Search

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

Unlabelled: 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) measured with PET as a biomarker of amino acid uptake has been investigated in brain tumor imaging. The aims of the current study were to determine whether the degree of (18)F-FDOPA uptake in brain tumors predicted tumor grade and was associated with tumor proliferative activity in newly diagnosed and recurrent gliomas., Methods: Fifty-nine patients (40 men, 19 women; mean age ± SD, 44.4 ± 12.3 y) with newly diagnosed (n = 22) or recurrent (n = 37) gliomas underwent (18)F-FDOPA PET perioperatively. Tumor tissue was obtained by resection or biopsy in all patients. The tumor grade and Ki-67 proliferation index were obtained by standard pathology assays. Tumor (18)F-FDOPA uptake was quantified by determining various standardized uptake value (SUV) parameters (mean SUV, maximum SUV [SUVmax], mean values of voxels with top 20% SUVs, and tumor-to-normal-brain tissue ratios) that were then correlated with histopathologic grade and Ki-67 proliferation index., Results: Fifty-nine lesions in 59 patients were analyzed. (18)F-FDOPA uptake was significantly higher in high-grade than in low-grade tumors for newly diagnosed tumors (SUVmax, 4.22 ± 1.30 vs. 2.34 ± 1.35, P = 0.005) but not for recurrent tumors that had gone through treatment previously (SUVmax, 3.36 ± 1.26 vs. 2.67 ± 1.18, P = 0.22). An SUVmax threshold of 2.72 differentiated low-grade from high-grade tumors, with a sensitivity and specificity of 85% and 89%, respectively, using receiver-operating-characteristic curve analysis (area under the curve, 0.86). (18)F-FDOPA PET uptake correlated significantly with Ki-67 tumor proliferation index in newly diagnosed tumors (r = 0.66, P = 0.001) but not in recurrent tumors (r = 0.14, P = 0.41)., Conclusion: (18)F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between (18)F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, (18)F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.

Meningiomas are one of the most common adult brain tumors. For most patients, surgical excision is curative. However, up to 20% recur. Currently, the molecular determinants predicting recurrence and malignant transformation are lacking. We performed retrospective global genetic and genomic analysis of 85 meningioma samples of various grades. Copy number alterations were assessed by 100K single-nucleotide polymorphism arrays and correlated with gene expression, proliferation indices and clinical outcome. In addition to chromosome 22q loss, which was detected in the majority of clinical samples, chromosome 6q and 14q loss was significantly more common in recurrent tumors and was associated with anaplastic histology. Five "classes" of meningiomas were detected by gene expression analysis that correlated with copy number alterations, recurrent status and malignant histology. These classes more accurately identified recurrent tumors relative to Ki-67 index and extent of surgical resection, and highlight substantial expression heterogeneity between meningiomas. These data offer the most complete description of the genomic landscape of meningiomas, and provide broad genomic information that may be used to further stratify meningioma patients into prognostic risk groups.

Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumors known as gliomas. They proliferate and invade extensively and yield short life expectancies despite aggressive treatment. Response to treatment is usually measured in terms of the survival of groups of patients treated similarly, but this statistical approach misses the subgroups that may have responded to or may have been injured by treatment. Such statistics offer scant reassurance to individual patients who have suffered through these treatments. Furthermore, current imaging-based treatment response metrics in individual patients ignore patient-specific differences in tumor growth kinetics, which have been shown to vary widely across patients even within the same histological diagnosis and, unfortunately, these metrics have shown only minimal success in predicting patient outcome. We consider nine newly diagnosed GBM patients receiving diagnostic biopsy followed by standard-of-care external beam radiation therapy (XRT). We present and apply a patient-specific, biologically based mathematical model for glioma growth that quantifies response to XRT in individual patients in vivo. The mathematical model uses net rates of proliferation and migration of malignant tumor cells to characterize the tumor's growth and invasion along with the linear-quadratic model for the response to radiation therapy. Using only routinely available pre-treatment MRIs to inform the patient-specific bio-mathematical model simulations, we find that radiation response in these patients, quantified by both clinical and model-generated measures, could have been predicted prior to treatment with high accuracy. Specifically, we find that the net proliferation rate is correlated with the radiation response parameter (r = 0.89, p = 0.0007), resulting in a predictive relationship that is tested with a leave-one-out cross-validation technique. This relationship predicts the tumor size post-therapy to within inter-observer tumor volume uncertainty. The results of this study suggest that a mathematical model can create a virtual in silico tumor with the same growth kinetics as a particular patient and can not only predict treatment response in individual patients in vivo but also provide a basis for evaluation of response in each patient to any given therapy.

Unlabelled: 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is used as a biomarker of cell proliferation. We investigated the kinetics of (18)F-FLT during treatment of malignant glioma with bevacizumab and irinotecan., Methods: Fifteen patients with recurrent high-grade brain tumors (2 grade III, 13 grade IV) were studied at baseline (study 1 [S1]), after 1 course of therapy (2 wk, study 2 [S2]), and at the end of therapy (6 wk, study 3 [S3]). (18)F-FLT (1.5 MBq/kg) was administered intravenously, and dynamic PET was performed for 1 h. Curves representing blood clearance and tumor uptake were derived from factor images and summed frames with thresholding techniques or with a fixed cube. The standard (18)F-FLT model was used to estimate the rate constants. (18)F-FLT uptake was measured at 2 time points (early standardized uptake value [SUV(early)] and late SUV [SUV(late)])., Results: Parameters appeared similar for curves derived from factor images and summed frames; the steepest drop occurred between S1 and S2 for transport, influx, SUV(early), and SUV(late). Three groups were distinguished on the basis of clinical outcome: patients who died within 6 mo (group 1 [G1], n = 4), survived 6-12 mo (group 2 [G2], n = 6), and survived more than 1 y (group 3 [G3], n = 5). None of the rate constants was significantly different between the groups. Long-term survivors (G3) showed a significantly different SUV change (in percentage) between S1 and S3, whereas short-term survivors (G1 and G2) did not., Conclusion: Overall, the relative SUV change from S1 to S3 predicted a favorable clinical outcome, whereas the SUV change from S1 to S2 did not. Long-term survivors (G3) showed a significant drop in SUV from S1 to S2 and from S1 to S3. Significant correlations were found between SUV and both the rate constant and the influx rate. The correlation coefficient between SUV(late) and influx rate was 0.91, permitting response monitoring by the measurement of (18)F-FLT uptake changes.

