Occupational exposure to magnetic fields and the risk of brain tumors.

We investigated the association between occupational exposure to extremely low-frequency magnetic fields (MFs) and the risk of glioma and meningioma. Occupational exposure to MF was assessed for 489 glioma cases, 197 meningioma cases, and 799 controls enrolled in a hospital-based case-control study. Lifetime occupational history questionnaires were administered to all subjects; for 24% of jobs, these were supplemented with job-specific questionnaires, or "job modules," to obtain information on the use of electrically powered tools or equipment at work. Job-specific quantitative estimates for exposure to MF in milligauss were assigned using a previously published job exposure matrix (JEM) with modification based on the job modules. Jobs were categorized as < or =1.5 mG, >1.5 to <3.0 mG, and > or =3.0 mG. Four exposure metrics were evaluated: (1) maximum exposed job; (2) total years of exposure >1.5 mG; (3) cumulative lifetime exposure; and (4) average lifetime exposure. Odds ratios (ORs) were calculated using unconditional logistic regression with adjustment for the age, gender, and hospital site. The job modules increased the number of jobs with exposure > or =3.0 mG from 4% to 7% relative to the JEM. No statistically significant elevation in ORs or trends in ORs across exposure categories was observed using four different exposure metrics for the three tumor types analyzed. Occupational exposure to MFs assessed using job modules was not associated with an increase in the risk for glioma, glioblastoma, or meningioma among the subjects evaluated in this study.

Treatment modalities for leptomeningeal metastases.

Secondary involvement of the leptomeninges represents an infrequent but devastating (and nearly always fatal) complication of solid tumors, hematologic malignancies (both leukemia and lymphoma), and primary brain tumors. Clinical suspicion of neoplastic meningitis (NM) may be raised by the appearance of multivariate neurological symptoms; however, a definitive diagnosis is often difficult to obtain. Improved treatments for primary malignancies and advances in diagnostic imaging technology have led to an apparent increase in the number of patients diagnosed with NM. Unfortunately, therapeutic options remain limited, particularly for patients with chemoresistant tumors. Optimized treatment remains controversial and may rely upon a combination of chemotherapy (intrathecal and/or intravenous) and concurrent focal radiotherapy. This review discusses the advantages and disadvantages of intra-cerebrospinal fluid (CSF) versus systemic strategies for treating NM. Clinical trial evidence is presented for the different treatment modalities. In addition, the therapeutic potential of intra-CSF therapy for cancer prophylaxis is discussed. Earlier diagnosis and more aggressive preventive treatment regimens may provide substantial increases in survival and favorably affect quality of life. Additional data from large-scale, well-controlled trials are required to more accurately assess the efficacy of intra-CSF versus systemic treatment in NM. Future treatment options using novel targets for intra-CSF therapy will be addressed as well.

Oxidative response gene polymorphisms and risk of adult brain tumors.

Oxidative stress is believed to play a key role in tumor formation. Although this mechanism could be especially pertinent for brain tumors given the high oxygen consumption of the brain, very little has been published regarding brain tumor risk with respect to genes mediating oxidative stress. Using data from non-Hispanic whites in a hospital-based case-control study conducted by the National Cancer Institute between 1994 and 1998, we evaluated risk of glioma (n=362), meningioma (n=134), and acoustic neuroma (n=69) compared to noncancer controls (n=494) with respect to nine single nucleotide polymorphisms from seven genes involved in oxidative stress response (CAT, GPX1, NOS3, PON1, SOD1, SOD2, and SOD3). We observed increased risk of glioma (odds ratio [OR](CT/CC)=1.3; 95% confidence interval [95% CI], 1.0-1.7) and meningioma (OR(CT/CC)=1.7; 95% CI, 1.1-2.7) with the C variant of SOD3 rs699473. There was also indication of increased acoustic neuroma risk with the SOD2 rs4880 Ala variant (OR(CT/CC)=2.0; 95% CI, 1.0-4.2) and decreased acoustic neuroma risk with the CAT rs1001179 T allele variant (OR(CT/TT)=0.6; 95% CI, 0.3-1.0). These relationships persisted when major groups of disease controls were excluded from the analysis. Our results suggest that common variants in the SOD2, SOD3, and CAT genes may influence brain tumor risk.

