RESUMEN
PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Femenino , Temozolomida/uso terapéutico , Lomustina/uso terapéutico , Pronóstico , Dacarbazina/efectos adversos , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Antineoplásicos Alquilantes/efectos adversosRESUMEN
Glioblastoma (GB) is the most common primary brain tumor, which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Targeted local combination immunotherapy is a promising strategy to overcome these obstacles. Here, we evaluated tumor-cell specific delivery of an anti-PD-1 immunoadhesin (aPD-1) via a targeted adeno-associated viral vector (AAV) as well as HER2-specific NK-92/5.28.z (anti-HER2.CAR/NK-92) cells as components for a combination immunotherapy. In co-culture experiments, target-activated anti-HER2.CAR/NK-92 cells modified surrounding tumor cells and bystander immune cells by triggering the release of inflammatory cytokines and upregulation of PD-L1. Tumor cell-specific delivery of aPD-1 was achieved by displaying a HER2-specific designed ankyrin repeat protein (DARPin) on the AAV surface. HER2-AAV mediated gene transfer into GB cells correlated with HER2 expression levels, without inducing anti-viral responses in transduced cells. Furthermore, AAV-transduction did not interfere with anti-HER2.CAR/NK-92 cell-mediated tumor cell lysis. After selective transduction of HER2+ cells, aPD-1 expression was detected at the mRNA and protein level. The aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T cells by efficiently disrupting the PD-1/PD-L1 axis. Moreover, high intratumoral and low systemic aPD-1 concentrations were achieved following local injection of HER2-AAV into orthotopic tumor grafts in vivo. aPD-1 was selectively produced in tumor tissue and could be detected up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 and Tu2449-HER2 immunocompetent mouse models, administration of the combination therapy significantly prolonged survival, including complete tumor control in several animals in the GL261-HER2 model. In summary, local therapy with aPD-1 encoding HER2-AAVs in combination with anti-HER2.CAR/NK-92 cells may be a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce systemic side effects of immune-checkpoint inhibitors.
Asunto(s)
Glioblastoma , Adenoviridae/genética , Animales , Antígeno B7-H1/genética , Línea Celular Tumoral , Citocinas , Glioblastoma/genética , Glioblastoma/terapia , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/trasplante , Ratones , ARN Mensajero , Receptor ErbB-2/metabolismo , Terapias en Investigación , Microambiente TumoralRESUMEN
BACKGROUND AND PURPOSE: Preclinical evidence points toward a metabolic reprogramming in isocitrate dehydrogenase (IDH) mutated tumor cells with down-regulation of the expression of genes that encode for glycolytic metabolism. We noninvasively investigated lactate and Cr concentrations, as well as intracellular pH using 1H/phosphorus 31 (31P) MR spectroscopy in a cohort of patients with gliomas. MATERIALS AND METHODS: Thirty prospectively enrolled, mostly untreated patients with gliomas met the spectral quality criteria (World Health Organization II [n = 7], III [n = 16], IV [n = 7]; IDH-mutant [n = 23]; IDH wild-type [n = 7]; 1p/19q codeletion [n = 9]). MR imaging protocol included 3D 31P chemical shift imaging and 1H single-voxel spectroscopy (point-resolved spectroscopy sequence at TE = 30 ms and TE = 97 ms with optimized echo spacing for detection of 2-hydroxyglutarate) from the tumor area. Values for absolute metabolite concentrations were calculated (phantom replacement method). Intracellular pH was determined from 31P chemical shift imaging. RESULTS: At TE = 97 ms, lactate peaks can be fitted with little impact of lipid/macromolecule contamination. We found a significant difference in lactate concentrations, lactate/Cr ratios, and intracellular pH when comparing tumor voxels of patients with IDH-mutant with those of patients with IDH wild-type gliomas, with reduced lactate levels and near-normal intracellular pH in patients with IDH-mutant gliomas. We additionally found evidence for codependent effects of 1p/19q codeletion and IDH mutations with regard to lactate concentrations for World Health Organization tumor grades II and III, with lower lactate levels in patients exhibiting the codeletion. There was no statistical significance when comparing lactate concentrations between IDH-mutant World Health Organization II and III gliomas. CONCLUSIONS: We found indirect evidence for metabolic reprogramming in IDH-mutant tumors with significantly lower lactate concentrations compared with IDH wild-type tumors and a near-normal intracellular pH.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/genética , Glioma/metabolismo , Lactatos/análisis , Adulto , Anciano , Neoplasias Encefálicas/patología , Estudios de Cohortes , Femenino , Glioma/patología , Humanos , Concentración de Iones de Hidrógeno , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