Genome wide methylation profiling of gliomas is likely to provide important clues to improving treatment outcomes. Restriction enzyme based approaches have been widely utilized for methylation profiling of cancer genomes and will continue to have importance in combination with higher density microarrays. With the availability of the human genome sequence and microarray probe sequences, these approaches can be readily characterized and optimized via in silico modeling. We adapted the previously described HpaII/MspI based Methylation Sensitive Restriction Enzyme (MSRE) assay for use with two-color Agilent 244K CpG island microarrays. In this assay, fragmented genomic DNA is digested in separate reactions with isoschizomeric HpaII (methylation-sensitive) and MspI (methylation-insensitive) restriction enzymes. Using in silico hybridization, we found that genomic fragmentation with BfaI was superior to MseI, providing a maximum effective coverage of 22,362 CpG islands in the human genome. In addition, we confirmed the presence of an internal control group of fragments lacking HpaII/MspI sites which enable separation of methylated and unmethylated fragments. We used this method on genomic DNA isolated from normal brain, U87MG cells, and a glioblastoma patient tumor sample and confirmed selected differentially methylated CpG islands using bisulfite sequencing. Along with additional validation points, we performed a receiver operating characteristics (ROC) analysis to determine the optimal threshold (p

Glioblastoma is the most common primary brain tumor with a relatively poor prognosis. This article reviews the current standard therapy and discusses new developments in treatment of this disease. Surgical resection followed by radiation and chemotherapy has proven to be the most effective initial therapy. Recent advancement in molecular targeted therapies has led to the Food and Drug Administration (FDA) approval of bevacizumab in the setting of recurrent glioblastoma. The molecular pathways of glioblastoma growth are highlighted in this review. While numerous molecular targets are currently being intensely investigated, vascular endothelial growth factor (VEGF) receptor targeted therapy has been the only one to have shown clinical effect. The role of bevacizumab in this context provides a dynamic breakthrough in cancer therapy. Clinical trials have demonstrated significantly increased overall survival and six month progression free survival (PFS) in recurrent glioblastoma treated with bevacizumab alone or in combination with irinotecan. The use of this agent has also dramatically changed the imaging characteristics of glioblastoma. The anti-angiogenesis effects of bevacizumab have complicated the criterion for determining tumor growth. This may lead to redefinition of progressive disease based on non-invasive monitoring.

Background: Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740)., Methods: BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma. Median corticosteroid dose for patients who used corticosteroids at baseline was summarized by treatment arm; the percentage of patients who had sustained (≥50% corticosteroid dose reduction for ≥50% of time on study drug) or complete (discontinuation of corticosteroid for ≥25% of time on study drug) reduction in corticosteroid dose overall and by objective response and progression-free survival was calculated. The incidence of corticosteroid-related adverse events was summarized., Results: In each treatment group, 50% of patients were using systemic corticosteroids at baseline. The majority of those experienced a reduction in dose while receiving BEV-based therapy. Thirteen (30.2%) BEV and 20 (46.5%) BEV + CPT-11 patients had a sustained reduction of corticosteroid dose; 7 (16.3%) BEV and 9 (20.9%) BEV + CPT-11 patients had a complete reduction of corticosteroid dose. The majority of patients who had an objective response or progression-free survival >6 months experienced corticosteroid dose reduction. Approximately 64% of patients who used corticosteroids while receiving BEV-based therapy experienced infection., Conclusion: BEV may have corticosteroid-sparing effects in patients with recurrent glioblastoma. Corticosteroid reduction may positively affect patient health-related quality of life. Given the exploratory nature of the analyses in a noncomparative study, these results should be interpreted cautiously.

Glioblastomas are the most aggressive primary brain tumors, characterized by their rapid proliferation and diffuse infiltration of the brain tissue. Survival patterns in patients with glioblastoma have been associated with a number of clinicopathologic factors including age and neurologic status, yet a significant quantitative link to in vivo growth kinetics of each glioma has remained elusive. Exploiting a recently developed tool for quantifying glioma net proliferation and invasion rates in individual patients using routinely available magnetic resonance images (MRI), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognostic significance. Using our biologically based mathematical model for glioma growth and invasion, examination of serial pretreatment MRIs of 32 glioblastoma patients allowed quantification of these rates for each patient's tumor. Survival analyses revealed that even when controlling for standard clinical parameters (e.g., age and Karnofsky performance status), these model-defined parameters quantifying biological aggressiveness (net proliferation and invasion rates) were significantly associated with prognosis. One hypothesis generated was that the ratio of the actual survival time after whatever therapies were used to the duration of survival predicted (by the model) without any therapy would provide a therapeutic response index (TRI) of the overall effectiveness of the therapies. The TRI may provide important information, not otherwise available, about the effectiveness of the treatments in individual patients. To our knowledge, this is the first report indicating that dynamic insight from routinely obtained pretreatment imaging may be quantitatively useful in characterizing the survival of individual patients with glioblastoma. Such a hybrid tool bridging mathematical modeling and clinical imaging may allow for stratifying patients for clinical studies relative to their pretreatment biological aggressiveness.

