Eficacia y seguridad de bevacizumab en eltratamiento del glioblastoma multiforme recurrente, irresecable y terapia previa con temozolamida / Efficacy and safety of bevacizumab in the treatment of recurrent, unresectable glioblastoma multiforme and previous therapy with temozolamide

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) ha recibido la solicitud de evaluar el uso de bevacizumab (BVZ) e irinotecan en pacientes adultos con diagnóstico de glioblastoma multiforme recurrente, irresecable que progresaron a temozolamida dentro del sistema de EsSalud, indicación actualmente no contemplada en el petitorio de medicamentos. Aspectos Generales: Los gliomas son el tipo más común de tumores cerebrales malignos. Ellos se desarrollan a partir de las células gliales que dan apoyo a las células nerviosas del cerebro y medula espinal. Existen cuatro tipos principales de gliomas: astrocitoma, ependimoma, oligliodendroglioma, y tumores mixtos. Los gliomas son clasificados de acuerdo a su 1.) potencial de proliferación ascendente, desde el grado 1 al grado 4. Los gliomas de grado 3 y 4 son conjuntamente referidos con glioblastomas, y son considerados como gliomas de alto grado. El glioma de grado 4 es llamado glioblastoma multiforme. Los síntomas del glioma de alto grado dependen del tamaño, la localización, y el grado de infiltración del tumor. Ellos incluyen dolor de cabeza, náuseas, vómitos, convulsiones, aIteración de la visión, problemas del lenguaje y cambios en las habilidades cognitivas o funcionales. Tecnología Sanitaria de Interés: Bevacizumab (Avastin, Roche) es un anticuerpo monoclonal anti-factor de crecimiento endotelial vascular (VEGF), que inhibe la inducción de la angiogénesis mediada por el VEGF. En consecuencia, se reduce la vascularización de los tumores, y también del crecimiento del mismo. METODOLOGIA: Estratégia de Busqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad del uso de BVZ en comparación con irinotecan, en el tratamiento del GBM con recurrencia o progresión, irresecable durante el tratamiento coadyuvante con TMZ, en las bases de \r\ndatos de MEDLINE, EMBASE, CENTRAL, DARE y TRIPDATABASE. Se hizo una búsqueda adicional en www.clinicaltrials.gov, para poder identificar ensayos clínicos aún en elaboración o que no hayan sido publicados. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales oncológicas y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC).\r\nRESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica que sustente el uso de BVZ en comparación con irinotecan, en el tratamiento del GBM con recurrencia o progresión, irresecable durante el tratamiento adyuvante con TMZ según la pregunta PICO. Para el \r\npresente documento se seleccionó el siguiente cuerpo de evidencia que es resumido a continuación.Guías Clínicas: Se identificaron cuatro GPC sobre el manejo del glioblastoma recurrente. Evaluaciones de tecnología sanitaria: no se identificaron documentos de ETS para el uso de bevacizumab en el GBM recurrente. Se identificó una evaluación planeada por NICE, la cual fue retirada después de conocer la decisión de la EMA de no aprobar el uso de BVZ para la indicación de GBM recurrente. Revisiones sistemáticas: no se identificó alguna revisión sistemática que haya evaluado el uso de BVZ en comparación con el de irinotecan en pacientes con GBM recurrente. Ensayos clínicos: no se identificó algún ensayo que haya comparado el uso de BVZ con el tratamiento con irinotecan. En su lugar, se identificaron y se han incluido en esta evaluación tres ensayos. Uno de fase II no comparativo que usó BVZ, y otros dos estudios \r\nde fase II aleatorizados que compararon los efectos de BVZ con el régimen de BVZ + irinotecan. Este tipo de evidencia es considerada como indirecta por no responder directamente a la pregunta PICO de esta evaluación. Ensayos Clínicos registrados: no se identificaron ensayos en progreso o aun sin publicar que puedan agregar información a la pregunta PICO de esta evaluación. CONCLUSIONES: Hasta el momento, no se ha identificado evidencia directa para responder si el uso de BVZ es más efectivo y seguro que irinotecan en el tratamiento de los pacientes con GBM recurrente, irresecable y que progresó con el uso de TMZ. Hasta la fecha no se ha identificado algún estudio que haya comparado directamente ambos medicamentos.