Asunto(s)
Antígenos CD/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Genes MHC Clase II , Sialiltransferasas/metabolismo , Antígenos CD/genética , Biomarcadores de Tumor/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Estudios de Cohortes , Metilación de ADN , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Melanoma/metabolismo , Melanoma/patología , Pronóstico , Regiones Promotoras Genéticas , Sialiltransferasas/genética , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Glioma/diagnóstico , Glioma/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Adulto , Anciano , Astrocitoma/diagnóstico , Astrocitoma/metabolismo , Astrocitoma/patología , Astrocitoma/terapia , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Estudios de Seguimiento , Glioma/patología , Glioma/terapia , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Oligodendroglioma/diagnóstico , Oligodendroglioma/metabolismo , Oligodendroglioma/patología , Oligodendroglioma/terapia , Pronóstico , Estudios Prospectivos , Retratamiento , Análisis de Supervivencia , Factores de TiempoRESUMEN
The treatment of patients with intrinsic brain tumors is radically changing. This change is currently not (yet) signified by the use of targeted therapy in clinical practice but more by the definition of molecular markers as predictors for response to therapy which have been used for a long time. While in the past the choice of treatment has been based solely on the tumor entity and its degree of malignancy derived from histological analyses, large randomized trials have now provided a solid basis for personalized molecular-guided treatment decisions. For instance, in the German NOA-08 trial a benefit of chemotherapy with temozolomide alone was only demonstrated in a subgroup of elderly patients with malignant gliomas displaying promoter hypermethylation of the DNA repair enzyme MGMT. This is only one of several examples where molecular analysis of tumor tissue becomes clinically relevant as these analyses can and should be taken into account for treatment decisions and not, as previously, just as an additional parameter for estimating prognosis. This article illustrates the current developments in the area of personalized neurooncology and critically reviews the impact on clinical decision-making in daily practice.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Terapia Genética/métodos , Oncología Médica/métodos , Neurología/métodos , Patología Molecular/métodos , Medicina de Precisión/métodos , Neoplasias Encefálicas/genética , Marcación de Gen , HumanosRESUMEN
PAX2 is a paired box transcription factor possessing a fundamental role in the embryogenesis of hindbrain and urinary tract. PAX genes are proto-oncogenes, PAX2 expression may contribute to the pathogenesis of renal cell carcinoma. Because of the expression of PAX2 in the developing hindbrain and its essential role in cerebellar development, it has been hypothesized that PAX2 may also be involved in medulloblastoma tumorigenesis. We investigated the expression pattern of PAX2 and various genes of the neuronal lineage in medulloblastoma and glioma cell lines. We found high expression of PAX2 mRNA and PAX2 protein in medulloblastoma cells and some glioma cell lines independent of their neuronal lineage gene expression signature. Gene suppression of PAX2 decreased the expression of the PAX2 transcriptional target GDNF in Daoy cells and had a profound cytotoxic effect in vitro on Daoy medulloblastoma and T98G glioma cells. Expression of PAX2 was then assessed in two separate medulloblastoma tissue microarrays with a total of 61 patient samples by immunohistochemistry. PAX2 expression was detected in the majority of medulloblastoma samples and correlated with less differentiated histology. Therefore, PAX2 is a biomarker for a more aggressive medulloblastoma phenotype and may represent a novel therapeutic target.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Neoplasias Cerebelosas/metabolismo , Regulación Neoplásica de la Expresión Génica , Meduloblastoma/metabolismo , Factor de Transcripción PAX2/genética , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Meduloblastoma/genética , Meduloblastoma/patología , Ratones , Factor de Transcripción PAX2/metabolismo , Factor de Transcripción PAX5/metabolismo , Factor de Transcripción PAX8 , Factores de Transcripción Paired Box/metabolismo , Interferencia de ARN , Análisis de Matrices TisularesRESUMEN