Purpose: To determine if apparent diffusion coefficient (ADC) histogram analysis can stratify progression-free survival in patients with recurrent glioblastoma multiforme (GBM) prior to bevacizumab treatment., Materials and Methods: The study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. Bevacizumab-treated and control patients (41 per cohort) diagnosed with recurrent GBM were analyzed by using whole enhancing tumor ADC histograms with a two normal distribution mixture fitting curve on baseline (pretreatment) magnetic resonance (MR) images to generate ADC classifiers, including the overall mean ADC as well as the mean ADC from the lower curve (ADC(L)). Overall and 6-month progression-free survival (as defined by the Macdonald criteria) was determined by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test., Results: For bevacizumab-treated patients, the hazard ratio for progression by 6 months in patients with less than versus greater than mean ADC(L) was 4.1 (95% confidence interval: 1.6, 10.4), and there was a 2.75-fold reduction in the median time to progression. For the control patients, there was no significant difference in median time to progression for the patients with low versus high ADC(L) (hazard ratio, 1.8; 95% confidence interval: 0.9, 3.7). For bevacizumab-treated patients, pretreatment ADC more accurately stratified 6-month progression-free survival than did change in enhancing tumor volume at first follow-up (73% vs 58% accuracy, P = .034)., Conclusion: Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with recurrent GBM., ((c) RSNA, 2009.)

First-line therapy for patients with glioblastoma multiforme includes treatment with radiation and temozolomide (TMZ), an oral DNA alkylating chemotherapy. Sensitivity of glioma cells to TMZ is dependent on the level of cellular O(6)-methylguanine-DNA methyltransferase (MGMT) repair activity. Several common coding-region polymorphisms in the MGMT gene (L84F and the linked pair I143V/K178R) modify functional characteristics of MGMT and cancer risk. To determine whether these polymorphic changes influence the ability of MGMT to protect glioma cells from TMZ, we stably overexpressed enhanced green fluorescent protein (eGFP)-tagged MGMT constructs in U87MG glioma cells. We confirmed that the wild-type (WT) eGFP-MGMT protein is properly localized within the nucleus and found that L84F, I143V/K178R, and L84F/I143V/K178R eGFP-MGMT variants exhibited nuclear localization patterns indistinguishable from WT. Using MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] proliferation and clonogenic survival assays, we confirmed that WT cells expressing eGFP-MGMT are resistant to TMZ treatment compared with control U87MG cells, and that each of the polymorphic eGFP-MGMT variants confers similar resistance to TMZ. However, upon exposure to O(6)-benzylguanine (O(6)-BG), a synthetic MGMT inhibitor, the L84F and L84F/I143V/K178R variants were degraded more rapidly than WT or I143V/K178R in a proteasome-dependent manner. Despite the increased O(6)-BG- stimulated protein turnover caused by the L84F alteration, cells expressing L84F eGFP-MGMT did not exhibit altered sensitivity to the combination of O(6)-BG and TMZ compared with WT cells. In conclusion, we demonstrated that the L84F polymorphic variant has altered protein turnover without modifying sensitivity of U87MG cells to TMZ or combined TMZ and O(6)-BG. These findings may provide a clue to determining the clinical significance of MGMT coding-region polymorphisms.

Purpose: This phase II study was designed to determine the overall survival time of adults with supratentorial glioblastoma treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC), in combination with and following radiation therapy (RT)., Methods and Materials: This was an open-label, single arm phase II study. Patients were treated with RT in combination with poly-ICLC followed by poly-ICLC as a single agent. Poly-ICLC was initiated 7-28 days after the surgical procedure that established the diagnosis; radiotherapy began within 7 days of the first dose of poly-ICLC and within 35 days of surgical diagnosis. Treatment with poly-ICLC continued following the completion of RT to a maximum of 1 year or until tumor progression., Results: 31 patients were enrolled in this study. One patient did not have a Glioblastoma mutiforme and was deemed ineligible. For the 30 eligible patients, time to progression was known for 27 patients and 3 were censored. The estimated 6-month progression-free survival was 30% and the estimated 1-year progression-free survival was 5%. Median time to progression was as 18 weeks. The 1-year survival was 69% and the median survival was 65 weeks., Conclusions: The combined therapy was relatively well-tolerated. This study suggests a survival advantage compared to historical studies using RT without chemotherapy but no survival advantage compared to RT with adjuvant nitrosourea or non-temozolomide chemotherapy. Our results suggest that poly-ICLC has activity against glioblastoma and may be worth further study in combination with agents such as temozolomide.

This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Fifty five patients were enrolled in the study. Ten were ineligible after central review of pathology. Eleven percent of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide.

We describe the development of a prototype tool for the construction of longitudinal cases studies that can be used for teaching files, construction of clinical databases, and for patient education. The test domain is neuro-oncology. The features of the tool include: 1) natural language processing tools to assist structuring report information; 2) integration of imaging data; 3) integration of drug information; 4) target data model that includes the dimensions of space, time, existence, and causality; 5) user interface that provides three levels of information including overview, filtered summarization, and details on demand. The results of this preliminary work include a full prototype for neuro-oncology patients that allow users an efficient means for scanning a patients imaging and support data.

Purpose: To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma., Methods and Materials: All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m(2) for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m(2) for 5 days every 4 weeks and continuation of BV every 2 weeks., Results: For these 10 patients, toxicities were compiled until study discontinuation or up to approximately 40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed., Conclusion: The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.

