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Background: Few large studies have investigated quality of life (QOL) for adults diagnosed with lower grade glioma (LGG). Methods: QOL was assessed for 320 adults with LGG (World Health Organization grade 2/3) enrolled in the International Low Grade Glioma Registry by using the Medical Outcomes Study 36‐Item Short Form health survey. Data on symptoms were also collected. QOL outcomes were examined by treatment group and also compared to those from a population‐based case‐control study of meningioma (the Meningioma Consortium), in which 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013 were enrolled and frequency matched to 1622 controls by age, sex, and geography. Results: The LGG sample average age is 45 years at the time of interview and 53.1% male. Almost 55% of patients had received radiation and chemotherapy (primarily temozolomide); 32.4% had received neither treatment. Two‐thirds of participants with LGG report difficulty with speaking, memory, or thinking, and over one of three reports personality change or difficulty driving. After controlling for age and other comorbidities, individuals with LGG report levels of physical, emotional, and mental health functioning below those reported in a meningioma as well as a general healthy population. Conclusions: Despite being relatively young, persons with LGG report significantly reduced QOL compared to persons with nonmalignant brain tumors and to a control population, which highlights the need to better acknowledge and manage these symptoms for this group of patients diagnosed in the prime of life. Despite their relatively young age, persons with lower grade glioma (LGG) report a high symptom burden and significantly reduced quality of life (QOL) compared to persons with nonmalignant brain tumors and healthy controls. These findings emphasize the need to better recognize the symptoms that patients with LGG experience and develop accessible rehabilitative interventions for symptom management and QOL maintenance. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Dental X-Rays and Risk of Meningioma" in the 2012 issue, is presented.