P53 has an important role in the processing of starvation signals. P53-dependent molecular mediators of the Warburg effect reduce glucose consumption and promote mitochondrial function. We therefore hypothesized that the retention of wild-type p53 characteristic of primary glioblastomas limits metabolic demands induced by deregulated signal transduction in the presence of hypoxia and nutrient depletion. Here we report that short hairpin RNA-mediated gene suppression of wild-type p53 or ectopic expression of mutant temperature-sensitive dominant-negative p53(V135A) increased glucose consumption and lactate production, decreased oxygen consumption and enhanced hypoxia-induced cell death in p53 wild-type human glioblastoma cells. Similarly, genetic knockout of p53 in HCT116 colon carcinoma cells resulted in reduced respiration and hypersensitivity towards hypoxia-induced cell death. Further, wild-type p53 gene silencing reduced the expression of synthesis of cytochrome c oxidase 2 (SCO2), an effector necessary for respiratory chain function. An SCO2 transgene reverted the metabolic phenotype and restored resistance towards hypoxia in p53-depleted and p53 mutant glioma cells in a rotenone-sensitive manner, demonstrating that this effect was dependent on intact oxidative phosphorylation. Supplementation with methyl-pyruvate, a mitochondrial substrate, rescued p53 wild-type but not p53 mutant cells from hypoxic cell death, demonstrating a p53-mediated selective aptitude to metabolize mitochondrial substrates. Further, SCO2 gene silencing in p53 wild-type glioma cells sensitized these cells towards hypoxia. Finally, lentiviral gene suppression of SCO2 significantly enhanced tumor necrosis in a subcutaneous HCT116 xenograft tumor model, compatible with impaired energy metabolism in these cells. These findings demonstrate that glioma and colon cancer cells with p53 wild-type status can skew the Warburg effect and thereby reduce their vulnerability towards tumor hypoxia in an SCO2-dependent manner. Targeting SCO2 may therefore represent a valuable strategy to enhance sensitivity towards hypoxia and may complement strategies targeting glucose metabolism.
Asunto(s)
Apoptosis , Proteínas Portadoras/fisiología , Respiración de la Célula , Neoplasias del Colon/terapia , Glioma/terapia , Proteínas Mitocondriales/fisiología , Proteína p53 Supresora de Tumor/fisiología , Secuencia de Bases , Hipoxia de la Célula , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Glioma/metabolismo , Glioma/patología , Glucosa/metabolismo , Humanos , Chaperonas Moleculares , Datos de Secuencia Molecular , Necrosis , Proteína p53 Supresora de Tumor/antagonistas & inhibidoresRESUMEN
After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Astrocitoma/secundario , Neoplasias Encefálicas/patología , Carboplatino/administración & dosificación , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Esquema de Medicación , Etopósido/administración & dosificación , Femenino , Glioma/secundario , Humanos , Ifosfamida/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Temozolomida , Insuficiencia del TratamientoRESUMEN
OBJECTIVE: Despite novel multimodal therapeutic approaches, the vast majority of glial tumors are not curable. Patients may search for complementary therapies in order to contribute to the fight against their disease or to relieve symptoms induced by their brain tumor. The extent of the use of complementary or alternative therapies, the patients' rationale behind it, and the cost of complementary therapy for gliomas are not known. We used a questionnaire and the database of the German Glioma Network to evaluate these questions. METHODS: A total of 621 questionnaires were available for evaluation from patients with glial tumors of WHO grades II to grade IV. The patients were recruited from 6 neuro-oncologic centers in Germany. Complementary therapy was defined as methods or compounds not used in routine clinical practice and not scientifically evaluated. RESULTS: Forty percent of the responding patients reported the use of complementary therapies. Significant differences between the group of complementary therapy users and nonusers were seen with respect to age (younger > older), gender (female > male), and education (high education level > low education level). The motivation for complementary therapy use was not driven by unsatisfactory clinical care by the neuro-oncologists, but by the wish to add something beneficial to the standard of care. CONCLUSIONS: In clinical practice, patients' use of complementary therapies may be largely overseen and underestimated. The major motivation is not distrust in conventional therapies. Neuro-oncologists should be aware of this phenomenon and encourage an open but critical dialogue with their patients.