Glioblastoma multiforme (GBM) are morphologically heterogeneous tumors, with varying amounts of necrosis, and edema. Previous studies have shown that treatments incorporating the VEGF antibody bevacizumab can reduce edema and tumor burden in GBM. Additionally it has been suggested that bevacizumab regimen treatment reduces the percent of tumoral necrosis. Therefore we sought to (1) determine the time course of change in necrosis, tumor, and edema volume in patients who respond to bevacizumab regimen treatment and (2) determine if GBM that progress following a response to bevacizumab regimen treatment are morphologically different from their appearance at prior tumor progression. Therefore, we retrospectively assessed tumor, necrosis, and edema volumes on MRI scans from 15 patients with recurrent GBM who responded to bevacizumab regimen treatment, and had extended (>7 month) follow-up. We found that the median time to best tumor response was 158 days (range, 16-261, SD = 63). The median best response was 72.1% reduction in tumor volume and 72.8% reduction in peritumoral edema. Most tumors (77.8%) showed resolution of necrotic areas. The relative reduction of edema and necrosis was sustained, even in patients (n = 7) who developed tumor progression. Thus the mean ratio of edema-to-tumor volume at progression on bevacizumab regimen treatment was 38.4% lower than that for the same tumors seen on progression scans following prior chemotherapy. The percentage of necrotic tumor also was diminished following progression on bevacizumab regimen treatment. These findings illustrate the time course of changes in edema and tumor volume with prolonged bevacizumab regimen treatment, and support the conclusion that the morphology of recurrent GBM following bevacizumab regimen therapy is distinct from that on other chemotherapy.

Purpose: This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide., Patients and Methods: Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m(2)/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m(2)/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only., Results: For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC(0-24hr) at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h., Conclusion: The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.

Purpose: To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38., Design: Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m(2)) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m(2), which was escalated to 550 mg/m(2) in 50-mg/m(2) increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1., Results: Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m(2)., Conclusions: The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m(2), administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan.

Purpose: 18F-labeled deoxy-fluorothymidine (FLT), a marker of cellular proliferation, has been used in PET tumor imaging. Here, the FLT kinetics of malignant brain tumors were investigated., Methods: Seven patients with high-grade tumors and two patients with metastases had 12 studies. After 1.5 MBq/kg 18F-FLT had been administered intravenously, dynamic PET studies were acquired for 75 min. Images were reconstructed with iterative algorithms, and corrections applied for attenuation and scatter. Parametric images were generated with factor analysis, and vascular input and tumor output functions were derived. Compartmental models were used to estimate the rate constants., Results: The standard three-compartment model appeared appropriate to describe 18F-FLT uptake. Corrections for blood volume, metabolites, and partial volume were necessary. Kinetic parameters were correlated with tumor pathology and clinical follow-up data. Two groups could be distinguished: lesions that were tumor predominant (TumP) and lesions that were treatment change predominant (TrcP). Both groups had a widely varying k1 (transport across the damaged BBB, range 0.02-0.2). Group TrcP had a relatively low k3 (phosphorylation rate, range 0.017-0.027), whereas k3 varied sevenfold in group TumP (range 0.015-0.11); the k3 differences were significant (p < 0.01). The fraction of transported FLT that is phosphorylated [k3/(k2+k3)] was able to separate the two groups (p < 0.001)., Conclusion: A three-compartment model with blood volume, metabolite, and partial volume corrections could adequately describe 18F-FLT kinetics in malignant brain tumors. Patients could be distinguished as having: (1) tumor-predominant or (2) treatment change-predominant lesions, with significantly different phosphorylation rates.

Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy., Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors., Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

Unlabelled: We evaluated the amino acid and glucose metabolism of brain tumors by using PET with 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine ((18)F-FDOPA) and (18)F-FDG., Methods: Eighty-one patients undergoing evaluation for brain tumors were studied. Initially, 30 patients underwent PET with (18)F-FDOPA and (18)F-FDG within the same week. Tracer kinetics in normal brain and tumor tissues were estimated. PET uptake was quantified by use of standardized uptake values and the ratio of tumor uptake to normal hemispheric tissue uptake (T/N). In addition, PET uptake with (18)F-FDOPA was quantified by use of ratios of tumor uptake to striatum uptake (T/S) and of tumor uptake to white matter uptake. The accuracies of (18)F-FDOPA and (18)F-FDG PET were determined by comparing imaging data with histologic findings and findings of clinical follow-up of up to 31 mo (mean, 20 mo). To further validate the accuracy of (18)F-FDOPA PET, (18)F-FDOPA PET was performed with an additional 51 patients undergoing brain tumor evaluation., Results: Tracer uptake in tumors on (18)F-FDOPA scans was rapid, peaking at approximately 15 min after intravenous injection. Tumor uptake could be distinguished from that of the striatum by the difference in peak times. Both high-grade and low-grade tumors were well visualized with (18)F-FDOPA. The sensitivity for identifying tumors was substantially higher with (18)F-FDOPA PET than with (18)F-FDG PET at comparable specificities, as determined by simple visual inspection, especially for the assessment of low-grade tumors. Using receiver-operating-characteristic curve analysis, we found the optimal threshold for (18)F-FDOPA to be a T/S of greater than 1.0 (sensitivity, 96%; specificity, 100%) or a T/N of greater than 1.3 (sensitivity, 96%; specificity, 86%). The high diagnostic accuracy of (18)F-FDOPA PET at these thresholds was confirmed with the additional 51 patients (a total of 81 patients: sensitivity, 98%; specificity, 86%; positive predictive value, 95%; negative predictive value, 95%). No significant difference in tumor uptake on (18)F-FDOPA scans was seen between low-grade and high-grade tumors (P = 0.40) or between contrast-enhancing and nonenhancing tumors (P = 0.97). Radiation necrosis was generally distinguishable from tumors on (18)F-FDOPA scans (P < 0.00001)., Conclusion: (18)F-FDOPA PET was more accurate than (18)F-FDG PET for imaging of low-grade tumors and evaluating recurrent tumors. (18)F-FDOPA PET may prove especially useful for imaging of recurrent low-grade tumors and for distinguishing tumor recurrence from radiation necrosis.