Objective: The relationship between patient and meningioma characteristics and hormone receptors (HRs) of progesterone, estrogen, and androgen remains poorly defined despite literature suggesting that meningiomas are sensitive to gonadal steroid hormones. Therefore, the authors sought to collect and compare data on this topic by performing a systematic review and meta-analysis of reported studies of HR status in meningiomas., Methods: A MEDLINE PubMed literature review conducted for articles published between January 1, 1951, and December 31, 2020, resulted in 634 unduplicated articles concerning meningiomas and HRs. There were 114 articles that met the criteria of detailed detection protocols for progesterone receptor (PR), estrogen receptor (ER), and/or androgen receptor (AR) using immunohistochemistry (IHC) or ligand-binding (LB) assays and simultaneous reporting of HR status with at least one variable among age, sex, histology, location, grade, or recurrence. Between-study heterogeneity and risk of bias were evaluated using graphical and statistical methods. The authors performed a multilevel meta-analysis using random-effects modeling on aggregated data (n = 4447) and individual participant data (n = 1363) with subgroup results summarized as pooled effects. A mixed-effects meta-regression using individual participant data was performed to analyze independently associated variables., Results: The 114 selected articles included data for 5810 patients with 6092 tumors analyzed to determine the expression of three HRs in human meningiomas: PRs, ARs, and ERs. The proportions of HR+ meningiomas were estimated to be 0.76 (95% CI 0.72-0.80) for PR+ and 0.50 (95% CI 0.33-0.66) for AR+ meningiomas. ER+ meningioma detection varied depending on the measurement method used and was 0.06 (95% CI 0.03-0.10) with IHC and 0.11 (95% CI 0.06-0.20) with LB assays. There were associations between age and PR and ER expression that varied between male and female patients. PR+ and AR+ were more common in female patients (OR 1.84, 95% CI 1.47-2.29 for PR and OR 4.16, 95% CI 1.62-10.68 for AR). Additionally, PR+ meningiomas were enriched in skull base locations (OR 1.89, 95% CI 1.03-3.48) and meningothelial histology (OR 1.86, 95% CI 1.23-2.81). A meta-regression showed that PR+ was independently associated with age (OR 1.11 95% CI 1.09-1.13; p < 0.0001) and WHO grade I tumors (OR 8.09, 95% CI 3.55-18.44; p < 0.0001). ER+ was negatively associated with meningothelial histology (OR 0.94, 95% CI 0.86-0.98; p = 0.044) and positively associated with convexity location (OR 1.12, 95% CI 1.05-1.18; p = 0.0003)., Conclusions: The association between HRs and meningioma features has been investigated but unexplained for decades. In this study the authors demonstrated that HR status has a strong association with known meningioma features, including WHO grade, age, female sex, histology, and anatomical location. Identifying these independent associations allows for a better understanding of meningioma heterogeneity and provides a foundation for revisiting targeted hormonal therapy in meningioma on the basis of proper patient stratification according to HR status.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 ( P  = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3 , and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research., Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities., Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants., Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries., Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management., Methods: We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms., Results: We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score., Conclusion: We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ovarian cancers, raising the possibility of genetic pleiotropy., Methods: We performed imputation-based fine-mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28 108 cases, 22 209 controls), and ovarian cancer (25 509 cases, 40 941 controls). Analyses were stratified by sex (meningioma), estrogen receptor (ER) status (breast), and histotype (ovarian), then combined using subset-based meta-analysis in ASSET. Lead variants were assessed for association with additional traits in UK Biobank to identify potential effect-mediators., Results: Two-sided subset-based meta-analysis identified rs7084454, an expression quantitative trait locus (eQTL) near the MLLT10 promoter, as lead variant (5.7 × 10 -14 ). The minor allele was associated with increased risk of meningioma in females (odds ratio (OR) = 1.42, 95% Confidence Interval (95%CI):1.20-1.69), but not males (OR = 1.19, 95%CI: 0.91-1.57). It was positively associated with ovarian (OR = 1.09, 95%CI:1.06-1.12) and ER+ breast (OR = 1.05, 95%CI: 1.02-1.08) cancers, and negatively associated with ER- breast cancer (OR = 0.91, 95%CI: 0.86-0.96). It was also associated with several adiposity traits ( P < 5.0 × 10 -8 ), but adjusting for body mass index did not attenuate its association with meningioma. MLLT10 and ESR1 expression were positively correlated in normal meninges ( P = .058) and meningioma tumors (P = .0065)., Conclusions: We identify a MLLT10 eQTL positively associated with risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, and implicate a potential estrogenic mechanism underlying this pleiotropy., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aims: Known racial, ethnic, age, and socioeconomic disparities in video telemedicine engagement may widen existing health inequities. We assessed if telemedicine disparities were alleviated among patients of high-video-use providers at a large cardiovascular practice., Methods and Results: All telemedicine visits from 16 March to 31 October 2020 and patient demographics were collected from an administrative database. Providers in the upper quintile of video use were classified as high-video-use providers. Descriptive statistics and a multivariable logistic model were calculated to determine the distribution and predictors of a patient ever having a video visit vs. only phone visits. A total of 24 470 telemedicine visits were conducted among 18 950 patients by 169 providers. Video visits accounted for 48% of visits (52% phone). Among telemedicine visits conducted by high-video-use providers ( n  = 33), ever video patients were younger ( P < 0.001) and included 78% of Black patients vs. 86% of White patients ( P < 0.001), 74% of Hispanic patients vs. 86% of non-Hispanic patients ( P < 0.001), and 79% of public insurance patients vs. 91% of private insurance patients ( P < 0.001). High-video-use provider patients had 9.4 (95% confidence interval 8.4-10.4) times the odds of having video visit compared to low-video-use provider patients., Conclusion: These results suggest that provider-focused solutions alone, including promoting provider adoption of video visits, may not adequately reduce disparities in telemedicine engagement. Even in the presence of successful clinical infrastructure for telemedicine, individuals of Black race, Hispanic ethnicity, older age, and with public insurance continue to have decreased engagement. To achieve equity in telemedicine, patient-focused design is needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 -4 ; 11p11.12, p = 7.0 × 10 -4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10 -6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 -4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 -4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies., (© 2019 UICC.)