Genetic variation in insulin-like growth factors and brain tumor risk.

Many studies support a role for insulin-like growth factors (IGFs) in the regulation of tumor cell biology. We hypothesized that single-nucleotide polymorphisms (SNPs) in IGF genes are risk factors for glioma and meningioma. To test the hypothesis, we examined associations of brain tumor risk with nine variants in five IGF genes in a hospital-based case-control study. The study was conducted at hospitals in Boston, Phoenix, and Pittsburgh between 1994 and 1998. Eligible cases were individuals (18 years or older) newly diagnosed with glioma or meningioma. Controls were selected among patients who were admitted to the same hospitals for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race, and distance from residence. The present analysis was restricted to non-Hispanic whites. DNA was extracted from blood samples collected from 354 glioma cases, 133 meningioma cases, and 495 control individuals. We evaluated nine SNPs in five IGF genes (IGF1, IGF1R, IGF2, IGF2R, and IGFBP3). The majority of the analyzed IGF SNPs did not display statistically significant associations with glioma or meningioma. For glioma, one IGF1R SNP (rs2272037) indicated a possible association. No indications of association were seen for glioblastoma, but for low-grade gliomas, the odds ratio under a dominant model was 0.56 (95% confidence interval [CI], 0.35-0.90) for IGF1 rs6220, 2.98 (95% CI, 1.65-5.38) for IGF1R rs2272037, and 1.60 (95% CI, 0.90-2.83) for IGF1R rs2016347. Overall, our results do not provide strong evidence of associations of brain tumor risk with IGF polymorphic variants but identify several associations for glioma that warrant further examination in other, larger studies.

Polymorphisms in apoptosis and cell cycle control genes and risk of brain tumors in adults.

Despite the potential importance of the cell cycle and apoptosis pathways in brain tumor etiology, little has been published regarding brain tumor risk associated with common gene variants in these pathways. Using data from a hospital-based case-control study conducted by the National Cancer Institute between 1994 and 1998, we evaluated risk of glioma (n = 388), meningioma (n = 162), and acoustic neuroma (n = 73) with respect to 12 single nucleotide polymorphisms from 10 genes involved in apoptosis and cell cycle control: CASP8, CCND1, CCNH, CDKN1A, CDKN2A, CHEK1, CHEK2, MDM2, PTEN, and TP53. We observed significantly decreased risk of meningioma with the CASP8 Ex14-271A>T variant [odds ratio (OR)(AT), 0.8; 95% confidence interval (95% CI), 0.5-1.2; OR(AA), 0.5; 95% CI, 0.3-0.9; P(trend) = 0.03] and increased risk of meningioma with the CASP8 Ex13+51G>C variant (OR(GC), 1.4; 95% CI, 0.9-2.1; OR(CC), 3.6; 95% CI, 1.0-13.1; P(trend) = 0.04). The CT haplotype of the two CASP8 polymorphisms was associated with significantly increased risk of meningioma (OR, 1.7; 95% CI, 1.1-2.6), but was not associated with risk of glioma or acoustic neuroma. The CCND1 Ex4-1G>A variant was associated with increased risk for glioma, and the Ex8+49T>C variant of CCNH was associated with increased risk of glioma and acoustic neuroma. The MDM2 Ex12+162A>G variant was associated with significantly reduced risk of glioma. Our results suggest that common variants in the CASP8, CCND1, CCNH, and MDM2 genes may influence brain tumor risk. Future research in this area should include more detailed coverage of genes in the apoptosis/cell cycle control pathways.

Lead, genetic susceptibility, and risk of adult brain tumors.

