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Survival prediction in patients with glioblastoma multiforme by human telomerase genetic variation.

PURPOSE: Glioblastoma multiforme (GBM) is the most common and aggressive glioma with the poorest survival. Use of biomarkers for screening patients with GBM may be used to modify treatments and improve outcomes. The level of human telomerase (hTERT) expression is an independent predictor of outcome of many cancers, and a functional variant of hTERT MNS16A (shorter tandem repeats or short [S] allele) is associated with increased hTERT mRNA expression. We investigated whether hTERT MNS16A variant genotype predicted survival in GBM patients. PATIENTS AND METHODS: We genotyped hTERT MNS16A in 299 GBM patients using polymerase chain reaction and determined hTERT genotype by classifying the DNA band of 243 or 272 base pairs (bp) as S allele and 302 or 333 bp as long (L) allele. We compared overall survival using Kaplan-Meier estimates and equality of survival distributions using the log-rank test, and we computed univariate and multivariate Cox proportional hazards models to estimate the effects of selected variables. RESULTS: Overall survival differed significantly by hTERT MNS16A genotype, with median survivals of 25.1, 14.7, and 14.6 months for the SS, SL, and LL genotypes, respectively. Compared with the SS genotype, the hazard ratios for the SL and LL genotypes were 1.69 and 1.87, respectively, after adjustment for other factors. Multivariate Cox regression analysis showed an independent statistically significant association between the hTERT MNS16A variant genotype and outcome. CONCLUSION: A functional hTERT MNS16A genotype is a potential biomarker for assessment of survival outcome of GBM. Larger studies are needed to verify these findings.

Adult↗

Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme.

Forty-seven adult patients with glioblastoma multiforme (GBM) were treated in a phase I/II study combining continuous intravenous (IV) infusions of iododeoxyuridine (IdUrd) and hyperfractionated radiation therapy. IdUrd was administered as a continuous infusion (24 h/d) for two separate 14-day infusion periods. The dose of IdUrd was escalated from 500 to 1,200 mg/m2/d. The initial wide-field tumor volume was treated to 45 Gy at 1.5 Gy fractions twice daily over 3 weeks. Following a planned 2-week break, a reduced-field boost of 25 Gy was delivered using 1.25 Gy fractions twice daily over 2 weeks (total dose, 70 Gy over 9 weeks). The IdUrd infusion preceded both the wide-field and reduced-field irradiation by 1 week. All treatment was performed on an outpatient basis. Dose-limiting systemic toxicity to the bone marrow (primarily thrombocytopenia) and gastrointestinal (GI) tract (both stomatitis and diarrhea) established the maximum tolerable dose (MTD) at 1,000 mg/m2/d for a 14-day infusion. Significant local toxicity (within the radiation field) was not seen. The kinetics of IdUrd were linear with dose escalation and reached steady-state plasma concentrations of 1.3 to 3.4 mumol/L. The total body clearance of IdUrd was .82 L/min/m2. The primary metabolite, 5-iodouracil (IUra) approached steady state by day 6 of the infusion when plasma levels were 60 times higher than IdUrd. Plasma levels of uracil and thymine, but not thymidine, were elevated throughout the infusion. With a minimum follow-up of 1 year, ten patients remain alive, while 33 patients died of progressive disease, and four patients died of other causes (including one treatment-related death). The median survival for all 47 patient and for the 40 patients receiving the MTD was 45 and 47 weeks, respectively, with 12% and 14% survivals at 24 months. Using a Cox regression analysis, age (less than or equal to 50 years v greater than 50 years) and pretreatment performance status (PS) (Eastern Cooperative Oncology Group [ECOG]-PS 0 to 1 v PS 2 to 3) were independent, statistically significant (P2 less than .05) predictors of survival, with the ECOG status being a better predictor. Patients with a PS 0 to 1 (28 patients) had a median survival of 64 weeks with 21% survival at 24 months, compared with a median survival of 29 weeks and 0% survival at 12 months in the 19 patients with PS 2 to 3. The overall and subgroup survival data are at least comparable to other combined modality treatment approaches in patients with GBM.

