Cohort Of High-grade Gliomas Research Articles

Abstract 5137: BRAF mutations in primary central nervous system tumors

Abstract Background: BRAF alterations are present in a variety of primary central nervous system (CNS) tumors from 3% in glioblastomas to 60% in pleomorphic xanthoastrocytomas. BRAF V600E mutation is the most common BRAF alteration found in tumors and has been successfully targeted by combining BRAF/MEK inhibitors in different tumor types, including gliomas. We aimed to describe the clinical and genomic features of primary CNS tumors harboring BRAF alterations and real-world data on BRAF-targeted therapy including our experience sequencing BRAF-directed therapies (BDI) in gliomas. Methods: Single-center retrospective analysis of patients with diagnosis of primary CNS tumors with NGS testing. Clinical, histological and molecular characteristics were analyzed. Results: 44 patients with BRAF mutant primary CNS tumors were included, 28 (64%) were male. 24 (55%) had histology consistent with high-grade glioma (HGG), 14 (32%) low grade glioma (LGG), 4 (9%) low grade neuroepithelial tumors and 2 (4%) others. Missense mutations were found in 77%, followed by amplifications (9%), fusions (9%) and in/del alterations (5%). V600E was the most common mutation (63%), followed by class 2 (16%) and 3 (7%) mutations and amplifications (9%). Co-occurring mutations were found in CDKN2A/B (22), TERT (20) and MTAP (12), median TMB was 2 mut/mb and only 2 patients had high TMB. 4 patients had commuted IDH1 (3 R132H), non-concurring with a V600E mutation. For patients with HGG, median age at diagnosis was 47 years and 16 (66%) were male. Lesions were more frequent in left hemisphere (70%) and temporal lobe (54%). V600E was found in 50% of cases, KIAA1549-BRAF fusion was found in 1 case. Median follow-up was 40 months (95% CI 11-68) and median overall survival (OS) was 22 months (3.4-40) for the whole population, and 56 (4-109) months for patients treated with BDI (n=4). All 4 patients had an OS >30 months. In the LGG cohort, median age at diagnosis was 34 years (IQR 24-46), 8 (57%) were male. 50% of the lesions were in the left side and 21% of the tumors were in the posterior fossa. 78% had a V600E mutation, with no statistical difference with HGG cohort (p=.082). Median follow up was 11 months, median OS was not reached. For 5 patients treated at recurrence with BDI, median PFS was 15 months (3-27).5 patients were treated with plixorafenib (PLX8394) on clinical trial achieving disease control (PR +SD) in 4 cases. Upon progression, 4 were rechallenged with dabrafenib + trametinib and 1 with another BDI. 4 patients had a partial response with duration of response >6 months in 3 cases. Conclusion: BRAF mutant CNS tumors are a heterogeneous disease. Longer survival was observed in the small group of HGG patients treated with BDI compared to SoC (56 months vs 22months). BDI rechallenge showed durable responses in heavily pretreated patients. Further molecular characterization of these patients is ongoing. The best therapeutical sequencing strategy for BDI remains uncertain. Citation Format: Juan B. Blaquier, Fulvio D'Angelo, Dalissa Tejera, Ruham A. Nasany, Gaurav Saigal, Antonio Iavarone, Macarena I. de la Fuente. BRAF mutations in primary central nervous system tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5137.

Short-course Palliative Hypofractionated Radiotherapy in Patients with Poor-prognosis High-grade Glioma: Survival and Quality of Life Outcomes from a Prospective Phase II Study