BACKGROUND: Although few etiologic factors for brain tumors have been identified, limited data suggest that lead may increase the risk of brain tumors, particularly meningioma. The ALAD G177C polymorphism affects the toxicokinetics of lead and may confer genetic susceptibility to adverse effects of lead exposure. METHODS: We examined occupational exposure to lead and risk of brain tumors in a multisite, hospital-based, case-control study of 489 patients with glioma, 197 with meningioma, and 799 non-cancer controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to hospital. ALAD genotype was assessed by a Taqman assay for 355 glioma patients, 151 meningioma patients, and 505 controls. Exposure to lead was estimated using a rigorous questionnaire-based exposure assessment strategy incorporating lead measurement and other occupational data abstracted from published articles and reports. RESULTS: Increased risk of meningioma with occupational lead exposure (estimated by odds ratios and 95% confidence intervals) was most apparent in individuals with the ALAD2 variant allele, for whom risk increased from 1.1 (0.3-4.5) to 5.6 (0.7-45.5) and 12.8 (1.4-120.8) for estimated cumulative lead exposures of 1 to 49 microg/m3-y, 50 to 99 microg/m3-y, and >or=100 microg/m3-y, respectively, compared with unexposed individuals (two-sided P trend = 0.06). This relationship became stronger after excluding occupational lead exposures characterized by a low confidence level or occurring in the 10 years before meningioma diagnosis. Occupational lead exposure was not associated with glioma risk. CONCLUSIONS: Although our results indicate that lead may be implicated in meningioma risk in genetically susceptible individuals, these results need to be interpreted with caution given the small numbers of exposed cases with a variant genotype.

Variation in genes relevant to aromatic hydrocarbon metabolism and the risk of adult brain tumors.

Genes involved in phase I and phase II regulation of aromatic hydrocarbon-induced effects exhibit sequence variability that may mediate the risk of adult brain tumors. We evaluated associations between gene variants in CYP1A1, CYP1B1, GSTM3, EPHX1, and NQO1 and adult brain tumor incidence. Cases were patients with glioma (n = 489), meningioma (n = 197), or acoustic neuroma (n = 96) diagnosed from 1994 to 1998 at three U.S. hospitals. Controls were 799 patients admitted to the same hospitals for nonmalignant conditions. DNA was extracted from blood samples collected from 1277 subjects, and genotyping was conducted for CYP1A1 I462V, CYP1B1 V432L, EPHX1 Y113H, GSTM3 *A/*B (intron 6 deletion), and NQO1 P187S. The CYP1B1 V432L homozygous variant was associated with decreased risk of meningioma (odds ratio [OR] = 0.6; 95% CI, 0.3-1.0) but not the other tumor types. The GSTM3 *B/*B genotype was associated with increased risk of glioma (OR = 2.3; 95% CI, 1.0-5.2) and meningioma (OR = 3.6; 95% CI, 1.3-9.8). Increased risks associated with GSTM3 *B/*B were observed in younger subjects (age < 50) and older subjects (age > or = 50), in men and women, and within each study site. The magnitude of association for GSTM3 with glioma and meningioma was greater among ever-smokers than among those who had never smoked. None of the other genotypes showed consistent associations with any tumor type. The association with the GSTM3 *B allele, while intriguing, requires replication, and additional research is needed to clarify the function of the GSTM3 alleles studied here.

A changing paradigm of glioma biology.

The past 30 years have witnessed a major paradigm shift in brain tumor research with the development of a wide variety of molecular biology techniques. These methods have permitted a better understanding of the pathogenesis of gliomas including the finding of neural stem cells that contribute to the establishment and continuous population of brain tumors. Molecular biology has contributed to our understanding of prognosis in these tumors with findings of genetic correlations to patient age, response to treatment, and outcome. Gene therapy has been made possible by molecular techniques that contribute to new treatment options. Nevertheless, if these advances are to make substantial clinical improvements, attention must be paid to issues of tumor evolution, local versus general pathogenesis, tumor heterogeneity, both general and regional, and the development of resistance to treatment. Appropriate clinical trials will be needed to test these new findings.

Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points.

PURPOSE: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases. PATIENTS AND METHODS: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points. RESULTS: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium's tumor selectivity was established with MRI. CONCLUSION: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.