Adult↗

Chemotherapy for glioblastoma multiforme.

Treatment for the patient with a glioblastoma multiforme often includes chemotherapy with many specific nursing implications directly associated with this form of treatment. While the four agents described share some common adverse effects such as nausea and vomiting, even with this relatively common adverse effect, the onset, duration and severity varies. Multiple other adverse effects like nephrotoxicity, ototoxicity, thrombocytopenia and leukocytopenia vary greatly from agent to agent in occurrence and severity. Knowing the mode of action for each agent, which adverse effects to expect, when to expect them and appropriate treatment measures will help the nurse, patient and family to better manage these effects and improve quality of life.

Antineoplastic Agents↗

Phase I/II trial of superselective arterial 5-FU infusion with concomitant external beam radiation for patients with either anaplastic astrocytoma or glioblastoma multiforme.

From August 1987 through September 1989, 25 patients with either anaplastic astrocytoma (8 patients) or glioblastoma multiforme (17 patients) were entered into a Phase I trial of combined intra-arterial 5-fluorouracil (5-FU) and external beam radiation therapy. The intra-arterial 5-FU was given in a superselective, supraopthalmic fashion, in escalating doses from 200 mg to 600 mg on a weekly basis during the radiotherapy. Each patient received from 1-4 courses of 5-FU. Radiotherapy consisted of 5,000 rads in 25 fractions given to partial brain fields including the mass and surrounding edema plus a 3-cm margin as defined by computed tomography scan. There were a total of 4 significant acute complications out of a total of 70 infusions. These included 3 ischemic events of which 2 were transient. In addition, 1 patient experienced a cerebral bleed. No patients developed ocular complications. Electroencephalograms (EEGs) were performed immediately before and during 21 intra-arterial infusions. Two patients developed significant EEG changes during intra-arterial infusion, and both of these patients experienced untoward reactions. The remaining patients showed no EEG changes during their infusions. The median survival for patients with glioblastoma multiforme was 15 months. We believe the toxicity of superselective intra-arterial 5-FU infusion combined with external beam radiotherapy is acceptable. This type of treatment deserves further study.

Adult↗

Accelerated fractionation radiotherapy for hospitalized glioblastoma multiforme patients with poor prognostic factors.

The standard 6 week course of post-operative radiotherapy for glioblastoma multiforme (astrocytoma grade IV) is lengthy, considering the poor prognosis. The standard schedule is especially unsuitable for hospitalized patients and for those with poor prognostic factors (such as old age and poor performance status) since their survival is particularly short. In order to improve the survival-treatment time ratio, we entered a total of 14 hospitalized patients with glioblastoma multiforme (GBM) and poor prognostic factors (mean age 62, mean KPS 57%) into a Phase I trial of accelerated fractionation (AF) external beam radiotherapy. A total tumor dose of 5400-5500 cGy was given in 3 weeks: 4300-4500 cGy whole brain using 100 cGy tid fractions on weekdays plus a 900-1200 cGy boost using single daily fractions of 150-200 cGy on weekends. Only one patient entered did not complete therapy, due to the development of pulmonary embolism resulting in death. Mean survival for all 14 patients from the time of surgical diagnosis was 30.4 weeks. The schedule was well tolerated and resulted in a substantial decrease in treatment time compared to conventional fractionation in these patients. AF schedules should continue to be explored since they may be more appropriate than conventional fractionation schedules for GBM patients with poor prognostic factors, particularly when hospitalized.

Aged↗

Experiences with reoperation on recurrent glioblastoma multiforme.