Prediction of Response to Concurrent Chemoradiotherapy with Temozolomide in Glioblastoma: Application of Immediate Post-Operative Dynamic Susceptibility Contrast and Diffusion-Weighted MR Imaging

OBJECTIVE: To determine whether histogram values of the normalized apparent diffusion coefficient (nADC) and normalized cerebral blood volume (nCBV) maps obtained in contrast-enhancing lesions detected on immediate post-operative MR imaging can be used to predict the patient response to concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ). MATERIALS AND METHODS: Twenty-four patients with GBM who had shown measurable contrast enhancement on immediate post-operative MR imaging and had subsequently undergone CCRT with TMZ were retrospectively analyzed. The corresponding histogram parameters of nCBV and nADC maps for measurable contrast-enhancing lesions were calculated. Patient groups with progression (n = 11) and non-progression (n = 13) at one year after the operation were identified, and the histogram parameters were compared between the two groups. Receiver operating characteristic (ROC) analysis was used to determine the best cutoff value for predicting progression. Progression-free survival (PFS) was determined with the Kaplan-Meier method and the log-rank test. RESULTS: The 99th percentile of the cumulative nCBV histogram (nCBV C99) on immediate post-operative MR imaging was a significant predictor of one-year progression (p = 0.033). ROC analysis showed that the best cutoff value for predicting progression after CCRT was 5.537 (sensitivity and specificity were 72.7% and 76.9%, respectively). The patients with an nCBV C99 of < 5.537 had a significantly longer PFS than those with an nCBV C99 of ≥ 5.537 (p = 0.026). CONCLUSION: The nCBV C99 from the cumulative histogram analysis of the nCBV from immediate post-operative MR imaging may be feasible for predicting glioblastoma response to CCRT with TMZ.

Kaurene diterpene induces apoptosis in U87 human malignant glioblastoma cells by suppression of anti-apoptotic signals and activation of cysteine proteases

Gliomas are the most common and malignant primary brain tumors in humans. Studies have shown that classes of kaurene diterpene have anti-tumor activity related to their ability to induce apoptosis. We investigated the response of the human glioblastoma cell line U87 to treatment with ent-kaur-16-en-19-oic acid (kaurenoic acid, KA). We analyzed cell survival and the induction of apoptosis using flow cytometry and annexin V staining. Additionally, the expression of anti-apoptotic (c-FLIP and miR-21) and apoptotic (Fas, caspase-3 and caspase-8) genes was analyzed by relative quantification (real-time PCR) of mRNA levels in U87 cells that were either untreated or treated with KA (30, 50, or 70 µM) for 24, 48, and 72 h. U87 cells treated with KA demonstrated reduced viability, and an increase in annexin V- and annexin V/PI-positive cells was observed. The percentage of apoptotic cells was 9% for control cells, 26% for cells submitted to 48 h of treatment with 50 µM KA, and 31% for cells submitted to 48 h of treatment with 70 µM KA. Similarly, in U87 cells treated with KA for 48 h, we observed an increase in the expression of apoptotic genes (caspase-8, -3) and a decrease in the expression of anti-apoptotic genes (miR-21 and c-FLIP). KA possesses several interesting properties and induces apoptosis through a unique mechanism. Further experiments will be necessary to determine if KA may be used as a lead compound for the development of new chemotherapeutic drugs for the treatment of primary brain tumors.

Temozolomide-Associated Bronchiolitis Obliterans Organizing Pneumonia Successfully Treated with High-Dose Corticosteroid

Temozolomide is an oral alkylating agent with clinical activity against glioblastoma multiforme (GM). It is generally well-tolerated and has few pulmonary side effects. We report a case of temozolomide-associated brochiolitis obliterans organizing pneumonia (BOOP) requiring very high-dose corticosteroid treatment. A 56-yr-old woman presented with a 2-week history of exertional dyspnea. For the treatment of GM diagnosed 4 months previously, she had undergone surgery followed by chemoradiotherapy, and then planned adjuvant chemotherapy with temozolomide. After the 1st cycle, progressive dyspnea was gradually developed. Chest radiograph showed diffuse patchy peribronchovascular ground-glass opacities in both lungs. Conventional dose of methylprednisolone (1 mg/kg/day) was begun for the possibility of BOOP. Although transbronchial lung biopsy findings were compatible with BOOP, the patient's clinical course was more aggravated until hospital day 5. After the dose of methylprednisolone was increased (500 mg/day for 5 days) radiologic findings were improved dramatically.

