Increasing value of autopsies in patients with brain tumors in the molecular era Abstract Background Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report. Methods We performed a retrospective analysis of brain tumor autopsies at Boston Children’s Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses. Results Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry. Conclusion Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.

Underweight and weight loss are predictors of poor outcome in patients with brain metastasis Abstract Purpose Overweight may be associated with favorable outcome whereas tumor cachexia may be associated with worse outcome in patients with metastatic cancer. Here we evaluate the association of abnormal body mass index and weight change with outcome in patients with brain metastasis. Methods Patients with a diagnosis of brain metastasis treated at the University Hospital Zurich (n = 703) were assessed for associations of body mass index, weight change, comorbidities and survival. Results Compared with patients with normal body mass index of 18.5–24.9 kg/m2 and a median overall survival of 9 months (95% confidence interval 7.5–10.5), overall survival was inferior in patients with body mass index < 18.5 kg/m2 (overall survival 6 months, 95% confidence interval 1.6–10.3, p = 0.04), but superior in patients with body mass index > 25 kg/m2 (overall survival 13 months, 95% confidence interval 11.0–15.0; p = 0.033). We report a median relative weight loss of 5% within the first 6 months of diagnosis of brain metastasis (95% confidence interval 3.3–6.5), and reduction exceeding the median was associated with an unfavorable outcome (weight loss < 5% 22.0 months, 95% confidence interval 19.2–24.8; weight loss > 5% 14.0 months, 95% confidence interval 11.9–16.). Conclusion High body mass index is associated with better, and underweight with worse outcome in patients with brain metastasis. Conversely, weight loss above median may predict poor outcome. Future studies need to address whether vigorous treatment of tumor cachexia, e.g. by specific nutrition management, might improve outcome of patients with brain metastasis. In contrast, regimens associated with weight loss such as ketogenic diet may be detrimental.

Carbon ion radiotherapy in the treatment of gliomas: a review Abstract Introduction Gliomas are among the most common primary brain malignancies, with a poor prognosis for high grade gliomas despite aggressive therapy. Carbon ions, which exhibit favorable biological and physical characteristics, have recently been studied in intracranial malignancies as a way to escalate dose to the tumor while minimizing dose to normal tissue. Methods Pubmed/Medline, SCOPUS, EMBASE, CINAHL and the Cochrane database were systematically reviewed using the search terms “carbon ion” and “glioma” or “glioblastoma” in August 2019. Out of 332 articles screened, 43 were included in this analysis. Results This comprehensive review describes the pertinent physics and radiation biology studies relevant to the treatment of gliomas with carbon ions and summarizes the important clinical studies for both high and low grade gliomas. Studies investigating carbon ions as both definitive radiotherapy and as a boost to traditional radiotherapy are reviewed. The use of carbon ion radiotherapy in the setting of recurrent disease is also described. Conclusions Carbon ion radiotherapy is both efficacious and safe based on early clinical studies. Current trials, including the CLEOPATRA and CINDERLLA trials, hope to define the role of carbon ion radiotherapy in the treatment of gliomas.

Efficacy of initial temozolomide for high-risk low grade gliomas in a phase II AINO (Italian Association for Neuro-Oncology) study: a post-hoc analysis within molecular subgroups of WHO 2016 Abstract Introduction The optimal management of high risk WHO grade II gliomas after surgery is debated including the role of initial temozolomide to delay radiotherapy and risk of cognitive defects. Methods A post-hoc analysis of a phase II multicenter study on high risk WHO grade II gliomas, receiving initial temozolomide alone, has re-evaluated the long-term results within the molecular subgroups of WHO 2016. The primary endpoint of the study was response according to RANO, being seizure response, PFS and OS secondary endpoints. Results Response rate among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency > 50% was observed in 87% of patients and a seizure freedom in 72%. The probability of seizure reduction > 50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Sixty-seven percent of patients with oligodendroglioma IDH mutant and 1p/19q codeleted did not recur with a median follow up of 9.3 years, while 59% did not receive radiotherapy at recurrence with a median follow up of 8.2 years. Conclusions The beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery alone, or with intractable seizures, should receive temozolomide as initial treatment with salvage radiotherapy and/o reoperation and/or second-line chemotherapy at recurrence.

Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study Abstract Background The Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males. Methods Genotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case–Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings. Results The rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample. Conclusions These results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.

Cognitive functioning and predictors thereof in patients with 1–10 brain metastases selected for stereotactic radiosurgery Abstract Purpose Information on predictive factors of cognitive functioning in patients with (multiple) brain metastases (BM) selected for radiosurgery may allow for more individual care and may play a role in predicting cognitive outcome after radiosurgery. The aim of this study was to evaluate cognitive performance, and predictors thereof, in patients with 1–10 BM before radiosurgery. Methods Cognition was measured before radiosurgery using a standardized neuropsychological test battery in patients with 1–10 BM (expected survival > 3 months; KPS ≥ 70; no prior BM treatment). Regression formulae were constructed to calculate sociodemographically corrected z scores. Group and individual cognitive functioning was analyzed. Multivariable regression was used to explore potential predictors. Results Patients (N = 92) performed significantly worse than controls (N = 104) on all 11 test variables (medium-large effect sizes for 8 variables). Percentages of impairment were highest for information processing (55.3%), dexterity (43.2%) and cognitive flexibility (28.7%). 62% and 46% of patients had impairments in at least two, or three test variables, respectively. Models including combinations of clinical and psychological variables were predictive of verbal memory, psychomotor speed, information processing and dexterity. Neither number nor volume of metastases predicted patients’ test performance. Conclusions Already before radiosurgery, almost half of the patients suffered from severe cognitive deficits in at least three test variables. At group and individual level, information processing, cognitive flexibility, and dexterity were most affected. These cognitive impairments may impair daily functioning and patients’ ability to make (shared) treatment decisions. Both clinical (symptomatic BM; timing of BM diagnosis) and psychological (mental fatigue) characteristics influenced cognitive performance. Clinical trial information Cognition and Radiation Study A (CAR-Study A; ClinicalTrials.gov Identifier: NCT02953756; Medical Ethics Committee file number: NL53472.028.15/P1515).