AimsTo report longitudinal quality of life (QoL) outcomes and survival in patients with poor-prognosis high-grade glioma (HGG) treated with palliative hypofractionated radiotherapy. Materials and methodsPatients with poor-prognosis HGG were accrued on a prospective study of short-course palliative hypofractionated radiotherapy (35 Gy/10 fractions/2 weeks). The European Organization for Research and Treatment of Cancer QoL core questionnaire (QLQ-C30) and brain cancer module (BN20) were used in English or validated Indian vernacular languages (Hindi and Marathi) for QoL assessment at baseline (before radiotherapy), the conclusion of radiotherapy, 1 month post-radiotherapy and subsequently at 3-monthly intervals until disease progression/death. Baseline QoL scores were compared with corresponding scores from a historical HGG cohort. Summary QoL scores were compared longitudinally over time by related samples Friedman's two-way test. Progression-free survival and overall survival were calculated using the Kaplan–Meier method and reported as 1-year estimates with 95% confidence intervals. ResultsForty-nine (89%) of 55 patients completed the planned course of hypofractionated radiotherapy. Longitudinal QoL data were available in 42 (86%) of 49 patients completing radiotherapy, comprising the present cohort. The median age of included patients, comprised mainly of glioblastoma patients (81%), was 57 years, with an interquartile range (IQR) of 50–66 years and a median baseline Karnofsky score of 60 (IQR = 50–60). Baseline QoL scores were significantly worse for several domains compared with a historical institutional cohort of HGG patients treated previously with conventionally fractionated radiotherapy, indicating negative selection bias. QoL scores remained stable for most domains after palliative hypofractionated radiotherapy, with statistically significant improvements in fatigue (P = 0.032), dyspnoea (P = 0.042) and motor dysfunction (P = 0.036) over time. At a median follow-up of 8 months, Kaplan–Meier estimates of 1-year progression-free survival and overall survival were 33.3% (95% confidence interval 21.7–51.1%) and 38.1% (95% confidence interval 25.9–56%), respectively. ConclusionShort-course palliative hypofractionated radiotherapy in patients with poor-prognosis HGG is associated with stable and/or improved QoL scores in several domains, making it a viable resource-sparing regimen.

BIOM-11. ROR1 MRNA EXPRESSION IN GLIOMA - A NOVEL PROGNOSTIC BIOMARKER

Abstract BACKGROUND Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite maximal surgical resection followed by concomitant chemo-/radiotherapy, the three-year survival remains less than 5%. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) overexpression is associated with poor prognosis in several cancers. ROR1 therapeutics are in Phase I/II clinical trials making it an exciting novel target with translational potential to explore for glioblastoma treatment. The aim of this study was to examine the association between ROR1 mRNA expression and overall survival, by applying the WHO 2021 classification to transcriptomic glioma datasets. METHODS Clinical, histological, and molecular data was extracted from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Repository for Molecular Brain Neoplasia (REMBRANDT), and GSE16011 (GRAVENDEEL) projects via the GlioVis portal. Using the WHO 2021 classification, the dataset was appropriately re-classified. Only confirmed cases of astrocytoma, oligodendroglioma, or glioblastoma, and ROR1 mRNA expression data were included in the analysis, which included a total of 2,303 cases. 981 cases comprised the low-grade glioma cohort and 1322 cases were included in the high-grade glioma cohort. ROR1 mRNA expression from the four datasets was normalized within each dataset, combined, and divided into high and low expression groups. ROR1 expression and survival correlations were estimated with Kaplan-Meier survival analysis and Mantel-Cox test using GraphPad Prism v9. RESULTS Those with high ROR1 expression had an overall median survival of 4.5 months, as compared to 21.4 months in the low ROR1 expression cohort (p< 0.0001). High-grade gliomas had the highest ROR1 mRNA expression across the consortium when compared to the low-grade glioma cohort (p< 0.0001). CONCLUSION The results of this study indicate an association between overall survival in glioma and ROR1 expression. In addition, targeting ROR1 could hold translational importance for novel putative treatment in glioblastoma patients.

Racial/ethnic, socioeconomic, and geographic survival disparities in adolescents and young adults with primary central nervous system tumors.

Disparities in survival by race/ethnicity, socioeconomic status (SES), and geography in adolescent and young adult (AYA) patients with central nervous system (CNS) tumors have not been well studied. A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results (SEER) database was conducted for AYA patients diagnosed with primary CNS tumors. Adjusted hazard ratios (aHR) were calculated using a multivariate Cox proportional hazard model to evaluate the association between race/ethnicity, SES, rurality, and hazard of death. All minority groups showed an increased hazard of death with greatest disparities in the high-grade glioma cohort. Lower SES was associated with an increased hazard of death in non-Hispanic White (NHW) patients (aHR 1.12; 95% confidence interval [CI] 1.01-1.24), non-Hispanic Black (NHB) patients (aHR 1.34; 95% CI 1.00-1.80), and patients aged 25-29 years (aHR 1.29; 95% CI 1.07-1.55). Mediation analysis showed an indirect effect of SES on the effect of race/ethnicity on the hazard of death only among NHB patients, with SES accounting for 33.7% of the association between NHB and hazard of death. Rurality was associated with an increased hazard of death for patients in the lowest SES tertile (aHR 1.31; 95% CI 1.08-1.59) and NHW patients (aHR 1.20; 95% CI 1.08-1.34). Patients identified as a racial/ethnic minority, patients with a lower SES, and patients residing in rural areas had an increased hazard of death. Further studies are needed to understand and address the biological, psychosocial, societal, and economic factors that impact AYA neuro-oncology patients at highest risk of experiencing poorer outcomes.