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear 1,2 . Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Purpose: Telomere length-associated SNPs have been associated with incidence and survival rates for malignant brain tumors such as glioma. Here, we study the influence of genetically determined lymphocyte telomere length (LTL) by comparing telomerase associated SNPs between the most common non-malignant brain tumor, i.e. meningioma, and healthy controls., Methods/patients: One thousand fifty-three (1053) surgically treated meningioma patients and 4437 controls of Western European ancestry were included. Germline DNA was genotyped for 8 SNPs previously significantly associated with LTL. Genotypically-estimated LTL was then calculated by summing each SNP's genotypically-specified telomere length increase in base pairs (bp) for each person. Odds ratios for genotypically-estimated LTL in meningioma cases and controls were evaluated using logistic regression with the first two ancestral principal components and sex as covariates., Results: Three out of the eight evaluated LTL SNPs were significantly associated with increased meningioma risk (rs10936599: OR 1.14, 95% CI 1.01-1.28, rs2736100: OR 1.13, 95% CI 1.03-1.25, rs9420907: OR 1.22, 95% CI 1.07-1.39). Only rs9420907 remained significant after correction for multiple testing. Average genotypically-estimated LTL was significantly longer for those with meningioma compared to controls [mean cases: 560.2 bp (standard error (SE): 4.05 bp), mean controls: 541.5 bp (SE: 2.02 bp), logistic regression p value = 2.13 × 10 -5 ]., Conclusion: Increased genotypically-estimated LTL was significantly associated with increased meningioma risk. A role for telomere length in the pathophysiology of meningioma is novel, and could lead to new insights on the etiology of meningioma.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p 54-63 = 1.50x10 -9 , OR 54-63 = 1.28, 95%CI 54-63 = 1.18-1.39; p 64+ = 2.14x10 -11 , OR 64+ = 1.32, 95%CI 64+ = 1.21-1.43] and rs11979158 [p 54-63 = 6.13x10 -8 , OR 54-63 = 1.35, 95%CI 54-63 = 1.21-1.50; p 64+ = 2.18x10 -10 , OR 64+ = 1.42, 95%CI 64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p 18-53 = 9.30 × 10 -11 , OR 18-53 = 1.76, 95%CI 18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.', (© 2018 UICC.)

To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH)D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH)D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH)D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH)D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH)D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH)D levels and risk of GBM.

While salvage re-irradiation is often used for recurrent high-grade glioma (HGG), there have been few comparisons between various re-radiation dose/fractionation schedules or with bevacizumab alone. We analyzed patients with recurrent HGG who received re-irradiation at Dana-Farber Cancer Institute and Brigham and Women's Hospital from 2010 to 2014 (n = 67), as well as those who received bevacizumab alone (n = 177). Cox proportional hazards modeling was used to examine factors associated with overall survival (OS). Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Median time from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionations used were 6 Gy × 5 (36%), 3.5 Gy × 10 (21%), 2.67 Gy × 15 (15%), and 18-20 Gy × 1 (15%). No early or late toxicities >grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 and 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR] 1.6; 95% CI, 1.1-2.3; p = .007), and recurrence in a new brain location (vs. local-only; AHR 7.4; 95% CI, 2.4-23.1; p < .001) were associated with OS; dose/fractionation was not. Compared with bevacizumab alone, re-irradiated patients had a non-significant increase in OS (HR 0.80; 95% CI, 0.53-1.23; P = .31). Among patients with a local-only recurrence, there was a trend towards longer median OS after re-irradiation compared to bevacizumab alone (12.4 vs. 8.0 months; p = .12). Survival after re-irradiation for recurrent HGG appears independent of dose/fractionation and compares favorably with bevacizumab alone.

Epidemiological analyses of many cancers have demonstrated differences in incidence and outcome for patients from different racial backgrounds. The aim of this study was to determine the incidence of non-malignant CNS tumors by race and age to identify incidence variance. Data from the Central Brain Tumor Registry of the United States (CBTRUS) from 2009 to 2013 were used to calculate age-adjusted incidence rates (IR) per 100,000 population and 95% confidence intervals for selected tumors overall, by race, age group, and race stratified by age group. In those aged 0-14 years, Whites had significantly greater IR of neuronal and mixed neuronal-glial tumors (IR = 0.37) compared to Others (IR = 0.26) and Blacks (IR = 0.24). In those 15-39 years, Blacks had significantly greater IR of tumors of the pituitary (IR = 3.80) than Others (IR = 3.29) and Whites (IR = 3.15), and significantly greater IR of grade I meningioma (IR = 1.93) than Whites (IR = 1.59) and Others (IR = 1.21). In those 40 years and older, Blacks had significantly greater IR of grade I meningioma (IR = 19.16) compared to Whites (IR = 15.77) and Others (IR = 15.32), and significantly greater IR of tumors of the pituitary (IR = 10.47) than Others (IR = 5.85) and Whites (IR = 4.99). Others had significantly greater IR of nerve sheath tumors (IR = 4.00) compared to Whites (IR = 3.46) and Blacks (IR = 1.64). The incidence of non-malignant CNS tumors differs significantly by race and age in the USA. These differences may contribute to previously-described health outcome disparities.