Asunto(s)
Neoplasias Encefálicas/terapia , Encéfalo/patología , Terapias Complementarias/estadística & datos numéricos , Glioma/terapia , Factores de Edad , Anciano , Neoplasias Encefálicas/patología , Terapias Complementarias/métodos , Femenino , Alemania/epidemiología , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Observación , Índice de Severidad de la Enfermedad , Factores Sexuales , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Neurological complications of therapeutic procedures for brain tumors are increasingly being recognized. These encompass the classic types of central and peripheral neurotoxicity, such as radiotherapy-induced leukoencephalopathy and platinum-induced neuropathy. However, the advent of novel protocols and targeted therapeutics has expanded the spectrum of neurological complications. A problem of considerable importance is pseudoprogression after radiochemotherapy with temozolomide. Among the new targeted drugs complications of therapy with bevacizumab are the subject of intense discussion. In this review article the neurotoxic potential of intrathecal chemotherapy, kinase inhibitors, immunological strategies and local therapies are summarized. Knowledge about neurological complications of brain tumor therapy procedures is important for risk assessment and patient information.
Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Daño Encefálico Crónico/inducido químicamente , Daño Encefálico Crónico/diagnóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Encéfalo/efectos de los fármacos , Encéfalo/efectos de la radiación , Irradiación Craneana/efectos adversos , Traumatismos por Radiación/diagnóstico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/toxicidad , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/toxicidad , Anticuerpos Monoclonales Humanizados , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/toxicidad , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Bevacizumab , Neoplasias Encefálicas/mortalidad , Terapia Combinada , Supervivencia sin Enfermedad , Humanos , Inyecciones Espinales , Leucoencefalopatías/diagnóstico , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/toxicidad , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/efectos de la radiación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/toxicidadRESUMEN
Methotrexate (MTX)-associated myelopathy is a rare but serious subacute complication of MTX-based chemotherapy. We report the case of a woman with breast cancer and meningeal carcinomatosis who developed severe progressive myelopathy after four cycles of intrathecal MTX administration. We substituted high doses of the key metabolites of the methyl-transfer pathway: S-adenosylmethionine (SAM), 200 mg three times daily i.v.; folinate, 20 mg four times daily i.v.; cyanocobalamin, 100 microg once daily i.v.; and methionine, 5 g daily p.o. The patient's paraparesis improved rapidly thereafter, and magnetic resonance (MR) imaging showed resolution of the intramedullary lesions. Genetic analyses revealed homozygosity for the A allele of methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (p.E429A), whereas other genetic variants of folate/methionine metabolism associated with MTX neurotoxicity were not present. Substitution with multiple folate metabolites may be a promising strategy for the treatment of MTX-induced neurotoxicity.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Metionina/administración & dosificación , Metotrexato/efectos adversos , Enfermedades de la Médula Espinal/inducido químicamente , Enfermedades de la Médula Espinal/terapia , Complejo Vitamínico B/administración & dosificación , Neoplasias de la Mama/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Carcinomatosis Meníngea/tratamiento farmacológico , Carcinomatosis Meníngea/secundario , Persona de Mediana EdadRESUMEN
The authors performed a comprehensive analysis of the functional outcome of 10 patients who had survived 5 years from a diagnosis of glioblastoma. Neurologic deficits were mild in most patients, but neuropsychological testing demonstrated cognitive deficits in all patients. Depression and anxiety were common. Although most patients thought that their social functioning and work ability were impaired, little reduction in overall quality of life was perceived.