Glioblastoma multiforme y estudio de la resistencia a la quimioterapia mediada por transportadores ABC / Study of resistance to chemotherapy mediated by ABC transporters in biopsies of glioblastoma multiforme

Background: Mortality rate is dramatically high in high grade brain tumors. The presence of multiple drug resistance transporters in glioblastoma multiforme, has contributed largely to the poor effcacy of targeted therapy against cancer in the central nervous system. Aim: To analyze the percentage of survival and mortality of patients with glioblastoma multiforme in a cohort of patients in Chile and to co-rrelate the chemo-resistance of these cells with the expression level of multiple drug resistance transporters. Materials and Methods: Eighteen biopsies of glioblastoma multiforme were obtained from patients at the Institute of Neurosurgery Dr. Asenjo (INCA). The tumor cells were obtained from primary cultures and the expression and activity of multiple drug resistance transporters was assessed by RT-PCR and immunohistochemistry. Population-based study was performed using the databases of the Department of Neurosurgery of INCA. Results: The number of patients with glioblastoma multiforme increased between 2007 and 2009, from 3.5 percent to 7.9 percent of total brain tumors. Mortality of these tumors is 90 percent at three years. A high expression and activity of the multiple drugs resistance associated protein 1 (Mrp1) transporter was observed in primary cultures of biopsies. Conclusions: We propose that Mrp1 activity is responsible for the chemo-resistance of the glioblastoma multiforme and inhibition of this transporter could represent a plausible strategy for the treatment.

Glioblastoma: experiência uni-institucional com 48 pacientes tratados com cirurgia, radioterapia e quimioterapia / Glioblastoma: single institutional experience with 48 patients treated with surgery, radiotherapy and chemotherapy

OBJETIVO: Identificar fatores prognósticos e avaliar a evolução clínica de pacientes com diagnósticode glioblastoma submetidos a cirurgia e radioterapia, com ou sem quimioterapia adjuvante. MATERIAL E MÉTODO: trabalho retrospectivo com 48 pacientes portadores de glioblastoma tratadosno período de 1997 a 2007. Todos os pacientes foram classificados segundo critérios do recursive partitioning analysis (RPA). RESULTADOS: Observaram-se predominância do sexo feminino, idade maior ou igual a 50 anos, performance status maior ou igual a 70, e as classes mais prevalentes,de acordo com a classificação RPA, foram a V e VI. Em 72,9% dos pacientes foi realizada ressecção parcial da lesão e em 27,1%, ressecção subtotal ou total. Quimioterapia foi administrada em47,9% dos pacientes e a dose de radioterapia foi de 50û60 Gy em 72,9% dos casos. A sobrevida global mediana observada foi de 52 semanas. CONCLUSÃO: Os dados obtidos mostram que a sobrevida global de pacientes portadores de glioblastoma foi semelhante aos resultados encontrados na literatura e dependente de fatores como a adição de quimioterapia, dose de radioterapia eíndice de Karnofsky.

OBJECTIVE: To identify prognostic factors and evaluate the clinicaloutcome of patients with glioblastoma treated with surgery and radiotherapy combined or not with chemotherapy. MATERIAL AND METHOD: In this retrospective study, 48 patients with glioblastoma were treated between 1997 and 2007. All patients wereclassified according the recursive partitioning analysis (RPA) criteria.RESULTS: The majority of patients were female, with 50 years of age or above. Performance status of 70 or greater were found in 70.8% of cases, and RPA classes V and VI prevailed. Seventy-two percent of patients were submitted to partial resection and 27.1% to total or subtotal resection. Chemotherapy wasadministered in 47.9% of patients and doses between 50 and 60 Gy were delivered in 72.9%. The median overall survival was 52 weeks. CONCLUSION: Our data show an overall survival that approaches the related in others reports and were dependent of factors such as chemotherapy, dose of radiation and Karnofsky performance status.

Evidence-based adjuvant therapy for gliomas: current concepts and newer developments.