The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.

Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug., Experimental Design: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival., Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks., Conclusions: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.

Unlabelled: 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a recently developed PET tracer to image tumor cell proliferation. We characterized (18)F-FLT PET of brain gliomas and compared (18)F-FLT with (18)F-FDG PET in side-by-side studies of the same patients., Methods: Twenty-five patients with newly diagnosed or previously treated glioma underwent PET with (18)F-FLT and (18)F-FDG on consecutive days. Three stable patients in long-term remission were included as negative control subjects. Tracer kinetics in normal brain and tumor were measured. Uptake of (18)F-FLT and (18)F-FDG was quantified by the standardized uptake value (SUV) and the tumor-to-normal tissue (T/N) ratio. The accuracy of (18)F-FLT and (18)F-FDG PET in evaluating newly diagnosed and recurrent gliomas was compared. More than half of the patients underwent resection after the PET study and correlations between PET uptake and the Ki-67 proliferation index were examined. Patients were monitored for a mean of 15.4 mo (range, 12-20 mo). The predictive power of PET for tumor progression and survival was analyzed using Kaplan-Meier statistics., Results: (18)F-FLT uptake in tumors was rapid, peaking at 5-10 min after injection and remaining stable up to 75 min. Hence, a 30-min scan beginning at 5 min after injection was sufficient for imaging. (18)F-FLT visualized all high-grade (grade III or IV) tumors. Grade II tumor did not show appreciable (18)F-FLT uptake and neither did the stable lesions. The absolute uptake of (18)F-FLT was low (maximum-pixel SUV [SUV(max)], 1.33) but image contrast was better than with (18)F-FDG (T/N ratio, 3.85 vs. 1.49). (18)F-FDG PET studies were negative in 5 patients with recurrent high-grade glioma who subsequently suffered tumor progression within 1-3 mo. (18)F-FLT SUV(max) correlated more strongly with Ki-67 index (r = 0.84; P < 0.0001) than (18)F-FDG SUV(max) (r = 0.51; P = 0.07). (18)F-FLT uptake also had more significant predictive power with respect to tumor progression and survival (P = 0.0005 and P = 0.001, respectively)., Conclusion: Thirty-minute (18)F-FLT PET 5 min after injection was more sensitive than (18)F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, (18)F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.

Objectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs., Study Design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria., Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs., Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

In current clinical practice, histology-based grading of diffuse infiltrative gliomas is the best predictor of patient survival time. Yet histology provides little insight into the underlying biology of gliomas and is limited in its ability to identify and guide new molecularly targeted therapies. We have performed large-scale gene expression analysis using the Affymetrix HG U133 oligonucleotide arrays on 85 diffuse infiltrating gliomas of all histologic types to assess whether a gene expression-based, histology-independent classifier is predictive of survival and to determine whether gene expression signatures provide insight into the biology of gliomas. We found that gene expression-based grouping of tumors is a more powerful survival predictor than histologic grade or age. The poor prognosis samples could be grouped into three different poor prognosis groups, each with distinct molecular signatures. We further describe a list of 44 genes whose expression patterns reliably classify gliomas into previously unrecognized biological and prognostic groups: these genes are outstanding candidates for use in histology-independent classification of high-grade gliomas. The ability of the large scale and 44 gene set expression signatures to group tumors into strong survival groups was validated with an additional external and independent data set from another institution composed of 50 additional gliomas. This demonstrates that large-scale gene expression analysis and subset analysis of gliomas reveals unrecognized heterogeneity of tumors and is efficient at selecting prognosis-related gene expression differences which are able to be applied across institutions.

This adjunct to a prospective phase II blinded study of 48 patients with recurrent malignant glioma evaluated the predictive reliability of an extreme drug resistance (EDR) to identify clinical resistance to irinotecan (CPT-11), using fresh tumor biopsies obtained from recurrent patients immediately prior to their first dose of CPT-11 therapy. In vitro tumor response to SN38 (bioactive species of CPT-11 used in the EDR assay) determined prior to treatment was correlated with objective response, time to tumor progression (TTP) and survival following the administration of CPT-11. SN38 activity was tested in 19 of 29 tumors, with 15 of 18 assay results evaluable for correlation with clinical outcomes. In vitro drug resistance was classified as either extreme, intermediate (IDR), or low (LDR). TTP and survival were estimated by the Kaplan-Meier method, and compared using the Mantel-Haenszel log-rank and Fisher's exact test statistics. In vitro tumor response was bifurcated into either EDR (n = 4) or IDR/LDR (n = 11) categories for comparison with outcomes. Results correlated significantly with both TTP and survival. Median TTP for IDR/LDR cases was 3 months versus 6 weeks for EDR cases (log-rank test; p = 0.0288, hazards ratio = 3.06). A 13-week median survival for EDR cases was significantly shorter compared to 38 weeks for IDR/LDR cases (p = 0.029). Further, 100-day survival favored the IDR/LDR cases (Fisher's exact test; p = 0.008). At last follow-up, two of three survivors were patients who had tumors IDR/LDR to SN38. These prospective data support the notion that patients should avoid agents to which their tumor demonstrates EDR.