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Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/fisiopatología , Glioblastoma/complicaciones , Glioblastoma/fisiopatología , Sobrevivientes , Actividades Cotidianas , Adulto , Ansiedad/etiología , Neoplasias Encefálicas/psicología , Neoplasias Encefálicas/terapia , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Depresión/etiología , Femenino , Glioblastoma/psicología , Glioblastoma/terapia , Humanos , Relaciones Interpersonales , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/fisiopatología , Pruebas Neuropsicológicas , Calidad de Vida , Factores de Tiempo , TrabajoRESUMEN
Twenty-one patients with recurrent or progressive glioblastoma were enrolled in a prospective phase II trial to determine the safety and efficacy of a 1-week on/1-week off regimen of temozolomide administered at 150 mg/m2 on days 1 to 7 and days 15 to 21 of 28-day treatment cycles. Two patients achieved a partial response (10%), and 17 patients (81%) had stable disease. The median progression-free survival was 5 months. The progression-free survival at 6 months was 48%.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Dacarbazina/análogos & derivados , Dacarbazina/administración & dosificación , Glioblastoma/tratamiento farmacológico , Neoplasias Supratentoriales/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Terapia Combinada , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Estudios de Factibilidad , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Glioblastoma/radioterapia , Glioblastoma/cirugía , Enfermedades Hematológicas/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Terapia Recuperativa , Neoplasias Supratentoriales/radioterapia , Neoplasias Supratentoriales/cirugía , Análisis de Supervivencia , Temozolomida , Resultado del TratamientoRESUMEN
Hypoxia induces apoptosis in primary and transformed cells and in various tumor cell lines in vitro. In contrast, there is little apoptosis and predominant necrosis despite extensive hypoxia in human glioblastomas in vivo. We here characterize ultrastructural and biochemical features of cell death in LN-229, LN-18 and U87MG malignant glioma cells in a paradigm of hypoxia with partial glucose deprivation in vitro. Electron microscopic analysis of hypoxia-challenged glioma cells demonstrated early stages of apoptosis but predominant necrosis. ATP levels declined during hypoxia, but recovered with re-exposure to normoxic conditions unless hypoxia exceeded 8 h. Longer hypoxic exposure resulted in irreversible ATP depletion and delayed cell death. Hypoxia induced mitochondrial release of cytochrome c, but there was no cleavage of caspases 3, 7, 8 or 9, and no DNA fragmentation. Ectopic expression of BCL-XL conferred protection from hypoxia-induced cell death, whereas the overexpression of the antiapoptotic proteins X-linked-inhibitor-of-apoptosis-protein and cytokine response modifier-A had no effect. These findings suggest that glioma cells resist adverse effects of hypoxia until energy stores are depleted and then undergo necrosis rather than apoptosis because of energy deprivation.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Caspasas/metabolismo , Hipoxia de la Célula/fisiología , Metabolismo Energético/fisiología , Glioma/metabolismo , Mitocondrias/metabolismo , Adenosina Trifosfato/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/ultraestructura , Muerte Celular , Hipoxia de la Célula/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patología , Núcleo Celular/ultraestructura , Citocromos c/metabolismo , Citoplasma/metabolismo , Citoplasma/patología , Citoplasma/ultraestructura , Metabolismo Energético/efectos de los fármacos , Glioma/patología , Glioma/ultraestructura , Glucosa/deficiencia , Humanos , Factores Inmunológicos/metabolismo , Microscopía Electrónica , Necrosis , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Inanición/metabolismo , Células Tumorales Cultivadas , Proteína Inhibidora de la Apoptosis Ligada a X , Proteína bcl-XRESUMEN
The developmental control genes of the Pax family are essential for brain development. Several Pax genes are also involved in chromosomal translocations causing malignancies in humans, and Pax5 expression is deregulated in medulloblastomas. We have investigated whether Pax5 can induce tumors in the developing mouse brain. Primary mouse embryonic neuroectodermal cells were retrovirally transduced with mouse Pax5 and transplanted into the brain of syngeneic host mice. No tumors developed in 36 transplants after one year, and there were no alterations in the differentiation pattern of the neural transplants. We then generated transgenic mice expressing human Pax5 under control of the Engrailed-2 promoter, which is expressed in the cerebellar external granule cell layer and in medulloblastomas. Sustained expression was achieved in the cerebellum of transgenic animals throughout lifetime. Expression levels were similar to those observed in human medulloblastomas. Again, cerebellar morphogenesis was undisturbed, and no tumors arose. These results strongly argue against a dominant transforming activity of PAX5 in NEC and in cerebellar granule cell precursors of mice, and underline the restricted tissue-specificity of PAX5 related oncogenesis.