Delta-aminolevulinic acid dehydratase polymorphism and risk of brain tumors in adults.

The enzyme delta-aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme synthesis, can be inhibited by several chemicals, including lead, a potential risk factor for brain tumors, particularly meningioma. In this study we examined whether the ALAD G177C polymorphism in the gene coding for ALAD is associated with risk of intracranial tumors of the brain and nervous system. We use data from a case-control study with 782 incident brain tumor cases and 799 controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to the hospital. Blood samples were drawn and DNA subsequently sent for genotyping for 73% of subjects. ALAD genotype was determined for 94% of these samples (355 glioma, 151 meningioma, 67 acoustic neuroma, and 505 controls). Having one or more copy of the ALAD2 allele was associated with increased risk for meningioma [odds ratio (OR) = 1.6; 95% confidence interval (CI), 1.0-2.6], with the association appearing stronger in males (OR = 3.5; 95% CI, 1.3-9.2) than in females (OR = 1.2; 95% CI, 0.7-2.2). No increased risk associated with the ALAD2 variant was observed for glioma or acoustic neuroma. These findings suggest that the ALAD2 allele may increase genetic susceptibility to meningioma.

Handedness and risk of brain tumors in adults.

The objective of this study was to evaluate the relation between handedness, and the risk of malignant and benign brain tumors. Handedness has been hypothesized to serve as a behavioral marker of prenatal hormonal exposures or other factors that influence subsequent cancer risk. A case-control study was conducted at hospitals in three United States cities between 1994 and 1998. The cases were adult patients newly diagnosed with glioma (n = 489), meningioma (n = 197), or acoustic neuroma (n = 96), and the 799 frequency-matched controls were patients admitted to the same hospitals for a variety of nonmalignant conditions. Handedness was determined by interview. Unconditional logistic regression was used to estimate odds ratios (ORs) and calculate 95% confidence intervals (CIs). Persons who described themselves as left-handed or ambidextrous appeared to be at reduced risk of glioma relative to those who described themselves as right-handed (OR, 0.7; 95% CI, 0.5-0.9). The association was similar for men and women, and for left-sided and right-sided tumors. Neither meningioma (OR, 0.9; CI, 0.6-1.5) nor acoustic neuroma (OR, 0.9; CI, 0.5-1.7) showed significant associations with handedness. These findings require confirmation but raise the possibility that early neurodevelopmental events or genetic factors related to handedness also influence the risk of glioma among adults.

Cancer in first-degree relatives and risk of glioma in adults.

Relatively few studies have examined glioma risk in relation to history of cancer in first-degree relatives. We sought to describe such risks in a large hospital-based case-control study. Histologically confirmed incident adult glioma cases (n = 489) were identified at three regional referral hospitals between June 1994 and August 1998. Controls (n = 799) admitted to the same hospitals for nonmalignant conditions were frequency-matched on age, sex, race/ethnicity, hospital, and proximity of residence to hospital. Participants received a personal interview, including questions regarding cancer in family members. Odds ratios (ORs) were calculated to estimate the risk of glioma associated with a history of cancer in a first-degree relative using conditional logistic regression and compared with standardized incidence ratios among relatives of cases versus relatives of controls. Among participants reporting a family history of a brain cancer or a brain tumor, risk of glioma was 1.6 [95% confidence interval (CI), 0.5-5.3; n = 5] and 3.0 (95% CI, 0.9-10.8; n = 7), respectively, in comparison with those without such family histories. Participants who had a family history of stomach (OR, 2.2; 95% CI, 1.0-4.6), colon (OR, 1.4; 95% CI, 0.9-2.2), or prostate cancer (OR, 2.1; 95% CI, 1.1-3.8) or Hodgkin disease (OR, 2.4; 95% CI, 0.9-6.3) had an increased glioma risk. OR estimates were similar to the ratios of standardized incidence ratios for cancer in relatives of cases versus controls. Shared environmental or genetic factors in families may influence glioma risk. Our findings suggest that individuals with a family history of specific cancers other than glioma may have an increased glioma risk.

