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Background: Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear., Methods: We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers., Results: Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma-like tumors could stratify these tumors into low and high risk (P = 0.0014)., Conclusion: The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Although brainstem gliomas are a rare group of neoplasias, when they affect pregnant women, there can be challenges with diagnosis and management. This study describes a case of brainstem glioma diagnosed in pregnancy and systematically reviews the literature on brainstem gliomas in pregnancy to provide guidance for management. Material and methods: We searched five databases from inception until October 2016 using subject headings and keywords related to pregnancy and brainstem glioma, and included original research articles that described pregnancy outcomes in women with brainstem glioma. Data extraction and quality assessment using the Joanna Briggs Institute Critical Appraisal Checklist for case reports were performed in duplicate. Outcomes were reported as proportions. The study protocol was registered with the Prospero International Prospective Register of Systematic Reviews (CRD42017060196). Results: We screened 2737 titles and abstracts, and 89 full-texts. Twelve articles describing 17 pregnancies in 16 women were included in the analysis. The median gestational age at presentation was 23 weeks. All but one case presented with neurologic deficit. Magnetic resonance (MRI) imaging conclusively diagnosed all cases. Surgical tumor resection ( n  = 4) and radiation therapy ( n  = 3) were successfully undertaken during pregnancy. There were no reported sequelae of maternal oncological management on neonatal wellbeing. Maternal mortality was high (8/16, 50%) both during ( n  = 5) and within 4 weeks ( n  = 3) of pregnancy. Pregnancy losses included one pregnancy termination and four miscarriages (associated with maternal mortality). Of the 12 live-born babies, five were premature. Two of these were the result of spontaneous preterm labor and three were delivered prematurely to facilitate glioma management. There was one case of fetal growth restriction. Conclusions: Although the symptoms of brainstem gliomas often mimic those commonly encountered in pregnancy, neurologic deficits warrant urgent investigation. MRI is the diagnostic modality of choice in pregnancy. Brainstem gliomas are associated with high maternal mortality and appropriate management, including surgical tumor resection and radiation therapy, should not be delayed on account of pregnancy. Pregnancy outcomes are favorable although there is a risk of preterm birth.Key messageBrainstem gliomas are associated with high maternal mortality and timely diagnosis using magnetic resonance imaging and treatment including surgical resection and radiation therapy should not be delayed during pregnancy. Pregnancy outcomes are generally favorable except for risk of preterm birth.

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: There are very few studies about the role of repeat irradiation (RT2) for children with recurrent supratentorial high-grade glioma (HGG). It was the aim of this study to assess the effectiveness and safety of RT2 in this population., Procedure: This was a retrospective cohort study of 40 children age 18 years and under with recurrent supratentorial HGG who had received at least one course of RT. In-field reirradiation volumes included focal or whole brain RT, with doses ranging from 30 to 54 Gy. The primary endpoint was overall survival (OS) from the first day of RT2., Results: Fourteen patients underwent RT2. The median survival of these patients was 6.5 months. Patients with ≥12 months elapsed time between RT1 and RT2 experienced longer OS than patients who had < 12 months (P = 0.009). There was no difference in OS between patients with or without germline mutations (e.g., Lynch, Li-Fraumeni, or constitutional mismatch-repair deficiency, P = 0.20). Ten patients received RT2 that overlapped with RT1 volumes for locally recurrent disease. Of this group, 80% experienced clinical benefit from in-field RT2, defined as clinical/radiologic response or stable disease. Ninety-three percent completed the prescribed course of RT2, with one patient developing grade 3 radiation necrosis four months after RT2. When compared with 26 patients who were not offered reirradiation, those selected for RT2 had improved median survival from the time of first disease progression (9.4 vs 3.8 months, P = 0.005)., Conclusions: Reirradiation for children with recurrent supratentorial HGG is a safe, effective treatment that provides short-term disease control., (© 2019 Wiley Periodicals, Inc.)

Objective: Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach., Method: We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT., Results: Since January 2011, we identified 16 patients with progressive DIPG who received rRT. Median time from diagnosis to progression was 10.5 months (range, 4-37 months). rRT was given focally in 14 patients at a dose ranging from 21.6 to 36 Gy. rRT was well tolerated by all children but one. All but three patients showed neurological improvement. With a median follow-up from original diagnosis of 19.2 months, all patients died, with a median time from rRT to death of 6.48 months (range, 3.83-13.26 months). When compared to a historic cohort of 46 consecutive patients, the median time from progression to death was 92 days in the non-reirradiated patients versus 218 days in the reirradiated ones (P = 0.0001)., Conclusion: In this limited experience, rRT was safe and feasible in patients with progressive DIPG, providing neurological improvement and a prolonged life span in most patients. Prospective Canadian rRT protocols are ongoing to further assess the benefit of this approach, including quality of life assessment., (© 2018 Wiley Periodicals, Inc.)