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P(trend) <1.0 × 10(-8)). The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.

Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma that occurs in immunocompetent and human immunodeficiency virus (HIV) patients. Despite treatment advances, previous reports have produced conflicting information about survival trends over time. Using the Surveillance, Epidemiology, and End Results (SEER) data, 2,557 patients diagnosed with PCNSL between 1973 and 2004 were identified and classified by HIV status. Potential predictors of survival were evaluated using log-rank tests. Hazard ratios and 95% confidence intervals (CIs) were computed using a Cox proportional hazards regression model. The cohort included 1,732 (67.7%) HIV-negative patients and 825 (32.3%) HIV-positive patients. Median overall survival was 12 months (95% CI 10, 13) among HIV-negative patients. In this group, median survival increased over time, from 7.5 months (95% CI 6, 14) for patients diagnosed in the 1970s, to 14 months (95% CI 11, 20) for patients diagnosed in the 2000s. Independent predictors of mortality included older age (hazard ratio [HR] 1.03 [95% CI 1.02, 1.03]), earlier year of diagnosis (HR 0.98 [95% CI 0.98, 0.99]), male sex (HR 1.20 [95% CI 1.08, 1.34), married status (HR 0.70 [95% CI 0.63, 0.78]), and receipt of radiation therapy (HR 0.69 [95% CI 0.61, 0.77]). HIV positivity was a powerful adverse prognostic factor in the overall cohort (HR 4.55 [95% CI 4.01, 5.16]). Despite treatment advances, survival among PCNSL patients in the United States remains poor. However, in the subset of PCNSL patients who are HIV-negative, survival has improved over time.

Purpose: Limited data exist on long-term quality of life (QOL) for women diagnosed with breast carcinoma in situ (BCIS)., Participants and Methods: The data are on 795 BCIS participants diagnosed among female residents of Connecticut from September 15, 1994 to March 14, 1998, and 702 controls frequency-matched to the case participants by 5-year age intervals and geography. These women were participants in a large, population-based case/control study and subsequent follow-up study. Telephone interviews at follow-up were used to collect data on QOL at 5 years from initial diagnosis or contact, using the Medical Outcomes Study, Center for Epidemiologic Studies-Depression, and CAGE (Cut down, Annoyed, Guilty, Eye-opener) alcohol consumption scales. QOL outcomes were compared by case/control status and by case treatment group: lumpectomy, lumpectomy with adjuvant radiation therapy, and mastectomy., Results: At 5 years after diagnosis, women diagnosed with BCIS report levels of physical, emotional, and mental health functioning similar with those reported in a general healthy female population. Case participants and controls did not differ in reported levels of limitations due to physical health problems, bodily pain, social functioning, or overall physical functioning. Case participants who underwent lumpectomy with radiation reported lower levels of emotional functioning, general health perceptions, vitality, sexual interest, and overall mental health, as well as more depressive symptoms than did control subjects; although, the clinical significance of these statistical differences appears to be limited., Conclusion: At 5 years after treatment, women diagnosed with BCIS report good physical and emotional functioning relative to control populations.

Background: Detailed population-based estimates of long-term survival as well as patterns of care for patients with low-grade gliomas examined by age at diagnosis, gender, and race have not been widely available., Methods: Time to death was examined among 2009 individuals diagnosed with a supratentorial low-grade glioma and reported to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute from 1973-2001 using Kaplan-Meier estimation. A Cox proportional hazards model was used to assess the effect of age at diagnosis, race, gender, histology, anatomic location within the brain, first course of treatment, and year of diagnosis upon this risk., Results: The cumulative 5-, 10-, 15- and 20-year survival rates among all individuals initially diagnosed with a supratentorial low-grade glioma were 59.9% (95% confidence interval [95% CI], 57.6-62.2); 42.6% (95% CI, 39.9-45.2); 31.9% (95% CI, 29.0-34.8); and 26.0% (95% CI, 22.7-29.2), respectively. Improved survival was significantly associated with female gender (hazard ratio [HR], 0.84; 95% CI, 0.74-0.95), younger age, white race (HR, 0.70; 95% CI, 0.54-0.93), histology, and later year of diagnosis. Surgical treatment was associated with increased survival. The use of radiation therapy as a first course of treatment for these lesions has significantly decreased over time with the majority of patients receiving only surgery as a first course of treatment., Conclusions: Data for patients diagnosed with low-grade gliomas revealed increasing survival times over the past 25 years with a subset of patients surviving for decades. Differences in survival by race, gender, histology, and first course of treatment were appreciated. These data suggested that the clinical course of low-grade glioma for some patients may be more encouraging than previously perceived and that the identification of this group of patients may allow refinement of current treatment protocols., ((c) 2006 American Cancer Society.)