OBJECTIVE: The goal was to report the treatment results after a second operation on patients with recurrent glioblastoma multiforme (GBM) and to investigate if patient's quality of life is improved and survival is lengthened. - METHODS: Thirty-eight patients (17%) out of 224 patients with glioblastoma multiforme, treated at our department from 1/93 to 12/98, underwent re-operation due to clinical and neuroradiological significant recurrence of GBM. Not included were patients who had a lower malignant tumor at first operation and GBM on second operation. All 38 patients had completed radiation therapy. - RESULTS: Overall median survival of re-operated patients was 57 weeks. Interval between 1(st) and 2(nd) operation was 42 weeks and median survival after 2(nd) operation was 23 weeks. Total survival was significantly longer in patients under 50 years at time of re-operation, a time interval longer than 26 weeks between 1(st) and 2(nd) operation, complete resection and a Karnofsky Performance Scale (KPS) >/= 90 at the time of re-operation. Only in the subgroup Karnofsky Performance Scale more or equal 90 had a significant longer survival time after reoperation (29 weeks versus 18 weeks). Based on a KPS change of at least 10 points clinical status was improved in 22 patients, unchanged in 16 patients and no patient deteriorated. No perioperative mortality has occurred. - CONCLUSIONS: Prolongation of survival time after reoperation was statistically significant only in the Karnofsky Performance subgroup. In all other groups prolongation of survival was a relative constant measure of 23%%weeks. The well known favorable prognostic indicators, such as younger age, longer event-free period, had also in our investigation the longest survival times.

Brain Neoplasms↗

Glioblastoma multiforme of donor origin after renal transplantation: report of a case.

A case of transmission of a glioblastoma multiforme from the donor to a kidney transplant recipient in the absence of previous ventriculosystemic shunt is described. The recipient was a 48-year-old woman who developed a fever with no other associated symptoms 17 months posttransplant. Physical examination revealed a large nonpulsatile mass on the upper graft pole. Histopathologic examination showed a highly cellular neoplasm with fusiform and globoid cells, a high grade of nuclear pleomorphism and mitosis, necrosis with pseudopalisading, and vascular proliferation. Immunohistochemistry of the cells showed them to contain glial fibrillary acidic and S-100 proteins, consistent with a glioblastoma multiforme. We conclude that the risk of tumor transmission from donors with primary central nervous system tumors to kidney transplant recipients, is real and should be considered when evaluating a graft mass in such patients.

Adult↗

Survival trends in elderly patients with glioblastoma multiforme: resective surgery, radiation, and chemotherapy.

BACKGROUND: It is appropriate to investigate and to determine survival trends following glioblastoma multiforme treatment using resective surgery, radiation therapy, and/or chemotherapy in patients aged 59 years and higher. METHODS: We retrospectively reviewed 30 elderly patients (> or =59 years old) who were treated for histopathologically confirmed glioblastoma multiforme at our tertiary care institution from 1990 through 2002. All patients were treated with steroids. In addition, 22 patients underwent resective surgery (RS), 17 patients underwent radiation therapy (RT), and 10 patients underwent chemotherapy (C). Many patients underwent these treatments in various combinations: 6 underwent biopsy only, 7 RS only, 6 RS+RT only, and 9 RS+RT+C. For each case, pre-treatment Karnofsky performance scores (KPS), tumor location, presenting symptoms and signs, associated surgical morbidity, and pre-existing medical conditions were also recorded. Patients were categorized into one of four treatment subgroups: Biopsy only, RS only, RS+RT, and RT+RS+C. For each of these subgroups, pretreatment KPS and post-treatment survival were compared. RESULTS: Post-treatment survival following biopsy only was 3.2 +/- 0.8 months (mean +/- SE); RS 2.2 +/- 0.5; RS+RT 5.5 +/- 1.2; RS+RT+C 13.6 +/- 2.1. A longer survival trend was noted for the RS+RT versus RS group (two-tailed unpaired t test, p = 0.02;), as well as the RS+RT+C group, which showed consistently higher survival in comparison to most of the other groups (p = 0.0021, 0.00039, 0.013 vs. the biopsy only, RS only, and RS+RT groups, respectively). No significant difference was found in KPS, comparing all individual groups versus each other (p > or = 0.06). Remarkably, 6 patients survived over 14 months (range, 14.1-22.7 months), all of which received RS+RT+C. CONCLUSIONS: This study suggests a significant improvement in elderly patients treated with the combination of resective surgery, radiation therapy, and chemotherapy, rather than either treatment alone or other combination. This significant improvement does not appear to be biased by pretreatment KPS, as mean KPS values did not significantly differ between any of these groups. However, a greater number of patients in each group must be considered to achieve the power to make more definitive treatment guidelines.