The incidence of gliomas is increasing worldwide, including India. Of the 18,820 new cases of primary central nervous system (CNS) tumors diagnosed annually in the United States, gliomas account for over 60% with 30-40% of them being glioblastoma multiforme (GBM), 10% being anaplastic astrocytoma (AA), and 10% being low grade gliomas (LGGs). This is in contrast to one study from West Bengal, India, in which only 7.9% of the brain tumors were GBMs, while 46.8% were astrocytomas. Of all adult primary CNS tumors, GBM is the most common and the most malignant with about 7,000 to 8,000 new cases annually in the United States. Given poor outcomes, a number of treatment approaches have been investigated. Common to these approaches is the use of adjuvant radiation therapy, even as surgery alone, with or without chemotherapy, may be the mainstay for some lower grade and low-risk gliomas. Today, treatment typically involves external beam radiation, with concurrent and adjuvant chemotherapy for more aggressive histologies. Although gliomas are relatively uncommon, active research is ongoing. Results of landmark trials along with some of the recently published trials are presented. These trials and management strategies as well as evolving concepts are found by reviewing over 200 articles in the National Library Medical (NLM) database, PubMed, more than 60 of which are refrenced. Specifically, the database is searched using the following keywords, with various combinations: glioma, low-grade, anaplastic, astrocytoma, oligodendroglioma, oligoastrocytoma, glioblastoma multiforme, chemotherapy, radiation, new concepts, phase III, MGMT, CDX-110 (Celldex), temozolomide, 1p/19q deletion, and bevacizumab.

Isolated Richter's syndrome in central nervous system: case report

Linfoma não Hodgkin difuso de grandes células em paciente portador de leucemia linfóide crônica (LLC), ou síndrome de Richter, é complicação rara e grave nesta leucemia. Síndrome de Richter isolada no sistema nervoso central é muito rara, tendo sido encontrados apenas 12 casos descritos. Descrevemos paciente de 74 anos, que apresentou linfoma não Hodgkin difuso de grandes células em região frontal direita, simulando glioblastoma multiforme.

Administração intranasal do agente antitumoral álcool perílico: estratégia terapêutica para pacientes com glioblastoma recidivado / Intranasal delivery of anti-tumor agent perillyl alcohol: potential therapeutic alternative for patients with relapsed glioblastoma

Álcool perílico (AP) é um monoterpeno com ação antitumoral comprovada, em estudos pré-clínicos, sobre diferentes tipos de tumores induzidos em animais. Fase I e II de ensaios clínicos estão correntemente em desenvolvimento. O mecanismo de ação da atividade antitumoral do AP envolve a inibição da isoprenilação pós-traducional de proteinas G, incluindo a p21-Ras, bloqueando a transdução do sinal. A desregulação da função da p21-Ras, como resultado de mutação, superexpressão ou superativação dos fatores de crescimento, contribui para o crescimento de glioblastoma. A administração intranasal é uma abordagem prática e não-invasiva que permite que agentes terpêuticos que não cruzam a barreira hemato-encefálica alcancem o sistema nervoso central, reduzindo os efeitos colaterais provenientes da administração sistêmica. Este artigo discute a administração intranasal do AP, como potencial estratégia terapêutica multimodal para estas neoplasias e apresenta resultado preliminar em um caso.

Larga sobrevida en 5 pacientes con astrocitomas malignos / Long survival in 5 patients with malignant astrocytomas

Históricamente el tiempo de supervivencia promedio de los pacientes con glioblastoma multiforme y astrocitoma anaplásico ha sido de 6 a 12 meses y de 2 a 4 años respectivamente. Muy pocos pacientes alcanzan los 5 años de operados. El propósito fue identificar algún denominador común en los pacientes con larga sobrevida y diagnóstico histológico confirmado de astrocitoma anaplásico o glioblastoma multiforme. Se estableció comunicación con los familiares de 67 pacientes operados en el Instituto de Neurología y Neurocirugía entre los años 1983 a 1992. Se analizaron la edad de los pacientes al momento del diagnóstico, la localización del tumor, el estado neurológico en el comienzo de la enfermedad y el tiempo de evolución de esta, así como el tipo de tratamiento realizado. Se halló 5 pacientes con un tiempo de supervivencia mayor de 7 años. La edad menor de 35 años, la ubicación de la lesión en el lóbulo frontal derecho y el inicio clínico sin defecto neurológico focal, así como la exéresis quirúrgica total fue la norma en el 80 (por ciento) de estos casos. El Karnofsky inicial mayor de 70 puntos y el empleo de radioterapia y quimioterapia posquirúrgica fue común a todos. Los pacientes jóvenes con gliomas astrocíticos de alta malignidad ubicados en el lóbulo frontal derecho, que comienzan con un Karnofsky mayor de 70 puntos y son sometidos a exéresis quirúrgica total, radioterapia y quimioterapia posquirúrgica, tienen mayor probabilidad de prolongar su tiempo de sobrevivencia(AU)