Purpose: Temozolomide (TMZ) and 13-cis-retinoic acid (cRA) have shown activity in prior single-agent trials of recurrent malignant gliomas (MG). This phase II trial evaluated efficacy and toxicity of combination temozolomide and cRA treatment in recurrent MG., Patients and Methods: Adults with recurrent supratentorial MG for whom surgery, radiation, and/or chemotherapy failed were eligible. Treatment included oral TMZ 150 or 200 mg/m2/d, days 1 through 5, and cRA 100 mg/m2/d, days 1 to 21, every 28 days. Primary end point was progression-free survival at 6 months (PFS 6); secondary end points included response, survival, and PFS12., Results: Eighty-eight eligible patients (glioblastoma multiforme [n = 40]; anaplastic gliomas [n = 48; astrocytoma, 28; oligodendroglioma, 14; mixed glioma, six]) received treatment. PFS 6 was 43% (95% confidence interval [CI], 33% to 54%) and PFS12 was 16% (95% CI, 10% to 26%). Median overall PFS was 19 weeks (95% CI, 16 to 27 weeks), and median overall survival (OS) was 47 weeks (95% CI, 36 to 58 weeks). OS was 46% (95% CI, 36% to 57%) at 52 weeks and 21% (95% CI, 13% to 31%) at 104 weeks. Of 84 assessable patients, there were two (3%) complete responses and eight (12%) partial responses (complete plus partial response, 15%). Among 499 treatment cycles, the most common grade 3/4 events included granulocytopenia (1.8%), thrombocytopenia (1.4%), and hypertriglyceridemia (1.2%)., Conclusion: TMZ and cRA were active, exceeding our 20% thresholds for PFS 6 success, assuming 20% improvement over our previously reported database (glioblastoma multiforme: expected, 30%; observed, 32%; anaplastic glioma: expected, 40%; observed, 50%).

Very few studies have been performed utilizing DSM criteria to diagnose major depressive disorder (MDD) in adult brain tumor patients. This study aimed to diagnose MDD in this population using DSM-IV criteria.Eighty-nine adult brain tumor patients were examined in an ambulatory neuro-oncology clinic setting using a structured psychiatric interview which followed current DSM-IV diagnostic criteria for MDD. This sample was interviewed and evaluated on a one-time basis. The patients were referred for evaluation on a consecutive basis. Multiple regression was used to model critical independent variables to predict MDD.Twenty-eight percent of the sample (N=89) were found to have major depressive disorder using DSM-IV criteria. Key predictors of MDD included frontal region of tumor location (p=0.001), combined sadness and lack of motivation symptoms (p=0.0001), and family psychiatric history (p=0.006). The multiple regression models account for 37% of variance in predicting MDD (R(2)=0.37).A substantially higher incidence of MDD was found in this sample of adult brain tumor patients compared with other adult, ambulatory cancer patients previously evaluated with DSM criteria. The incidence of MDD was about triple that found in other published studies using DSM criteria., (Copyright 2002 John Wiley & Sons, Ltd.)

This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m(2)). The trial was based on preclinical data and a prior phase I study ( J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 nonhematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens.

Short-interval scanning of patients offers a detailed understanding of the natural progression of tumor tissue, as revealed through imaging markers such as contrast enhancement and edema, prior to therapy. Following treatment, short-interval scanning can also provide evidence of attenuation of growth rates. We present a longitudinal imaging study of a patient with glioblastoma multiforme (GBM) scanned 15 times in 104 days on a 3 T MR scanner. Images were analyzed independently by two automated algorithms capable of creating detailed maps of tumor changes as well as volumetric analysis. The algorithms, a nearest-neighbor-based tissue segmentation and a surface-modeling algorithm, tracked the patient's response to temozolomide, showing an attenuation of growth. The need for surrogate imaging end-points, of which growth rates are an example, is discussed. Further, the strengths of these algorithms, the insight gained by short-interval scanning, and the need for a better understanding of imaging markers are also described.

Purpose: To evaluate the cause of complications in intraarterial chemotherapy for brain tumors and validate a dosage algorithm based on arterial territory., Materials and Methods: Four hundred sixty-two procedures were performed in 113 patients. Technique included pulsatile infusion of a chemotherapeutic agent. Dosage was calculated per hemisphere and divided per arterial territory according to a spatial dose fractionation algorithm based on the vascular territories of major cerebral arteries: middle cerebral artery, 60%; anterior cerebral artery, 20%; posterior cerebral artery, 15%; and perforator arteries, 5%. Hospital charts of all patients were retrospectively reviewed for complications, with specific attention given to the angiograms to determine a cause. Then, subgroup analysis of the chemotherapy protocol with the largest patient population was performed to evaluate predictors of complications., Results: Six (1.3%) complications were asymptomatic; 12 (2.6%), transient neurologic; three (0.6%), permanent minor neurologic; three (0.6%), permanent major neurologic; and 32 (7.0%), seizures. In the subgroup analysis, the hemispheric dose administered according to the algorithm was strongly predictive of seizure and neurologic deficit., Conclusion: Neurotoxicity of intraarterial cerebral chemotherapy can be minimized by using pulsatile injection and the described spatial dose fractionation algorithm.