Although a number of predictors of adherence to mammography screening guidelines have been identified using traditional statistical methods, many women are not screening according to these guidelines. Recursive partitioning may aid in developing novel intervention strategies to promote this screening behavior by identifying subgroups of women that differ on adherence across predictor variables. In a prospective study of 1,229 African-American and White women in Connecticut whose adherence to mammography screening guidelines was ascertained over a 26-month follow-up period from initial screening in 1996-1998, recursive partitioning selected six of 22 candidate predictors and identified subgroups that differed on adherence across predictors by age (40-49 and 50-79 years). Among the five subgroups identified for women aged 50-79 years, the subgroup most adherent to screening guidelines during follow-up included four predictors: a history of adherence, annual family income of 15,000 dollars or more, a belief that mammograms were very useful, and low or moderate perceived breast cancer susceptibility. Among the three subgroups identified for women aged 40-49 years, the most adherent subgroup included only one predictor: receipt of a health-care provider's recommendation to obtain a mammogram. These findings suggest that recursive partitioning may be a useful statistical tool and may aid in developing interventions to promote adherence to mammography screening guidelines.

Meningiomas are the most frequently reported primary intracranial neoplasms, accounting for approximately 25% of all such lesions diagnosed in the United States. Few studies have examined the risk factors associated with a diagnosis of meningioma with two categories of exposure, hormones (both endogenous and exogenous) and radiation, most strongly associated with meningioma risk. Limited data are also available on long-term outcomes for meningioma patients, although it is clear that the disease is associated with significant morbidity and mortality. Recent legislation passed in the United States (The Benign Brain Tumor Cancer Registries Amendment Act [H.R. 5204]) mandates registration of benign brain tumors such as meningioma. This will increase the focus on this disease over the coming years as well as likely increase the reported prevalence of the disease. The increased emphasis on research dedicated to the study of brain tumors coupled with the advent of new tools in genetic and molecular epidemiology make the current era an ideal time to advance knowledge for intracranial meningioma. This review highlights current knowledge of meningioma epidemiology and new directions for research efforts in this field.

Background: No age-adjusted or histologic-adjusted assessments of the association between extent of resection and risk of either recurrence or death exist for neurosurgical patients who undergo resection of low-grade glioma using intraoperative magnetic resonance image (MRI) guidance., Methods: The current data included 156 patients who underwent surgical resection of a unifocal, supratentorial, low-grade glioma in the MRI suite at Brigham and Women's Hospital between January 1, 1997, and January 31, 2003. Estimates of disease-free and overall survival probabilities were calculated using Kaplan-Meier methodology. The association between extent of resection and these probabilities was measured using a Cox proportional hazards model. Observed death rates were compared with the expected death rate using age-specific and histologic-specific survival rates obtained from the Surveillance, Epidemiology, and End Results Registry., Results: Patients who underwent subtotal resection were at 1.4 times the risk of disease recurrence (95% confidence interval [95% CI], 0.7-3.1) and at 4.9 times the risk of death (95% CI, 0.61-40.0) relative to patients who underwent gross total resection. The 1-year, 2-year, and 5-year age-adjusted and histologic-adjusted death rates for patients who underwent surgical resection using intraoperative MRI guidance were 1.9% (95% CI, 0.3-4.2%), 3.6% (95% CI, 0.4-6.7%), and 17.6% (95% CI, 5.9-29.3%), respectively: significantly lower than the rates reported using national data bases., Conclusions: The data from the current study suggested a possible association between surgical resection and survival for neurosurgical patients who underwent surgery for low-grade glioma under intraoperative MRI guidance. Further study within the context of a large, prospective, population-based project will be needed to confirm these findings.