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Neoplasias Encefálicas/metabolismo , Encéfalo/embriología , Transformación Celular Neoplásica/metabolismo , Proteínas de Unión al ADN , Biosíntesis de Proteínas , Factores de Transcripción , Células 3T3 , Animales , Encéfalo/citología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , División Celular/fisiología , Transformación Celular Neoplásica/genética , Trasplante de Células , Cerebelo/metabolismo , Cerebelo/fisiología , Ectodermo/citología , Ectodermo/metabolismo , Ectodermo/fisiología , Proteínas del Ojo , Regulación del Desarrollo de la Expresión Génica , Vectores Genéticos/genética , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Factor de Transcripción PAX5 , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , Regiones Promotoras Genéticas/genética , Proteínas/genética , Proteínas Represoras , Retroviridae/genética , TransfecciónRESUMEN
BACKGROUND: Radio-gene therapy involves the delivery, to tumor cells, of a therapeutic transgene whose expression is controlled by irradiation. MATERIALS AND METHODS: Here, we sought to identify novel radio-inducible transcripts in U87MG human malignant glioma cells using suppression subtractive hybridization (SSH). RESULTS: Of 998 clones from a subtracted library of irradiated U87MG cells, 24 candidate clones were identified by dot blot and 3 clones were confirmed as having been induced by irradiation by Northern blot analysis. All three clones showed 99-100% homology to the cyclin-dependent kinase (cdk) inhibitor, p21(Waf/Cip1). A screening of 12 human malignant glioma cell lines revealed that irradiation increased p21 mRNA expression and p21 protein levels levels in all of the five cell lines retaining p53 wild-type activity in a p53 reporter assay, but in none of seven p53 reporter-negative cell lines. CONCLUSION: Irradiation induces p21 mRNA expression in a strictly p53-dependent manner and may only enhance the expression of a limited number of genes in glioma cells. We conclude that the identification of radio-inducible genomic sequences suitable for radio-gene therapy may turn out to be difficult.
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Ciclinas/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Terapia Genética/métodos , Glioma/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Glioma/terapia , Humanos , Hibridación de Ácido Nucleico , Células Tumorales CultivadasRESUMEN
Glial fibrillary acidic protein (GFAP)-v-src transgenic mice develop spontaneous gliomas with a high incidence of malignant progression. We characterize the first glial cell line derived from v-src transgenic mice, Tu-2449 in comparison with a virally induced murine glioma, SRB-10, and a spontaneous murine glioma, P497. Doubling times were lowest, as clonogenicity in soft agar was highest for Tu-2449, and to a lesser degree, Tu-2449 cells formed spheroids and showed migratory behaviour and invaded fetal rat brain aggregates. BCL-2 and BAX expression were lower in Tu-2449 and P497 than in SRB-10 cells. Only Tu-2449 cells accumulated p53 protein in response to genotoxic stress. Tu-2449 and SRB-10 cells that showed low CD95 expression were resistant to CD95 ligand (CD95L)-induced apoptosis unless coexposed to CD95L and inhibitors of RNA or protein synthesis. A chemosensitivity profile revealed Tu-2449 to be rather chemoresistant. Tu-2449 thus displays growth characteristics and patterns of resistance to apoptosis similar to those of other mouse and human glioma cell lines and may therefore become a valuable tool to evaluate new therapies for malignant gliomas in vitro and in vivo.