Genetic polymorphisms in GSTM1, -P1, -T1, and CYP2E1 and the risk of adult brain tumors.

GST and CYP2E1 genes are involved in metabolism of several compounds (e.g., solvents) that may play a role in brain cancer etiology. We evaluated associations between polymorphisms in these genes and adult brain tumor incidence. Cases were 782 patients with brain tumors diagnosed from 1994 to 1998 at three United States hospitals. Controls were 799 patients admitted to the same hospitals for nonmalignant conditions. DNA was extracted from blood samples that had been collected from 1277 subjects (80% of all subjects; 604 controls; 422 gliomas, 172 meningiomas, and 79 acoustic neuromas), and genotyping was successfully conducted for GSTM1 null, GSTT1 null, GSTP I105V, GSTP A114V, CYP2E1 RsaI, and CYP2E1 Ins96. The GSTP1 105 Val/Val genotype was associated with increased glioma incidence [odds ratio (OR), 1.8; 95% confidence limits (CLs), 1.2, 2.7], with the estimated effect following a trend of increasing magnitude by number of variant alleles (Ile/Ile: OR, 1.0; Ile/Val: OR, 1.3; Val/Val: OR, 2.1). The CYP2E1 RsaI variant was weakly associated with glioma (OR, 1.4; 95% CL, 0.9, 2.4) and acoustic neuroma (OR, 2.3; 95% CL, 1.0, 5.3), with some indication of stronger associations among younger subjects. Estimated effects of the gene variants differed by glioma subtype. There was evidence of supermultiplicativity of the joint effect of GSTP1 I105V and CYP2E1 RsaI variants on both glioma and acoustic neuroma, even following adjustment of estimates toward a common prior distribution using hierarchical regression models. Previously reported associations between the GSTT1 null genotype and overall glioma incidence were not replicated, but an association with meningioma was observed (OR, 1.5; 95% CL, 1.0, 2.3). These findings may provide clues to both genetic and environmental determinants of brain tumors.

Meningioma and schwannoma risk in adults in relation to family history of cancer.

Relatively little is known about factors that contribute to the development of meningioma and vestibular schwannoma, two intracranial nervous system tumors. We evaluated the risk of these tumors in relation to family history of malignant or benign tumors. Incident cases of meningioma (n = 197) or schwannoma (n = 96) were identified at three U. S. referral hospitals between June 1994 and August 1998. Controls (n = 799) admitted to the same hospitals for nonmalignant conditions were matched to cases on age, sex, race/ethnicity, hospital, and proximity of residence to hospital. We found that risk of meningioma was increased among persons reporting a family history of a benign brain tumor (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.0-21.0; n = 5) or melanoma (OR, 4.2; 95% CI, 1.2-15.0; n 5). A family history of breast cancer was associated with an elevated meningioma risk among participants aged 18 to 49 years (OR, 3.9; 95% CI, 1.4-11.0; n = 8) but a reduced risk among older respondents (OR, 0.2; 95% CI, 0.1-0.7; n = 3). Family history of cancer did not differ between schwannoma cases and controls, although the statistical power to detect associations was limited. Some relative risk estimates were based on a small number of observations and may have arisen by chance. Inheritance of predisposing genes, shared environmental factors, or both within families with a history of benign brain tumors, melanoma, or possibly breast cancer may be related to altered meningioma risk.

Sociodemographic indicators and risk of brain tumours.