EPCO-23. COMPARATIVE TRANSCRIPTOMICS TO IDENTIFY TARGETED THERAPY CANDIDATES IN HIGH GRADE GLIOMA

Abstract Genomic characterization is often used for the identification of therapeutic targets in tumors. Recently, comparative transcriptomics has begun to be utilized for this purpose. In this pilot, we compare the transcriptome of a patient with recurrent high grade glioma (HGG) to our cohort to identify potential therapies. We reviewed transcriptomic profiles from patients who had resection of HGG at our institution over the past year as well as the UCSC cancer compendium. Briefly, tumor RNA was extracted from embedded tumor tissue sections with tumor cellularity higher than 20%. RNA libraries were sequenced to obtain approximately 65 million reads on an Illumina HiSeq 4000 System utilizing patterned flow cell technology. The RNA profile of a 24 male with Li-Fraumeni syndrome and recurrent HGG with leptomeningeal spread underwent comparative transcriptomics to identify targets. A Bayesian statistical framework for gene expression outlier detection was used. These comparisons allowed for the identification of genes and pathways that are significantly overexpressed. Our internal HGG cohort consisted of 44 adult patients and was evenly distributed among the 4 HGG Verhaak subtypes. Our patient of interest had druggable outlier expression in HDAC1, STAT1 and STAT2 in comparison to our internal cohort indicating vorinostat and ruxolitinib as potential therapies, respectively. We then compared our patient of interest to 12,747 patients in the cancer compendium and STAT2 expression was high but not an outlier. In comparison to 738 glioma samples, STAT1 and STAT2 were outliers but not HDAC1 again indicating ruxolitinib as a potential targeted therapy. The patient did not have outlier expression in notch transcriptional targets or immune checkpoint biomarkers when compared to all cohorts. In conclusion, comparative Transcriptomics can identify therapeutic targets in a patient with recurrent HGG even in small cohorts. In our pilot, we identified ruxolitinib as a potential candidate to treat leptomeningeal recurrence.

NCOG-43. NEUROCOGNITIVE IMPAIRMENT AND FRAILTY IN GERIATRIC PATIENTS WITH HIGH GRADE GLIOMA AND THORACIC MALIGNANCY

Abstract BACKGROUND The median age at diagnosis for high grade glioma is 64 years. With peak incidence 75-84, malignant glial tumors are frequently a disease of the elderly. Common assessment measures fail to accurately gauge geriatric cancer patient fitness. Comprehensive Geriatric Assessment (CGA) is recommended in patients older than 65 to gauge risk of toxicity and tolerance of therapeutic intervention. We reviewed data for older patients with high grade glioma (HGG) and thoracic malignancy (TM) who underwent CGA via Senior Oncology Clinic (SOC) at Levine Cancer Institute. METHODS From 2015 to 2019 104 thoracic malignancy patients and 19 high grade glioma patients completed CGA via SOC before treatment or a required change in therapy. Data was incorporated into the LCI Senior Oncology Database by the REDCap secure web application, allowing for both quantitative and qualitative data analysis. RESULTS The median age was 77 in the HGG cohort compared to 80 years with TM. The physician rated Karnofsky Performance Status (KPS) for HGG and TM were similar (76% v 79%) as were the percentages of patients that were frail or prefrail (90% v 87%). Montreal Cognitive Assessment scores were lower in HGG (20 v 23). Considerably more HGG had falls in the 6 months before their assessment (58% v 30%) and gait speed was slower (0.76 m/s v 0.85 m/s). CONCLUSIONS Older patients with high grade gliomas compared to similar thoracic malignancies had more neurocognitive impairment, falls in the preceding 6 months, and slower gait speed. Physician rated KPS and frailty were similar in both groups. The results illustrate the limitations of physician-rated performance measures and highlight the importance of CGA in older brain tumor patients.