Background and Purpose: Two 3D image analysis algorithms, nearest-neighbor tissue segmentation and surface modeling, were applied separately to serial MR images in patients with glioblastoma multiforme (GBM). Rates of volumetric change were tracked for contrast-enhancing tumor tissue. Our purpose was to compare the two image analysis algorithms in their ability to track tumor volume relative to a manually defined standard of reference., Methods: Three-dimensional T2-weighted and contrast-enhanced T1-weighted spoiled gradient-echo MR volumes were acquired in 10 patients with GBM. One of two protocols was observed: 1) a nearest-neighbor algorithm, which used manually determined or propagated tags and automatically segmented tissues into specific classes to determine tissue volume; or 2) a surface modeling algorithm, which used operator-defined contrast-enhancing boundaries to convert traced points into a parametric mesh model. Volumes were automatically calculated from the mesh models. Volumes determined by each algorithm were compared with the standard of reference, generated by manual segmentation of contrast-enhancing tissue in each cross section of a scan., Results: Nearest-neighbor algorithm enhancement volumes were highly correlated with manually segmented volumes, as were growth rates, which were measured in terms of halving and doubling times. Enhancement volumes generated by the surface modeling algorithm were also highly correlated with the standard of reference, although growth rates were not., Conclusion: The nearest-neighbor tissue segmentation algorithm provides significant power in quantifying tumor volume and in tracking growth rates of contrast-enhancing tissue in patients with GBM. The surface modeling algorithm is able to quantify tumor volume reliably as well.

Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine. A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed. To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acid-eluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway.

This study sought to correlate quantitative presurgical proton magnetic resonance spectroscopic imaging (1H-MRSI) and diffusion imaging (DI) results with quantitative histopathological features of resected glioma tissue. The primary hypotheses were (1) glioma choline signal correlates with cell density, (2) glioma apparent diffusion coefficient (ADC) correlates inversely with cell density, (3) glioma choline signal correlates with cell proliferative index. Eighteen adult glioma patients were preoperatively imaged with 1H-MRSI and DI as part of clinically-indicated MRI evaluations. Cell density and proliferative index readings were made on surgical specimens obtained at surgery performed within 12 days of the radiologic scans. The resected tissue location was identified by comparing preoperative and postoperative MRI. The tumor to contralateral normalized choline signal ratio (nCho) and the ADC from resected tumor regions were measured from the preoperative imaging data. Counts of nuclei per high power field in 5-10 fields provided a quantitative measure of cell density. MIB-1 immunohistochemistry provided an index of the proportion of proliferating cells. There was a statistically significant inverse linear correlation between glioma ADC and cell density. There was also a statistically significant linear correlation between the glioma nCho and the cell density. The nCho measure did not significantly correlate with proliferative index. The results indicate that both ADC and spectroscopic choline measures are related to glioma cell density. Therefore they may prove useful for differentiating dense cellular neoplastic lesions from those that contain large proportions of acellular necrotic space.

Background and Purpose: Factors predictive of primary brain tumor outcome have been studied extensively, although the prognostic value of radiologic data, such as MR imaging and angiographic characteristics, has not been studied in depth. The purpose of this study was to determine whether radiologic data were prognostic factors among patients with recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy., Methods: Forty-six patients were enrolled in a Phase II study of intra-arterial chemotherapy with carboplatin and Cereport (Alkermes Inc.; Cambridge, MA), a bradykinin analog that selectively increases permeability of the blood-tumor barrier. MR imaging volumes of enhancing tumor, resection cavity, and T2 signal abnormality were measured with T1-weighted and T2-weighted sequences. Volumes were analyzed individually and in various combinations. Tumor vascularity was graded on angiograms. Outcome was measured by time to tumor progression and survival., Results: Of 46 patients included in this study, 41 underwent evaluation. Thirty were male and 11 were female; mean age was 48.5 years. Karnofsky scores ranged from 70 to 100. Thirty-two patients had glioblastoma multiforme, whereas nine had anaplastic astrocytoma. Twenty-eight patients had tumor progression and 13 had stable disease. Twenty-three patients died after an average of 205 days; 18 were surviving at an average of 324 days from the start of intra-arterial chemotherapy. In multivariate analysis, time from diagnosis to intra-arterial chemotherapy was predictive both of time to tumor progression and survival. Net tumor volume and vascularity also were significant for survival. Age, Karnofsky performance status, histologic findings, gender, MR imaging area, resection cavity volume, T2 signal abnormality volume, and various combined volumes were not significant., Conclusion: If confirmed by further studies, radiologic factors such as tumor volume and angiographic vascularity should be considered in design and stratification of future chemotherapy trials.

Object: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals., Methods: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells., Conclusions: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.

Objective: Animal and human studies have shown increased delivery of radiolabeled compounds across the blood-brain-tumor barrier using intra-arterial (IA) Cereport (RMP-7; Alkermes Inc., Cambridge, MA) with a radiolabeled tracer. This present study assesses the safety, tolerance, and preliminary efficacy of the IA administration of carboplatin with Cereport., Methods: An open-label dose escalation study of IA Cereport (10-300 ng/kg) with 100 mg of IA carboplatin was conducted in 11 patients with recurrent malignant gliomas and 1 patient treated adjuvantly after radiation therapy. Tumor size and laboratory and clinical statuses were assessed., Results: Adverse events were mainly neurological in nature and corresponded to the anatomic location of the tumor. Karnofsky performance scale scores did not decline, overall, for those patients who had tumor response. Tumor shrinkage was observed in three of six evaluable patients who received a dose of 300 ng/kg with durable responses of 60, 64, and 106+ weeks., Conclusion: Previous studies have demonstrated increased permeability in human gliomas using IA Cereport. This study demonstrates durable imaging responses using 100 mg of IA carboplatin in combination with Cereport. The drug combination in this patient population seems to be safe and acceptable, providing a novel means of antitumor dose intensification.