BACKGROUND: To better understand patterns of occurrence or diagnosis of brain tumours in different segments of the population, we evaluated associations between sociodemographic variables and the relative incidence of brain tumours as part of a multi-faceted case-control study. METHODS: The study was conducted at hospitals in three US cities between 1994 and 1998. In all, 489 glioma cases (354 high-grade, 135 low-grade), 197 meningioma cases, 96 acoustic neuroma cases, and 799 controls admitted to the same hospitals for any of a variety of non-neoplastic diseases or conditions were enrolled and interviewed. Logistic regression was used to estimate odds ratios (OR), calculate 95% CI, and test for trends. RESULTS: The OR showed significant positive associations with household income for low-grade glioma, meningioma, and acoustic neuroma, but not for high-grade glioma. Positive associations were observed with level of education for low-grade glioma and acoustic neuroma, but not for high-grade glioma or meningioma. Jewish religion was associated with a significantly elevated risk for meningioma (OR = 4.3; 95% CI: 2.0-9.0). Being single at the time of tumour diagnosis or enrolment was associated with significantly reduced risks for meningioma (OR = 0.4; 95% CI: 0.3-0.6) and low- or high-grade glioma (OR = 0.6; 95% CI: 0.5-0.8), but not for acoustic neuroma. CONCLUSIONS: Associations with sociodemographic variables varied considerably among the different subtypes of brain tumour, including between low-grade and high-grade glioma. The general pattern was for associations with indicators of affluence and education to be stronger for tumours that tend to grow more slowly and have less catastrophic effects, although the evidence was mixed for meningioma. We cannot isolate the specific factors underlying the observed associations, but intrapopulation differences in the completeness or timing of diagnosis may have played a role. There is less opportunity for such influences to operate for the rapidly progressing, high-grade gliomas than for more slowly growing tumours.

The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine.

OBJECTIVE: The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas. METHODS: The study involved a randomized comparison of surgery, external beam radiotherapy, and carmustine (BCNU) versus surgery, external beam therapy, interstitial radiotherapy boost, and BCNU in newly diagnosed malignant gliomas. (125)I was chosen as best suited for this effort because it allowed preimplantation planning and postimplantation quality assurance review. Two hundred ninety-nine patients met the eligibility criteria and were randomized into the two arms of the study between December 1987 and April 1994. Follow-up continued for an additional 3 years. Twenty-nine patients were identified as having committed protocol violations and were excluded, resulting in 270 subjects in the Valid Study Group. One hundred thirty-seven patients received external beam radiation and BCNU, and 133 underwent the (125)I implantation plus external beam radiation and BCNU therapy. RESULTS: The overall median survival for the Valid Study Group was 64.3 weeks. The median survival for patients receiving additional therapy of (125)I was 68.1 weeks, and median survival for those receiving only external beam radiation and BCNU was 58.8 weeks. The cumulative proportion surviving between the two treatment groups was not statistically significantly different (log-rank test, P = 0.101). As in other studies in the literature, age, Karnofsky score, and pathology were predictors of mortality. Additional analyses incorporating an adjustment for these prognostic variables, either in a stratified analysis or Cox proportional hazards model, did not result in statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups. CONCLUSION: We conclude that there is no long-term survival advantage of increased radiation dose with (125)I seeds in newly diagnosed glioma patients.

AKT pathway genes define 5 prognostic subgroups in glioblastoma.

Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU (median survival 5.8 vs. 1.5 years; BCNU/CCNU vs other treatments; respectively). AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets.

Magnetic resonance imaging volumetric assessment of the extent of contrast enhancement and resection in oligodendroglial tumors.