CGE19-063: Creating a Clinical-Molecular Database to Study Patients with BRAF V600E-Mutated Brain Tumors

Background: Glioblastoma remains incurable, but detailed molecular characterization has revealed different genomic subtypes have differential survival and sensitivity to therapies. Correlating clinical with molecular data has proven challenging, however, limiting the field’s insight into the effect of specific mutations. BRAF V600E, a targetable mutation with important therapeutic implications, is not well studied in adults with high-grade gliomas. With this study we sought to establish a consolidated clinical-molecular database in order to ascertain the range of primary brain tumors with BRAF V600E mutations that occur in adults, and the clinical and histopathological features of these tumors. Methods: We created a secure, web-based database using the REDCap tool. We analyzed data from 29 adults with primary brain tumors containing the BRAF V600E mutation, recording gender, age at diagnosis, tumor pathology, molecular tumor information, dates of surgeries, time to progression, treatments received, response to treatment, and survival. Results: The patient cohort’s median age at diagnosis was 33 ± 3.2 years. These patients were followed for a median of 4.2 ± 1.5 years. Tumor grades ranged from WHO I to IV, with 59% (n=17) of tumors classified as high grade by WHO criteria (III or IV). Of the patients with high-grade gliomas, 60% (n=6) received chemotherapy and radiation within 4 months of diagnosis. Three patients were treated at progression: 1 received standard therapy, the other 2 received an experimental targeted therapy of dabrafenib and trametinib (BRAF/MEK inhibitors). Overall, the high-grade glioma cohort received a median of one treatment (range 0–4) with a median follow up of 1.2 ± 0.9 years. Conclusion: Understanding the natural history of different genomic subtypes of glioblastoma is critical for the appropriate application of novel therapeutics. Here we demonstrate that a clinical-pathological database consisting of clinical and molecular data from patients with an uncommon mutation in brain tumors (BRAF V600E) is useful for understanding the prevalence, distribution, and natural history of this disease. This novel database tool also creates a systematic manner in which to track the clinical outcome in cohorts of patients with specific mutations, which is of broad interest for patients with glioblastoma and other potentially targetable mutations.

Post-radiotherapy apparent diffusion coefficient (ADC) in children and young adults with high-grade gliomas and diffuse intrinsic pontine gliomas

Objectives: Diffusion-weighted magnetic resonance imaging (DW-MRI) offers potential to monitor response and predict survival in high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). We hypothesized that post-radiotherapy DW-MRI may provide prognostic imaging biomarkers in children and young adults with these tumors. Methods: Patients aged ≤21 years diagnosed between 2005 and 2012 were eligible. The tumor median apparent diffusion coefficient (ADC) and its 5th percentile (C5-ADC) were determined at the first post-radiotherapy scan and at the time of radiological progression. DW-MRI parameters were correlated with survival endpoints, temozolomide use and pseudoprogression, when it occurred. Results: Out of 40 patients (20 HGG, 20 DIPG), 23 had evaluable DW-MRI post-radiotherapy and 25 at radiological progression. There were 6 episodes of pseudoprogression. Hazard ratios (95%CI) for progression-free survival were 0.998 (0.993–1.003) for median ADC and 1.003 (0.996–1.010) for C5-ADC. Hazard ratios (95%CI) for overall survival were 1.0009 (0.996–1.006) for median ADC and 0.998 (0.992–1.004) for C5-ADC. Post-radiotherapy median and C5-ADC values were not significantly different between patients treated with radiotherapy alone versus radiotherapy/temozolomide. The median and C5-ADC values were not significantly different at the time of pseudoprogression compared to those at tumor progression. Conclusions: Post-radiotherapy median ADC and C5-ADC were not prognostic, nor able to differentiate radiosensitization with temozolomide or occurrence of pseudoprogression in this cohort of HGG and DIPG patients. Further exploration of alternative DW parameters, study timepoints or data modeling may contribute to the development of prognostic/predictive imaging biomarkers for children and young adults with HGG or DIPG.