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Genes src/genética , Proteína Ácida Fibrilar de la Glía/genética , Glioma/metabolismo , Glioma/patología , Ratones Transgénicos/genética , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Camptotecina/farmacología , División Celular/genética , Movimiento Celular/genética , Resistencia a Antineoplásicos , Proteína Ligando Fas , Glicoproteínas de Membrana/farmacología , Ratones , Invasividad Neoplásica , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Ratas , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre , Proteína p53 Supresora de Tumor/biosíntesis , Proteína X Asociada a bcl-2 , Proteína bcl-X , Receptor fas/biosíntesisRESUMEN
To characterize the development of tissue damage following cryogenic injury to the mouse cortex, the time course of histopathological changes, transcriptional responses and DNA strand breaks following application of a liquid nitrogen-cooled probe to the surface of the parietal bone were assessed. Distinct phases of tissue damage were observed: after 30 min, there was demarcation of a core lesion followed by mainly necrotic cell death starting 2 h after injury. At 12 hours, progressive apoptotic death of scattered cells in the periphery of the core lesion was detected, resembling the penumbra observed in ischaemic stroke. In situ hybridization for c-fos revealed an absence of expression in the core region, suggesting early cessation of transcription. There was strong induction of c-fos in the penumbra 30 min after the lesion, which had spread over the ipsilateral hemisphere at 2 h, possibly caused by peri-infarction depolarization. At later time points, sustained expression of c-fos was observed in some cells in the penumbra. Since a role for c-fos has been postulated in the initiation or execution of apoptotic pathways, the susceptibility of c-fos deficient mice was explored (n=4) in this model. Cryoinjury-induced tissue injury was markedly attenuated in c-fos deficient mice. A model of the phases and mechanisms of cryogenic injury is proposed, which discriminates an early phase characterized by physical changes caused by hypothermia and their immediate consequences (i.e. transcriptional block), an intermediate phase where secondary changes lead to necrosis in the core region, and a final phase of delayed apoptotic cell death in the penumbra.
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Corteza Cerebral/patología , Frío/efectos adversos , Proteínas Proto-Oncogénicas c-fos/deficiencia , Animales , Apoptosis/genética , Muerte Celular , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Criocirugía/efectos adversos , Edema/etiología , Edema/patología , Femenino , Regulación de la Expresión Génica , Hemorragia/etiología , Hibridación in Situ , Etiquetado Corte-Fin in Situ , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Mutantes , Necrosis , Proteínas Proto-Oncogénicas c-fos/genética , Factores de TiempoRESUMEN
Mice lacking the epidermal growth factor receptor (EGFR) exhibit strain-dependent phenotypes ranging from placental to postnatal skin, lung and brain defects. After birth, all mutant mice develop a progressive neurodegeneration in the frontal cortex, olfactory bulb and thalamus, characterized by massive apoptosis and upregulation of c-fos. These defects occur in a strain-independent manner, since neither rescue of the placental phenotype by aggregation of diploid 129/Sv EGFR mutant and tetraploid wild-type embryos, nor promotion of lung maturation by transplacental dexamethasone administration alters the course of neurodegeneration. VEGF is not induced during the degenerative process, excluding hypoxia and ischemia as causes of cell death. A migratory disorder is detected in the hippocampus with nests of ectopic neurons, which are also apoptotic. Cerebral cortices from EGFR mutants contain lower numbers of GFAP positive astrocytes, which display reduced proliferation in vitro. Since EGFR is expressed in the affected cell-types, these results define a specific function for EGFR in the proliferation and/or differentiation of astrocytes and in the survival of postmitotic neurons.