Context: The distribution of BRCA1 and BRCA2 mutations in women diagnosed with noninvasive breast carcinoma is unknown., Objective: To estimate the BRCA1 and BRCA2 mutation prevalence in women with ductal carcinoma in situ (DCIS), unselected for age, family history, or ethnicity., Design, Setting, and Participants: The data were 369 DCIS cases diagnosed among female residents aged 20 to 79 years from the state of Connecticut between September 15, 1994, and March 14, 1998. These women were participants in a large population-based case-control study of breast carcinoma in situ. Telephone interviews were used to collect risk factor information and blood or buccal specimens were collected for BRCA1 and BRCA2 mutation testing., Main Outcome Measures: Prevalence of disease-associated mutations of BRCA1 and BRCA2 in women diagnosed with DCIS., Results: Three (0.8%) and 9 (2.4%) of 369 DCIS cases had disease-associated mutations in BRCA1 or BRCA2, respectively. One woman had a mutation in both genes (BRCA1 W321X and BRCA2 3398del5). Carriers were significantly more likely than noncarriers to report a first-degree (mother, sister, or daughter) family history of breast cancer (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.4), as well as a personal history of ovarian cancer. In addition, carriers were more likely than noncarriers to be diagnosed at an early age (<50 years) (OR, 3.4; 95% CI, 1.0-11.7), as well as to report at least 1 first-degree relative diagnosed with breast cancer before 50 years (OR, 10.6; 95% CI, 3.0-37.0)., Conclusions: Ductal carcinoma in situ is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer. These findings suggest that patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer.

Background: Women diagnosed with breast carcinoma in situ are at increased risk for developing a contralateral breast cancer. The magnitude of this risk and the relationship between this risk and age, time since diagnosis, histologic subtype, and treatment for the first breast cancer is continuing to be defined., Methods: The risk of developing a contralateral breast cancer is examined among 4198 women diagnosed with breast carcinoma in situ and reported to the Connecticut Tumor Registry (CTR) between January 1, 1975 and March 14, 1998 using Kaplan-Meier estimation. A Cox proportional hazards model is used to assess the effect of surgical treatment, radiation therapy, age at diagnosis, race, histology, marital status, anatomic location within the breast, and time since diagnosis upon this risk., Results: The cumulative 5- and 10-year probabilities of being diagnosed with a contralateral breast cancer among women initially diagnosed with a ductal breast carcinoma in situ (DCIS) were 4.3% (95% confidence interval, 3.6-5.0%) and 6.8% (95% confidence interval, 5.5-8.2%), respectively. These risks are 3.35 times greater than those for women without a history of breast cancer but are similar to those for women diagnosed with non-metastatic invasive ductal carcinomas of the breast. The cumulative 5- and 10-year probabilities of being diagnosed with a contralateral breast cancer among women initially diagnosed with a lobular breast carcinoma in situ (LCIS) were 11.9% (95% confidence interval, 9.5-14.3%) and 13.9% (95% confidence interval, 11.0-16.8%), respectively., Conclusions: Women diagnosed with LCIS were 2.6 (95% confidence interval, 2.0-3.4%) times more likely than women with DCIS to be diagnosed with a contralateral breast cancer within the first six months of the first breast primary. The risk of developing a contralateral breast cancer more than 6 months after the initial breast cancer was independent of surgical or radiation therapy, time since diagnosis, age at diagnosis, histology, race, marital status, or anatomic location of the cancer within the breast.

Unlabelled: Recent evidence suggests that oral contraceptive use is associated with little to no increased risk of invasive breast carcinoma. No study has examined the relationship between oral contraceptive use and the risk of non-invasive breast carcinoma, that is, breast carcinoma in situ., Objective: To define the role of oral contraceptive use in the development of breast carcinoma in situ., Methods: The data are 875 ductal carcinoma in situ (DCIS) cases diagnosed among residents of the state of Connecticut from September 15, 1994 to March 14, 1998 and between the age of 20 and 79 years as well as 999 control subjects. Controls are female Connecticut residents collected via random-digit-dial and frequency matched to the cases by 5-year age intervals. Telephone interviews were used to collect information on risk factors and cancer screening history. Logistic regression was used to provide maximum likelihood estimates of the odds ratios (OR) with 95% confidence intervals (95% CI)., Results: The risk of being diagnosed with DCIS for women who had ever used oral contraceptives was not increased relative to women who had never used them (OR: 1.0, 95% CI: 0.8, 1.2). The risk did not significantly increase with duration of oral contraceptive use, nor with duration of high estrogen use, time since last use, progestin or estrogen type, or age at first use. Furthermore, the association between oral contraceptive use and DCIS risk did not vary by the presence of a family history of breast cancer or by menopausal status., Conclusions: In these data, no evidence was found for an increased risk of ductal carcinoma in situ associated with the use of oral contraceptives.