Age Factors↗

Glioblastoma multiforme of the cerebellum in an elderly man.

A 74-year-old man was diagnosed with cerebellar glioblastoma multiforme (GBM). He initially presented with headache, nausea, vomiting, and truncal ataxia. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a round mass with ring enhancement in the vermis of the cerebellum. Subtotal removal of tumour was performed, and the pathological diagnosis was cerebellar glioblastoma multiforme. Subsequently, radiochemotherapy was performed. GBM of the cerebellum is rare and only accounts for a small fraction of all GBM. To our knowledge, there have only been 7 cases of senile cerebellar GBM reported. Our patient is one of the oldest cases recorded in the Asian literature.

Aged↗

Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme.

PURPOSE: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO. METHODS AND MATERIALS: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol. RESULTS: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. CONCLUSION: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.

Adult↗

[Magnetic resonance imaging in 67 cases of glioblastoma multiforme and occurrence of metastases].

PURPOSE: The purpose of this paper is to demonstrate the main MRI characteristics of glioblastoma multiforme (GBM), the most common CNS primary tumor, emphasizing its location and the occurrence of metastases. METHOD: The MR imaging of 67 pathologically proven cases of glioblastoma multiforme were retrospectively reviewed. The exams were realized in the period between 1995 and 2003, in one of three 1.5 Signa GE units (Milwaukee, WI). RESULTS: The ages of the patients ranged from 4 years to 86 years, mean 60 years, and the occurrence of the tumor was preponderant among men, with 39 cases (58%). The most common location was in the frontal lobes (47%) followed by the temporal lobes (18%) and the parietal lobes (16%). In 19% of the cases there were involvement of more than one site and long distance metastases were seen in 22% of the patients. CONCLUSION: According to the literature, the most common location of GBM was in the frontal lobe of older than 50 years old men. Metastases occurred in 22% of our cases.

Adolescent↗

Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme.

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O(6) position of guanine. The methylisocyanate species may inhibit O(6)-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m(2)) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.

Adult↗

Quantitative morphology of human glioblastoma multiforme microvessels: structural basis of blood-brain barrier defect.

Neoplastic invasion of the brain parenchyma results in a disruption of the ultrastructure of the blood vessel walls such that serum proteins extravasate into the surrounding tissue, resulting in cerebral edema. The structural changes involved are not well understood, since the pores through which serum constituents pass (permeability routes) in normal barrier vessels and in tumor vessels where the barrier is compromised, have not been extensively explored. In this study we investigate the ultrastructure of human brain microvessels in biopsied samples of control brain tissue and five glioblastoma multiforme tumors. Electron micrographs of a total of 78 vessels were analysed with computer assisted morphometry for ultrastructural evidence of permeability routes. Fenestrations in the endothelium were not seen. Pinocytotic vesicle number and arrangement did not differ significantly from that seen in control brain vessels. Interendothelial junctions with enlarged distensions (which may represent sections through transendothelial channels) were seen in some vessels from most tumors but not in control barrier vessels. In addition, large gaps in the endothelial layer were seen in less than two percent of tumor vessels. In conclusion, glioblastoma multiforme vessels in this study show subtle alterations in vessel morphology from that seen in controls. We suggest that the high vascular permeability and resultant brain edema seen in glioblastoma multiforme tumors is likely due to the presence of channels through interendothelial junctions, and rare but large breaks in the endothelial wall.

Adult↗

Glioblastoma multiforme: treatment by large dose fraction irradiation and metronidazole.