Historically, the average time of survival of the patients with glioblastoma multiforme and anaplastic astrocytoma has ranged from 6 to 12 months and from 2 to 4 years, respectively. A few patients survive 5 years after surgery. The aim of this paper was to identify some common denominator in patients with long survival and confirmed histological diagnosis of anaplastic astrocytoma or multiform glioblastoma. Communication was established with the relatives of 67 patients operated on at the Institute of Neurology and Neurosurgery between 1983 and 1992. The age of the patients, the localization of the tumor, the neurological state at the onset of the disease, the time of evolution and the treatment used were analyzed. 5 patients had a time of survival over 7 years. The youngest patient was 35. The localization of the injury on the right frontal lobule, the clinical beginning without focal neurological defect, as well as the total exeresis was the norm in 80 percent of these cases. The initial scoring over 70 in Karnofsky scale (KS) and the use of radiotherapy and chemotherapy after surgery was common to all of them. Young patients with highly malignant astrocytic gliomas located in the right frontal lobule that begin with a KS over 70 points and undergo total exeresis, postsurgery radiotherapy and chemotherapy have greater probabilities of prolonging their time of survival(AU)

Metastatic Glioblastoma in Cervical Lymph Node after Repeated Craniotomies: Report of a Case with Diagnosis by Fine Needle Aspiration

Head and neck metastasis from glioblastoma is rare event usually seen in patients with previous and repeated surgery. We present the case of a 35 yr-old-female suffering from metastatic glioblastoma in cervical lymph node that was diagnosed by fine needle aspiration. During the last 4 yr, she had four separate craniotomies for the recurrent brain tumors. Cytological diagnosis was made by light microscopy with immunostaining with glial fibrillay acid protein. Chemotherapy with vincristine and procarbazine was performed. The cervical masses were decreased in size and some disappeared while the intracranial glioblastoma continued to grow during chemotherapy. We discuss possible explanations for these different courses after chemotherapy in extraneural metastatic glioblastoma and primary intracranial glioblastoma.

Efeito do tratamento in vitro e in vivo do monoterpeno álcool perílico no crescimento e controle da expressão gênica no glioma de alto grau

A pesquisa para o desenvolvimento de novas drogas quimioterápicas, tem se baseado nas propriedades dos produtos de origem natural. Estudos experimentais em animais indicam que o álcool perílico (AP), um monoterpeno originalmente isolado dos óleos essenciais de várias plantas é capaz de causar a regressão de diferentes tipos de tumores. O tratamento clássico preconizado para os astrocitomas anaplásicos e glioblastoma multiforme consiste de: ressecção cirúrgica, radioterapia e/ou quimioterapia e raramente apresentam efeito curativo. O presente trabalho teve como objetivo analisar o efeito do AP na proliferação, na alteração da morfologia, na síntese de proteínas e migração celular de diferentes linhagens de glioblastoma murino e humano. Foram utilizados modelos in vitro de cultivo de células e ensaios in vivo de migração celular. O tratamento in vitro com o AP nas concentrações v/v de 0,003%, 0,02%, 0,03%, 0,3%, 3% e 30% nas linhagens de glioblastoma C6 de murinos e linhagens A 172 e U87MG de glioblastoma humano, mostrou que mesmo nas concentrações (v/v) mais baixas (0,03% e 0,3%) o AP promove a inibição da proliferação celular e da síntese de proteínas. O tratamento in vitro com o AP a 0,3% v/v causou após 15 minutos perda da permeabilidade celular e mais tardiamente, 50 minutos, alterações acentuadas na citoarquitetura das linhagens C6, U87MG e A172. Nos ensaios in vivo com ovos embrionados, o tratamento com o AP nas concentrações v/v 0,3% e 0,03% causou efeito inibitório na migração celular da linhagem C6. Os resultados sugerem uma eficácia quimioterápica do AP na citotoxidade e na inibição da migração celular de linhagens de glioblastoma murino e humano

The search for new chemotherapeutic drugs has increased, especially for those that have a natural origin. Perillyl alcohol (POH), is a naturally occurring monoterpene, found in the essential oils of citrus fruits and other plants, with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. Standard treatment of anaplastic gliomas and glioblastoma multiforme consisting of surgical resection, radiation therapy and/or chemotherapy is rarely curative. This work aimed to evaluate in vitro and in vivo effects of POH treatment, cell proliferation, changes in morphology, protein synthesis, and migration of distinct lineage of glioblastoma cells. It was chosen in vitro culture systems and in vivo assays for assessing cellular migration. In vitro treatment of POH at concentrations of (v/v) 0.003%, 0.02%, 0.03%, 0.3%, 3% and 30%, consistently inhibited proliferation of murine C6 and human A172 and U87MG of glioblastoma cells. In vitro treatment of POH at low concentrations 0.03% v/v and 0.3% v/v also produced marked changes in cell morphology and inhibited protein synthesis. Likewise in vitro assays with 0.3% v/v POH treatment for 15 minutes, initially caused marked alteration in membrane permeability and later (50 minutes) drastic changes in the cytoarchitecture of C6, U87MG and A172 cells. Furthermore, previous in vitro treatment of glioblastoma cells with 0.3% v/v and 0.03% v/v POH showed inhibition of cell migration and anti-metastatic activity in the in vivo model of the chick embryo with C6 cell line. Such results indicate the chemotherapeutic action of POH by promoting cytotoxicity and arresting migration of murine and human glioblastoma cell lines