Unlabelled: A family history of breast cancer is an important risk factor for breast carcinoma in situ (BCIS), however, there are no detailed analyses of its variation in effect by number, type, laterality or age at onset of affected relatives nor by association with ovarian cancer. In addition, the role of the breast cancer susceptibility genes, BRCA1 and BRCA2, in the development of BCIS is unclear., Objective: To better define the role of: (1) a family history of breast and ovarian cancer and (2) the cancer susceptibility genes, BRCA1 and BRCA2, in the development of BCIS., Methods: The data are 875 ductal carcinoma in situ (DCIS) and 123 lobular carcinoma in situ (LCIS) cases diagnosed among residents of the state of Connecticut from September 15, 1994 to March 14, 1998 and between the age of 20 and 79 years. Controls (n = 999) are female Connecticut residents collected via random-digit-dial and frequency matched to the cases by 5-year age intervals. Telephone interviews were used to collect information on risk factors and cancer screening history. Logistic regression was used to provide maximum likelihood estimates of the odds ratios (OR) with 95% confidence intervals (95% CI). The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each case and control, using family history of breast and ovarian cancer, age/age at diagnosis for relatives, prevalence and penetrance data for BRCA1/BRCA2, and self-report of Jewish heritage., Results: Cases with DCIS or LCIS were significantly more likely to report a first degree family history of breast cancer (OR: 1.6, 95% CI: 1.3, 2.1 and 1.8, 95% CI: 1.2, 2.9, respectively) than were controls. In addition, DCIS cases were 2.4 (95% Cl: 0.8, 7.2) times more likely than controls to report both an affected mother and sister. An inverse association was suggested between age at onset and DCIS risk with cases aged 49 years or younger at 2.1 (95% CI: 1.3, 3.4) times the risk of controls (95% CI) versus 1.5 (95% CI: 1.1, 2.0) for cases older than 49 years. An elevated risk of DCIS was associated with a family history of ovarian cancer but did not reach statistical significance (OR: 1.3, 95% CI: 0.7, 2.5). Approximately 3.7% and 1.9% of DCIS cases were predicted to carry a mutation in BRCA1 and BRCA2, respectively., Conclusions: A family history of breast cancer is associated with an increased risk of DCIS and LCIS, particularly among women with multiple relatives affected at early ages. Statistical risk models predict a low prevalence rate of BRCA1 and BRCA2 in DCIS; these estimates await confirmation through laboratory testing.

HER-2/neu overexpression occurs in a proportion of invasive breast carcinomasand is an adverse prognostic indicator, although its apparent strength as a prognostic indicator varies in different studies. Paradoxically, HER-2/neu is overexpressed with particularly high frequency in ductal carcinoma in situ (DCIS). We have hypothesized and presented supporting data that HER-2/neu is actively signaling in a subset of the tumors in which it is overexpressed. We use an activation state-dependent anti-HER-2/neu monoclonal antibody (PN2A) produced in our laboratory to study this paradigm immunohistochemically. In this report, we analyze the characteristics of 219 cases of DCIS with respect to HER-2/neu expression and activation state. We find that 58% of cases of DCIS with overexpression have the receptor in the activated state, a substantially greater proportion than we have previously noted for invasive carcinomas. Although HER-2/neu overexpression in general was inversely correlated with hormone receptor expression, cases with activated HER-2/neu had the lowest hormone receptor positivity rate. Statistically significant correlations with activated HER-2/neu were not noted for tumor size, presence of calcifications, necrosis or fibrosis, or indicators of angiogenesis. These results suggest that examination of activated HER-2/neu status may better reflect the biology of a tumor than overall determination of HER-2/neu levels. Our finding that active signaling by HER-2/neu, as detected by this assay, is more frequent in DCIS than previously noted for invasive carcinoma implicates signaling by HER-2/neu as having a critical role in the early stages of breast tumorigenesis.