In an attempt to overcome the possible radioresistance of glioblastoma multiforme related to the large shoulder on the in vitro survival curves and to sensitize hypoxic tumor cells, a treatment protocol was instituted at Yale University Medical Center and affiliated hospitals, using large dose fraction irradiation therapy in conjunction with the hypoxic cell sensitizer metronidazole. Nineteen patients with biopsy-confirmed, previously untreated, cerebral grade IV glioblastoma multiforme were, following surgery, irradiated once a week at 600 rad per fraction, 3.5 to 4 hours after ingestion of metronidazole, 6 gm/m2. A total of 7 treatments were employed, with all patients maintained on antiseizure medications and corticosteroids. Metronidazole levels were determined prior to each treatment and patients were followed closely clinically and with serial computerized tomography (CT) scans. The treatment was well tolerated, in general, with no untoward side effects related to the high dose fraction irradiation. The majority of the patients experienced varying degrees of gastrointestinal upset lasting up to several hours following metronidazole administration. Three patients died of pulmonary emboli. One patient experienced moderately severe ototoxicity. A median survival of 9.4 months was obtained for all 19 patients, suggestive of a prolongation of survival compared to historical controls treated with conventionally fractionated radiation or with unconventional radiation fractionation schemes and metronidazole or misonidazole.

Adolescent↗

[The multicentric glioblastoma multiforme].

The authors report on two cases of multicentric glioblastoma multiforme, one of them being a trilocular glioblastoma, whereas in the second case a second focus developed contralaterally. Both patients received whole skull radiation of 40 Gy. The patient who suffered from the primarily unilocal tumour was given a tumour boost. The article reports on the imaging via CT and MR.

Brain Neoplasms↗

Is there an optimal hemoglobin level for patients with glioblastoma multiforme?

PURPOSE: The purpose of this study was to assess the relationship between hemoglobin levels and survival for patients treated with radiation therapy for glioblastoma multiforme. METHODS/MATERIALS: Between 1992 and 2001, 89 patients with newly diagnosed glioblastoma multiforme were treated with a minimum of 50 Gy of radiation therapy. The primary study endpoint was overall survival. The independent variables analyzed included peak hemoglobin level, age, sex, extent of surgery, and duration of therapy. The peak hemoglobin level was the highest hemoglobin value obtained within 1 week before the initiation of radiation therapy or at some point during radiation therapy. The peak hemoglobinlevel was stratified into values of less than or equal and values greater than for each of the following hemoglobin values: 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, and 14.0 g/dL. RESULTS: On univariate analysis, age (< or = 50 years of age) and surgical treatment (resection) were significant for increased survival at 1 year. When univariate analysis was performed on the stratification of the peak hemoglobin, levels greater than 11.0, 13.5, and 14.0 g/dL reached statistical significance for increased survival. Multivariate analysis was then performed on models composed of the hemoglobin levels that reached significance, and the other independent variables were investigated. In all models, both age and the peak hemoglobin level tested were prognostic for survival. However, for the hemoglobin level of 11.0 g/dL, an interaction was detected between hemoglobin and age. CONCLUSION: We found that increasing hemoglobin levels may have prognostic implications and could thus influence clinical outcome. We will be seeking to verify our results in larger cohorts.

Adult↗

Prognostic value of plasma transforming growth factor-beta in patients with glioblastoma multiforme.

We investigated whether the postoperative concentration of circulating transforming growth factor beta (TGF-beta) yields prognostic value in patients with glioblastoma multiforme (gbm). Blood was collected from 20 healthy volunteers and in 28 patients with mainly glioblastoma multiforme (gbm), both before radiotherapy, during and after 4 weeks of irradiation. Both latent and active TGF-beta were quantified directly in the blood plasma using a bioassay with mink lung epithelial cells transfected with a plasminogen activator inhibitor-1 promotor luciferase construct. The average plasma concentration of TGF-beta before radiotherapy for gbm patients was 26.2 ng/ml, which was significant higher than in normal controls (16.2 ng/ml, p=0.02). No correlation was found between TGF-beta and survival, nor between plasma TGF-beta and the diameter of the postoperative contrast-enhancing lesion. The pattern of plasma TGF-beta during radiotherapy did not correlate with the clinical course of patients, nor with the fractionation scheme. Plasma TGF-beta did not reveal a clinical useful prognostic value for gbm patients, which is partly due to the large variation in TGF-beta plasma levels between individual patients.

Aged↗