OBJECT: Oligodendrogliomas that enhance on MR images are associated with poor prognosis. However, the importance of the volume of enhancing tumor tissue, and the extent of its resection, is uncertain. The authors examined the prognostic significance of preoperative and residual postoperative enhancing tissue volumes in a large single-center series of patients with oligodendroglioma. They also examined the relationship between enhancement and characteristic genetic signatures in oligodendroglial tumors, specifically deletion of 1p and 19q (del 1p/19q). METHODS: The authors retrospectively analyzed 100 consecutive cases of oligodendroglioma involving patients who had undergone T1-weighted gadolinium-enhanced MRI at diagnosis and immediately after initial surgical intervention. The presence of preoperative enhancement was determined by consensus. Preoperative and residual postoperative volumes were measured using a quantitative, semiautomated method by a single blinded observer. Intrarater reliability for preoperative volumes was confirmed by remeasurement in a subset of patients 3 months later. Intrarater and interrater reliability for residual postoperative volumes was confirmed by remeasurement of these volumes by both the original and a second blinded observer. Multivariate analysis was used to assess the influence of contrast enhancement at diagnosis and the volume of pre- and postoperative contrast-enhancing tumor tissue on time to relapse (TTR) and overall survival (OS), while controlling for confounding clinical, pathological, and genetic factors. RESULTS: Sixty-three of 100 patients had enhancing tumors at initial presentation. Presence of contrast enhancement at diagnosis was related to reduced TTR and OS on univariate analysis but was not significantly related on multivariate analysis. In enhancing tumors, however, greater initial volume of enhancing tissue correlated with shortened TTR (p = 0.00070). Reduced postoperative residual enhancing volume and a relatively greater resection of enhancing tissue correlated with longer OS (p = 0.0012 and 0.0041, respectively). Interestingly, patients in whom 100% of enhancing tumor was resected had significantly longer TTR (174 vs 64 weeks) and OS (392 vs 135 weeks) than those with any residual enhancing tumor postoperatively. This prognostic benefit was not consistently maintained with greater than 90% or even greater than 95% resection of enhancing tissue. There was no relationship between presence or volume of enhancement and del 1p/19q. CONCLUSIONS: In enhancing oligodendrogliomas, completely resecting enhancing tissue independently improves outcome, irrespective of histological grade or genetic status. This finding supports aggressive resection and may impact treatment planning for patients with these tumors.

Reevaluating the imaging definition of tumor progression: perfusion MRI quantifies recurrent glioblastoma tumor fraction, pseudoprogression, and radiation necrosis to predict survival.

INTRODUCTION: Contrast-enhanced MRI (CE-MRI) represents the current mainstay for monitoring treatment response in glioblastoma multiforme (GBM), based on the premise that enlarging lesions reflect increasing tumor burden, treatment failure, and poor prognosis. Unfortunately, irradiating such tumors can induce changes in CE-MRI that mimic tumor recurrence, so called post treatment radiation effect (PTRE), and in fact, both PTRE and tumor re-growth can occur together. Because PTRE represents treatment success, the relative histologic fraction of tumor growth versus PTRE affects survival. Studies suggest that Perfusion MRI (pMRI)-based measures of relative cerebral blood volume (rCBV) can noninvasively estimate histologic tumor fraction to predict clinical outcome. There are several proposed pMRI-based analytic methods, although none have been correlated with overall survival (OS). This study compares how well histologic tumor fraction and OS correlate with several pMRI-based metrics. METHODS: We recruited previously treated patients with GBM undergoing surgical re-resection for suspected tumor recurrence and calculated preoperative pMRI-based metrics within CE-MRI enhancing lesions: rCBV mean, mode, maximum, width, and a new thresholding metric called pMRI-fractional tumor burden (pMRI-FTB). We correlated all pMRI-based metrics with histologic tumor fraction and OS. RESULTS: Among 25 recurrent patients with GBM, histologic tumor fraction correlated most strongly with pMRI-FTB (r = 0.82; P < .0001), which was the only imaging metric that correlated with OS (P<.02). CONCLUSION: The pMRI-FTB metric reliably estimates histologic tumor fraction (i.e., tumor burden) and correlates with OS in the context of recurrent GBM. This technique may offer a promising biomarker of tumor progression and clinical outcome for future clinical trials.

Selected human leukocyte antigen class II polymorphisms and risk of adult glioma.

Few studies have examined the relationship between human leukocyte antigen (HLA) polymorphisms and adult glioma, particularly at class II loci. We evaluated the association between selected HLA class II polymorphisms and adult glioma in a large, hospital-based case-control study, using unconditional logistic regression. DQB1 06 (OR=1.67, 95% CI=1.17-2.39) and DRB1 13 (OR=1.69, 95% CI=1.08-2.64) alleles were associated with an increased risk of glioma, while the DQB1 05 allele showed an inverse association (OR=0.63, 95% CI=0.43-0.93). These results, which were of borderline significance once controlled for the false discovery rate, suggest a potential role for the DQB1 06, DQB1 05, and DRB1 13 alleles in glioma susceptibility.