Background

In 2016, the World Health Organization reclassified the definition of glioblastoma (GBM), dividing these tumors into isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant GBM, where the vast majority of GBMs are IDH-wild-type. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a nomogram for IDH-wild-type patients with newly diagnosed GBM.

Methods

Data were obtained from newly diagnosed GBM patients from the Ohio Brain Tumor Study (OBTS) and the University of California San Francisco (UCSF) for diagnosis years 2007-2017 with the following variables: age at diagnosis, sex, extent of resection, concurrent radiation/temozolomide (TMZ) status, Karnofsky Performance Status (KPS), O⁶-methylguanine-DNA methyltransferase (MGMT) methylation status, and IDH mutation status. Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the OBTS data and independently validated using the UCSF data. Models were internally validated using 10-fold cross-validation and externally validated by plotting calibration curves.

Results

A final nomogram was validated for IDH-wild-type newly diagnosed GBM. Factors that increased the probability of survival included younger age at diagnosis, female sex, having gross total resection, having concurrent radiation/TMZ, having a high KPS, and having MGMT methylation.

Conclusions

A nomogram that calculates individualized survival probabilities for IDH-wild-type patients with newly diagnosed GBM could be useful to physicians for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: https://gcioffi.shinyapps.io/Nomogram_For_IDH_Wildtype_GBM_H_Gittleman/.

Purpose

The integrated histopathologic and molecular diagnoses of the 2016 WHO classification of central nervous system tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically diagnosed diffuse gliomas are unknown.

Experimental design

Patients with newly diagnosed ICD-O-3 (International Classification of Diseases) histologically encoded diffuse gliomas from 2010-2015 were identified from the National Cancer Database, the misclassification rates and overall survival (OS) of which were assessed by WHO grade and 1p/19q status. In addition, misclassification rates by isocitrate dehydrogenase (IDH), ATRX, and p53 statuses were examined in an analogous multi-institutional cohort of registry-encoded diffuse gliomas.

Results

Of 74,718 patients with diffuse glioma, only 74.4% and 78.8% of molecularly characterized WHO grade II and III oligodendrogliomas were in fact 1p/19q-codeleted. In addition, 28.9% and 36.8% of histologically encoded grade II and III "oligoastrocytomas", and 6.3% and 8.8% of grade II and III astrocytomas had 1p/19q-codeletion, thus molecularly representing oligodendrogliomas if also IDH mutant. OS significantly depended on accurate WHO grading and 1p/19q status.

Conclusions

On the basis of 1p/19q, IDH, ATRX, and p53, the misclassification rates of histologically encoded oligodendrogliomas, astrocytomas, and glioblastomas are approximately 21%-35%, 6%-9%, and 9%, respectively; with significant clinical implications. Our findings suggest that when compared with historical histology-only classified data, in national registry, as well as, institutional databases, there is the potential for false-positive results in contemporary trials of molecularly classified diffuse gliomas, which could contribute to a seemingly positive phase II trial (based on historical comparison) failing at the phase III stage. Critically, findings from diffuse glioma clinical trials and historical cohorts using prior histology-only WHO schemes must be cautiously reinterpreted.

Background

The Central Brain Tumor Registry of the United States (CBTRUS) uses a histology grouping model based on the World Health Organization (WHO) classifications to group records for clinically relevant statistical reporting. Newly identified genetic markers more accurately stratify patients than histology alone and were incorporated into the 2016 update to the WHO Classification.

Methods

CBTRUS and consulting neuropathologists reviewed and aligned histology groupings with the 2016 WHO update. "Obsolete" (terms not currently in use) histology nomenclature along with their International Classification of Disease, Oncology 3rd edition (ICD-O-3) codes were identified, some histologies were reclassified to 2016 WHO, and new codes found in 2016 WHO were incorporated. An evaluation of the frequency of histology codes affected in the realignment process, and incidence and survival pre- and post-realignment was conducted.

Results

After review, 67 codes were noted as obsolete, 51 codes were reclassified, and 12 new codes were incorporated. Histology groups most affected were mesenchymal tumors and neuronal/mixed neuronal-glial tumors. Reorganization resulted in 2588 (0.65%) cases with grouping reassignment or reporting change, indicating that the 2016 WHO Classification revision has impacted the collection and reporting of primary brain and other CNS tumors.

Conclusion

This work demonstrates the need to be responsive to changes in classification and coding in order to ensure the most up-to-date and accurate statistics for brain and CNS tumors. This will require collaboration from all stakeholders within the brain tumor community, so to have the ability to reconcile clinical practices and surveillance requirements.

Background

Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.

Methods

In the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.

Results

Among 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.

Conclusions

Higher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.

Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults.

Purpose

The Electronic Medical Record Search Engine (EMERSE) is a software tool built to aid research spanning cohort discovery, population health, and data abstraction for clinical trials. EMERSE is now live at three academic medical centers, with additional sites currently working on implementation. In this report, we describe how EMERSE has been used to support cancer research based on a variety of metrics.

Methods

We identified peer-reviewed publications that used EMERSE through online searches as well as through direct e-mails to users based on audit logs. These logs were also used to summarize use at each of the three sites. Search terms for two of the sites were characterized using the natural language processing tool MetaMap to determine to which semantic types the terms could be mapped.

Results

We identified a total of 326 peer-reviewed publications that used EMERSE through August 2019, although this is likely an underestimation of the true total based on the use log analysis. Oncology-related research comprised nearly one third (n = 105; 32.2%) of all research output. The use logs showed that EMERSE had been used by multiple people at each site (nearly 3,500 across all three) who had collectively logged into the system > 100,000 times. Many user-entered search queries could not be mapped to a semantic type, but the most common semantic type for terms that did match was "disease or syndrome," followed by "pharmacologic substance."

Conclusion

EMERSE has been shown to be a valuable tool for supporting cancer research. It has been successfully deployed at other sites, despite some implementation challenges unique to each deployment environment.

Background

Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.

Methods

In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).

Results

CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients.

Conclusions

Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.

Background

While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium.

Methods

Families with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires.

Findings

The study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at <40y, and in 12% both were diagnosed under 40y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I-II were on average 17y younger than those with grades III-IV.

Interpretation

Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of individuals with a family history of glioma.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.