Blood-Based Biomarkers in High Grade Gliomas: a Systematic Review

High-grade gliomas (HGG) are the most common malignant primary brain tumor in adults. During the course of disease, several challenges occur, like measuring tumor burden, monitoring of treatment response, estimating the patient's prognosis, and distinguishing between true progression and pseudo-progression. So far, no blood-based biomarker has been established in the clinical routine to address these challenges. The aim of this systematic review was to analyze the present evidence on blood-based biomarkers for HGG. We systematically searched in PubMed, Web of Sciences, Scopus, and Cochrane Library databases for publications before 30th of March 2018 reporting on associations of blood-based biomarkers in HGG patients with different endpoints as overall survival, progression-free survival, and postoperative monitoring. Quality assessment of the studies according to QUIPS and STARD guidelines was performed. In accordance with the GRADE guidelines, level of evidence (I-IV) for each of the tested biomarkers was assessed. One thousand six hundred eighty unique records were identified. Of these, 170 original articles were included to this review. Four hundred fifteen different blood-based biomarkers analyzed in 15.041 patients with HGG as also their corresponding recurrent tumors. Ten predictive biomarkers reached level II of evidence. No biomarker achieved level I of evidence. In this review, 10 blood-based biomarkers were selected as most promising biomarkers for HGG: α2-Heremans-Schmid glycoprotein (AHSG), albumin, glucose, insulin-like growth factor- binding protein 2 (IGFBP-2), macrophage inflammatory protein 1δ (MIP-1 δ), macrophage inflammatory protein 3ß (MIP-3ß), neutrophil-lymphocyte ratio (NLR), red blood cell distribution width (RDW), soluble glycoprotein 130 (Sgp130), and chitinase-3-like protein 1 (YKL-40). To further assess the clinical significance of these biomarkers, the evaluation in a larger cohort of HGG and their corresponding subgroups would be necessary.

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific real-time PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n = 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532-40. ©2017 AACR.

RT-26 * RE-RESECTION FOR RECURRENT HIGH GRADE GLIOMA IN THE SETTING OF RE-IRRADIATION: SURVIVAL OUTCOMES UPDATE

BACKGROUND: While patients with high grade gliomas (HGG) experience a high rate of recurrence, current treatment at recurrence remains controversial. Historically, re-resection for recurrent GBM demonstrates a significant survival benefit following reoperation of 3-13 months compared to 1-2 months without treatment. Here we investigate whether re-resection will improve survival in patients receiving fractionated stereotactic radiotherapy (FSRT) for recurrence. METHODS: 231 patients with recurrent HGG treated with re-irradiation between 1994 and 2012 at our institution were analyzed. FSRT was delivered using daily fractions of 3.5 Gy, median total dose of 35 Gy. 105 patients also underwent re-resection. Survival was then analyzed comparing patients with and without re-resection. Median survival time (MST) was defined as survival from initial diagnosis. Survival time was analyzed using the Kaplan-Meier method. Univariate and multivariate analysis was performed. RESULTS: The MST for the entire group is 22.5 months. There is no significant difference in survival between patients who received re-resection vs no re-resection, the MST was 23 months, and 21.9 months respectively (HR 1.1, p = 0.6). Those undergoing re-resection, 30 received gross total resection and 75 subtotal resection, with a MST of 22.0 and 26 months, respectively (p = 0.24). On univariate analysis, age and histology were significant factors (P < 0.05). On multivariate analysis, age remained significant for survival but no other factor (chemotherapy, histology, extent of resection, eloquent location, KPS) was significant. CONCLUSIONS: Our data reveals there is no significant improvement in survival with the addition of re-resection to patients who received FSRT for recurrent HGG. To our knowledge, this data analyzes the largest cohort of HGG treated with FSRT with and without surgical resection after recurrence. We hypothesize that the favorable survival seen in our cohort is derived from local control benefit due to the addition of FSRT.

P13.19 * HYPOFRACTIONATED RADIOTHERAPY IN PATIENTS WITH HIGH GRADE GLIOMAS AND POOR PROGNOSTIC FACTORS: A RETROSPECTIVE STUDY