Risk factors for intraoperative stimulation-related seizures during awake surgery: an analysis of 109 consecutive patients Abstract Introduction During surgery for lesions in eloquent areas the goal is to achieve the widest resection possible, without loss of neurological function. Intraoperative seizures may lead to abandonment of the procedure or damages to the patient. Awareness regarding the predictors of IOS would help the surgeon. The aim of this retrospective study was to identify the factors associated with the occurrence of IOS in patients who underwent awake surgery for removal of gliomas in eloquent areas. Methods This was a retrospective analysis of prospectively collected data of 109 patients who underwent awake craniotomy between January 2010 and December 2017 for removal of gliomas. IOS were defined as tonic–clonic seizures or loss of consciousness resulting in communication difficulties with the patient occurring during cortical and subcortical mapping. Results A total of 109 patients were included in this study and IOS occurred in 9 (8.2%) patients. Demographic and clinical factors were comparable between patients with and without IOS. In the IOS group, 7 (77.8%) patients had seizures preoperatively and 4 (57.1%) were on more than one perioperative antiepileptic drugs (AED). Conclusions The current series add some hints to the poorly studied IOS risk during awake surgery. The risk of IOS appears to be relatively higher in patients with anteriorly located tumors and in patients operated without intraoperative brain activity monitoring and different patterns of stimulation for language and sensory-motor mapping. Further studies are needed to clarify the role of intraoperative techniques.

Increased cochlear radiation dose predicts delayed hearing loss following both stereotactic radiosurgery and fractionated stereotactic radiotherapy for vestibular schwannoma Abstract Purpose Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) are noninvasive therapies for vestibular schwannomas providing excellent tumor control. However, delayed hearing loss after radiation therapy remains an issue. One potential target to for improving hearing rates is limiting radiation exposure to the cochlea. Methods We retrospectively reviewed 100 patients undergoing either SRS with 12 Gy (n = 43) or fSRT with 50 Gy over 28 fractions (n = 57) for vestibular schwannoma. Univariate and multivariate analysis were carried out to identify predictors of hearing loss as measured by the Gardner Robertson scale after radiation therapy. Results Deterioration of hearing occurred in 30% of patients with SRS and 26% with fSRT. The overall long term (> 2 year) progression rates were 20% for SRS and 16% for fSRT. Patients with a decrease in their Gardner Robertson hearing score and those that loss serviceable hearing had significantly higher average minimal doses to the cochlea in both SRS and fSRT cohorts. ROC analysis showed that a cut off of 5 Gy and 35 Gy, for SRS and fSRT respectively, predicted hearing loss with high sensitivity/specificity. Conclusion Our data suggests the minimal dose of radiation that the cochlear volume is exposed to is a predictor of delayed hearing loss after either SRS or fSRT. A threshold of 5 Gy/35 Gy may lead to improved hearing preservation after radiotherapy. Further prospective multi center studies can further elucidate this mechanism.

Oligodendroglioma confers higher risk of radiation necrosis Abstract Background Radiation therapy (RT) remains a mainstay for the treatment of lower grade gliomas. Radiation neurotoxicity is a serious complication, carrying high morbidity in the absence of tumor progression. The incidence remains poorly categorized and known risk factors identified are related to the radiation modality. We hypothesized that patients with oligodendroglioma have a higher risk of radiation necrosis (RN) as compared to patients with astrocytoma. Methods We conducted a retrospective review of adults with lower grade diffuse gliomas over a 10-year span. The primary outcome was RN, either pathologically confirmed or clinically diagnosed. Cases without pathological confirmation must have been symptomatic, requiring administration of bevacizumab or high-dose steroids. Cox proportional hazard ratios were used for multivariate analyses. Results In 319 patients, we identified RN in 41 patients (12.9%): 28 patients (21.3%) with oligodendroglioma and 13 (6.9%) with astrocytoma (HR 3.42, p < 0.001). Patients with oligodendroglioma who received > 54 Gy had a higher incidence (31.2%) than those receiving ≤ 54 Gy (14.3%, HR 6.9, p = 0.002). There was no similar correlation among patients with astrocytoma. There was no difference in incidence based on use of concomitant temozolomide. Radiation necrosis appeared within 24 months from radiation in 80.5% of patients. Conclusion Our study suggests that patients with oligodendroglioma are at higher risk of developing RN. The incidence increases with increasing radiation dose in patients with oligodendroglioma but not with astrocytoma. RN usually appears within 24 months from RT. Patients with oligodendroglioma receiving > 54 Gy are at highest risk.

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma Abstract Purpose Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM. Methods We performed a retrospective cohort study of patients 18–45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18–45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA). Results Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3–31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18). Conclusions EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.