Magnetic resonance spectroscopy and diffusion magnetic resonance imaging (MRI) characteristics of human intracranial glioma were studied. Present knowledge suggests a hypothetical inverse relationship between the characteristic choline signal intensity elevation and the apparent diffusion coefficient (ADC) in glioma. Twenty cases of glioma were examined with diffusion-weighted echoplanar imaging and proton magnetic resonance spectroscopic imaging (1H-MRSI). A statistically significant inverse correlation between the choline signal intensity and the ADC was found (P = 0.0004) in radiologically defined tumor-containing regions. This study is the first in which diffusion MRI and 1H-MRSI were used to evaluate human intracranial glioma jointly. It provides insight into how to interpret choline signal intensity elevation in terms of tumor cellularity and proliferative potential when ADC images are also available.

Purpose: To perform in intra-arterial dose escalation study of carboplatin based on hemispheric blood-flow estimation in patients with recurrent malignant glioma. The primary purpose was to determine the maximally tolerated intra-arterial dose., Methods and Patients: Methods included: 1) selective intra-arterial delivery performed with modern microcatheters, 2) pulsatile infusion, and 3) dosage based on local cerebral blood-flow estimation (middle cerebral artery 60%, anterior cerebral artery 20%, posterior cerebral artery 15%, and anterior choroidal artery 5% of the hemispheric blood-flow). The deliveries were performed above the ophthalmic artery in the anterior circulation, or above the anterior inferior cerebellar arteries in the posterior circulation. The doses were escalated from 200 mg/hemisphere at 50 mg increments. Twenty-one patients were studied (14 with glioblastoma multiforme, five anaplastic astrocytoma, one aggressive low-grade glioma, one metastasis). Patients had recurrent glioma limited to one hemisphere and Karnofsky score of 50 or greater. Concomitant therapies were allowed., Results: Carboplatin was escalated to a dose of 1400 mg/hemisphere. One patient had a permanent neuromotor decline. The predominant toxicity was hematopoietic. The median time to tumor progression was 22 weeks, median survival 39 weeks, and the response rate 70% (50% SD and 20% PR) of 19 patients., Conclusions: Hemispheric blood-flow estimation allowed us to escalate the dose of intra-arterial carboplatin to twice what was previously considered safe. Responses compared favorably to previous studies. Further studies are needed to determine if this method will provide improved and durable responses.

Traditional study design for treatment of malignant gliomas does not allow tumor progression to be greater than 25-50 percent without terminating treatment. This design may prevent recognition of patients who benefit from the treatment either by slowed growth or delayed response. A delayed response or slowed growth may be characteristic of biologic agents being evaluated in the treatment of malignant glioma. Because of the low toxicity of certain biologic drugs, continued treatment through tumor growth can be ethically considered in study design. The effect of biologic agents on a neoplasm may include cellular differentiation, retardation of growth, cytostasis, cytocidal effects, or apoptosis. Such effects may clinically translate into a complete response, partial response, stable disease or retardation of growth with or without an eventual reduction of tumor. We present a patient with a recurrent malignant glioma who was continued on high dose tamoxifen despite radiologic documented doubling of the tumor size and who eventually showed a delayed response to this agent nine months after initiation of treatment. Strong consideration should be given to the prolonged treatment of non-toxic biologic agents in a controlled clinical trial, where agents have shown some benefit in phase one studies.

The bradykinin analog, RMP-7, was investigated for its ability to increase selectively the transport of 68Ga ethylenediamine tetraacetic acid (EDTA) into recurrent malignant gliomas in nine patients. For each patient, two position emission tomography (PET) studies (one with and one without RMP-7) were performed. For studies with RMP-7, 10 to 300 ng/kg of the compound was infused into the supraophthalmic carotid artery over 15 minutes. In each PET study, a sequence of PET scans was initiated simultaneously with an intravenous bolus of 68Ga EDTA (5-10 mCi). Arterial samples were taken to provide the input function. All PET scans were coregistered to the magnetic resonance (MR) images of the patient. Regions of interest were defined for tumor and normal tissue regions on MR images and were copied to the coregistered PET dynamic images to provide brain tissue-time activity curves. The constant (Ki) for the transport of gallium-68 from plasma to brain tissue was determined using a simple compartmental model. Intracarotid infusion of RMP-7 significantly increased transport into tumor regions with an average increase of 46 +/- 42% (mean +/- standard deviation, p < 0.05). Permeability in normal tissue regions was not significantly increased. Tumors in three of six patients treated with 300 ng/kg RMP-7 and carboplatin had at least a 50% reduction in tumor volume as measured by MR imaging. Intracarotid infusion of RMP-7 is a novel technique for selective delivery of antitumor compounds into brain tumors.

Vasoactive agents have been identified through studies of peritumoral edema and effects on systemic capillaries. Abnormal blood-brain barrier or blood-tumor barrier can develop transient increases in permeability with the intraarterial delivery of vasoactive agents. Normal blood-brain barrier resists the effects of these compounds because of a biochemical barrier that may inactivate or become inert to vasoactive agents. Vasoactive compounds, including leukotrienes, bradykinin, and histamine appear to selectively increase permeability in abnormal brain capillaries. Intracarotid infusion of leukotrienes, bradykinin, and other vasoactive agents can increase drug delivery to diseased tissue.

Median nerve somatosensory evoked potentials were recorded from exposed cerebral cortex during craniotomies. This technique is valuable when knowledge of the motor cortex location can influence surgical decisions about resection limits or biopsy sites. Two different recording techniques were compared: strips of electrodes and arrays of electrodes. The arrays recorded electrical potentials suitable for topographic mapping. We found that motor cortex could be identified more quickly when using the topographic mapping of SEPs from arrays. We conclude that topographic mapping of SEP from sensorimotor regions during craniotomies works well in general and can be done more quickly than the traditional electrode strip technique.