PURPOSE: The standard treatment for patients with high-grade gliomas (HGG) and limited life expectancy is not well defined. Patients with an age over 65 years, poor Karnofsky performance status (KPS) and surgical biopsy/partial resection could not benefit from the combination of radiotherapy (60 Gy in 30 fractions) and chemotherapy with temozolomide (TMZ). In these patients hypofractionated radiotherapy (HypoRT) or TMZ alone have been suggested adequate treatments without significant differences in term of overall survival (OS) and progression free survival (PFS) compared to the standard approach. Furthermore, new clinical trials are investigating the role of a combination of HypoRT and TMZ. The aim of this retrospective study is to evaluate the outcome of HypoRT, with or without TMZ, in a cohort of HGG with poor prognostic factors. MATERIALS AND METHODS: Between January 2006 and December 2013, 69 patients with a diagnosis of HGG and poor prognostic factors (age ≥65 and/or KPS ≤60) were treated at our Institution. All patients were discussed in the Brain Tumor Board and treated with a dose of 42 Gy in 14 fractions with a conformal radiation treatment technique. TMZ was added either in elderly patients with no comorbidities or in poor KPS patients with younger age. Concomitant TMZ was given at a dose of 75 mg/m2 /d while adjuvant TMZ at a dose of 150-200 mg/m2 for 5 days every 28 days until tumor progression or unacceptable toxicity. During follow up a contrast-enhanced MRI was performed 4 weeks after the HypoRT, and thereafter every 3 months. The primary endpoint was overall survival (OS) measured from HypoRT start, according to the Kaplan-Meier method. RESULTS: Median age was 65 years (range, 34-80 years) and median KPS was 60 (range, 50-90). Fifty-four patients (78.3%) received a surgical resection (51 partial and 3 complete resections) and 15 patients (21.7%) underwent a biopsy. Fifty-eight patients had an histological diagnosis of glioblastoma, 7 of grade III glioma and 4 of high grade gliomas (not other specified). Five patients (7%) received concomitant, 5 (7%) concomitant and adjuvant and 13 (19%) adjuvant only TMZ. Median follow-up was 7.7 months (range, 1-34 months). The median survival time (MST) was 7 months; 6-month and 12-month OS rates were 54.4% and 29.5%, respectively. Univariate analysis was used to test the effects of prognostic factors on survival and none of these showed a statistical significance. After multivariate analysis there was a trend toward a better outcome with the addition of adjuvant TMZ (MST 9 vs. 6 months, Log Rank p = 0.06). CONCLUSIONS: Median survival of this cohort of HGG with poor prognostic factors is comparable to the data published in the literature. Adjuvant chemotherapy could improve OS, but prospectives studies with larger sample size and longer follow-up are needed.

Changes in Functional Performance Measures in Adults Undergoing Chemoradiation for Primary Malignant Glioma: A Feasibility Study

To investigate the feasibility of longitudinal assessment of functional performance measures in newly diagnosed postsurgical malignant glioma patients. Patients with histologically confirmed, clinically stable, postsurgical, and previously untreated high-grade glioma (HGG) or low-grade glioma (LGG) were studied. Using a prospective design, all participants performed a cardiopulmonary exercise test with expired gas analysis to assess cardiorespiratory function (VO(2peak)) immediately following surgical resection (mean, 10 days). Additional functional outcomes were skeletal muscle cross-sectional area (CSA) via magnetic resonance imaging, isokinetic muscle strength (isokinetic dynamometry), and body composition (air displacement plethysmography). Quality of life (QOL) was assessed by the Functional Assessment of Cancer Therapy-Brain scale. All study assessments were repeated at 6 and 24 weeks following surgery. Thirty-five patients (HGG, n = 25; LGG, n = 10) completed baseline assessments. Of these, 20 HGG (80%) and nine LGG (90%) and 15 HGG (60%) and nine LGG (90%) patients completed study assessments at 6 weeks and 24 weeks, respectively. Intention-to-treat analyses indicated several significant time-by-group interactions, with favorable improvements in functional and QOL endpoints from baseline to 24 weeks in the LGG cohort and unfavorable changes in the HGG cohort. Per-protocol analyses including participants assessed at all three study timepoints indicated significant improvements in VO(2peak) and fatigue from baseline to 24 weeks in the HGG cohort; peak workload, body composition, and muscle strength improved from baseline to 6 weeks (all p-values < .05). Longitudinal quantitative functional assessments are safe and feasible among select patients undergoing chemoradiation for primary malignant glioma. Large prospective studies investigating the clinical importance of these measures appear warranted.

Different Aetiology of Familial Low-Grade and High-Grade Glioma? A Nationwide Cohort Study of Familial Glioma

An increased risk for first-degree relatives (FDR) of glioma patients has previously been observed. The novel objective of this study was to investigate differences in familial risk among FDR of low-grade glioma (LGG) and high-grade glioma (HGG) cases, respectively. Two cohorts were constructed, one from 15,321 FDR of LGG cases and the other from 26,635 FDR of HGG cases calculating standardised incidence ratios (SIR). The risk for LGG among FDR of LGG cases was significantly increased, SIR 3.65 (95% CI 2.31–5.47). The risk was even higher in the cohort of siblings, SIR 7.00 (95% CI 3.35–12.87), and especially in the younger siblings (<40 years), SIR 9.01 (95% CI 4.31–16.57). When calculating the risk for HGG in the LGG cohort and the risk for HGG in the HGG cohort, there was a generally twofold increased risk, but no trends of increased risk in relatives of younger probands. Two different methods calculating familial risk displayed similar results. LGG families apparently have features manifesting a distinct pedigree pattern with sibpairs affected at a young age. These families could provide new insights into the aetiology of glioma.