Tumores do sistema nervoso central / Tumors of the central nervous system

A autora destaca a importância dos tumores do sistema nervoso central em Pediatria, visto tratar-se do segundo grupo de neoplasias em frequência. Estuda os gliomas de alto e baixo grau de malignidade, os astrocitomas cerebelares, gliomas supratentoriais e de linha média, de vias ópticas e do tronco cerebral, o meduloblastoma e os tumores da regiäo pineal, analisando seu quadro clínico, diagnóstico, evoluçäo e tratamento

Mechanism of photosensitization of glioblastoma and neuroblastoma cells by merocyanine 540: a lipid peroxidation study.

Mechanism of merocyanine 540 (MC540) mediated photosensitization in glioblastoma (U-87MG) and neuroblastoma (Neuro 2a) cells was investigated. Photoinduced lipid peroxidation was measured in the presence of mechanistic probes-deuterium oxide (D2O), sodium azide, superoxide dismutase (SOD), mannitol and sodium benzoate. In both the types of cells, the photoinduced lipid peroxidation was enhanced in D2O whereas it showed inhibition in the presence of sodium azide. SOD also inhibited the lipid peroxidation while sodium benzoate and mannitol had no effect. These results suggest that photosensitization of U-87MG and Neuro 2a cells by MC 540 involves both type I (free radical mediated) and type II (singlet oxygen mediated) mechanisms.

Comparative study to evaluate the safety and efficacy of high dose tamoxifen and dexamethasone versus dexamethasone alone in the management of recurrent malignant gliomas

This study included 19 [15 males and 4 females] evaluable patients with recurrent malignant gliomas who failed treatment with external radiotherapy, they were randomly assigned into two arms [A and B] by a simple toss test. Arm A included ten patients [eight males and two females] treated with tamoxifen in an escalating dose to reach the target dose of 160 mg/day in the third week of treatment and dexamethasone in a dose of 12 mg/day. Arm B included nine patients [seven males and two females] treated with dexamethasone only in the same dose. In arm A, a clinical improvement was detected in three patients and radiological improvement was detected in one of them and two patients had a stable disease. The remaining five patients had a rapid progressive disease despite of treatment. In arm B, two patients had clinical improvement of a short duration and one patient had a stationary course and no radiological improvement was detected in any patients. The remaining six patients deteriorated rapidly. No major side effects were reported in both arms apart from one patient in arm A who developed deep venous thrombosis [DVT] and responded to medical treatment

Structural alterations induced by photodynamic action of hematoporphyrin derivative (HpD) in plasma membrane of glioblastoma (U-87MG) cells: time dependent fluorescence spectroscopic study.

Photodynamic action of hematoporphyrin derivative (HpD) on the plasma membrane of human glioblastoma U-87MG cells was investigated using lipid and protein specific fluorescent probes trimethylammonium-1,6-diphenyl 1,3,5-hexatriene (TMA-DPH) and N-(1-pyrene)-maleimide (PM) respectively. Steady state anisotropy, decay time and time dependent anisotropy of these probes in U-87MG cells were measured. Light irradiation caused an increase in the steady state anisotropy of TMA-DPH in cells treated with HpD; however, no change in decay time was observed. Time dependent anisotropy measurements were performed and the data were analyzed using wobbling in cone model. A decrease in the rotational relaxation time (phi) as well as the cone angle (theta(c)) and an increase in the order parameter (S) of TMA-DPH were observed on photosensitization of cells. A decrease in the order parameter (S) of TMA-DPH were observed on photosensitization of cells. A decrease in the steady rate anisotropy and the rotational relaxation time (phi) of PM and enhancement in the lipid peroxidation were also observed. Our results show that the photodynamic action of HpD increases the order in the lipid bilayer and the mobility of the proteins in the plasma membrane of cells.