos S.A., Le Locle, Switzerland). Clinical data were gathered from the patients' records and clinical notes by an investigator blinded to patients' ventricular volumes. Ventricular volume was measured using 3D Slicer, an image analysis and interactive visualization software package developed and maintained at the Surgical Planning Laboratory at Brigham and Women's Hospital. RESULTS: Eighty-six percent of patients with gait disturbance at presentation showed improvement of this symptom, 70% experienced improvement in incontinence, and 69% experienced improvement in dementia. For the group showing 100% clinical improvement, the correlation coefficient of average changes in valve pressure over time (delta P/delta T) and average changes in ventricular volume over time (delta V/delta T) were high at 0.843 (P < 0.05). For the group experiencing no or only partial improvement, the correlation coefficient was 0.257 (P = 0.32), indicating no correlation between average delta V/delta T and average delta P/delta T for each patient. CONCLUSION: This was a carefully analyzed modeling study of idiopathic normal pressure hydrocephalus treatment made possible only by adjustable valve technology. With careful volumetric analysis, we found that changes in ventricular volume correlated with adjustments in valve pressure settings for those patients who improved clinically after shunting. This suggests that positive clinical responders retained parenchymal elasticity, emphasizing the importance of dynamic changes in this cohort.