Diffuse intrinsic pontine glioma (DIPG) is an aggressive infiltrative glioma for which no curative therapy is available. Radiation therapy (RT) is the only potentially effective intervention in delaying tumor progression, but only transiently. At progression, re-irradiation is gaining popularity as an effective palliative therapy. However, at second progression, exclusive symptomatic treatment is usually offered. Here we report two patients with DIPG at second progression who were treated with a second re-irradiation course with good response. Importantly, treatment was well tolerated with no irradiation associated acute toxicity identified.

Background: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma., Methods: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model., Results: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS., Conclusions: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

Background: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown., Methods: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database., Results: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes., Conclusions: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients., (© 2016 American Cancer Society.)

Diencephalic syndrome (DS) is a clinical disorder of metabolism associated with poor outcome in children with low-grade gliomas (LGGs). Since survival has been primarily reported with aggressive therapy, we report outcome data for these patients using a current, contrasting chemotherapy-driven approach. We performed a population-based review of DS patients treated with chemotherapy from 1997-2012. Metabolic rate was assessed in selected cases using open-circuit calorimetry to generate resting energy expenditure (REE) data. Tumor tissue was analyzed for BRAF alterations. Survival was compared with an age-related, radiotherapy naïve cohort of non-DS children with location-matched LGGs. Nine children (1.7% of 520 LGG diagnoses) fulfilled DS criteria. The median diagnostic age was 1.49 years (0.55-2.69 years), although neurofibromatosis Type-I patients were older (p = 0.005). All tumors analyzed exhibited either NF1 mutation or BRAF fusion. Seven tumors were histologically confirmed as low grade astrocytomas, one demonstrated neurocytic features, and one NF1 case was diagnosed using imaging and clinical criteria. All patients received chemotherapy, with seven cases also receiving initial nutritional supplementation. All nine gained weight after only 6 months of treatment. Two DS patients had serial REE measurements, revealing a hypermetabolic state (over 200% of predicted REE) at diagnosis which reduced to normal range with therapy. First-line chemotherapy treatment resulted in one minor response, stable disease in four cases, with progression in the remaining four patients. Although DS patients demonstrated inferior initial progression-free survival when compared to non-DS counterparts (5 years: 22 versus 60%, p = 0.015), all DS children remain alive at a median follow up of 5.3 years (1.2-14.9 years) with none requiring radiotherapy. Long-term sequelae included pituitary and visual dysfunction, learning difficulties and paradoxical, inappropriate weight gain. DS can be managed with non-aggressive chemotherapeutic, radiation-sparing strategies supplemented by temporary nutritional support. Multiple lines of therapy may be required to overcome disease progression but excellent survival and metabolic outcomes can be achieved. Continued surveillance is mandatory to prevent significant weight gain and support affected children with clinical sequelae.

Objective: This systematic review examines the role of chemotherapy following surgery and external beam radiotherapy for adults with newly diagnosed malignant glioma., Methods: MEDLINE, EMBASE, and the Cochrane Library databases were searched to August 2006 to identify relevant randomized controlled trials (RCTs) and meta-analyses. Proceedings from the 1997 to 2006 annual meetings of the American Society of Clinical Oncology were also searched., Results: Two RCTs reported a survival advantage in favour of radiotherapy with concomitant and adjuvant temozolomide compared with radiotherapy alone in patients with anaplastic astrocytoma or glioblastoma. Twenty-six RCTs and two meta-analyses detected either no advantage or a small survival advantage in favour of adjuvant chemotherapy., Conclusion: Concomitant temozolomide during radiotherapy and post-radiation adjuvant temozolomide is recommended for all patients ages 18-70 with newly diagnosed glioblastoma multiforme who are fit for radical therapy (ECOG 0-1). Temozolomide may be considered in other situations (i.e., ECOG 2, biopsy only, age > 70, intermediate grade glioma), but there is no high-level evidence to support this decision. Moreover, there are few data on long-term toxicities or quality of life with temozolomide. Adjuvant chemotherapy may be an option for younger patients with anaplastic (grade 3) astrocytoma and patients with pure or mixed oligodendroglioma. However, there is no evidence of a survival advantage from adjuvant chemotherapy in these patients, and treatment-related adverse effects and their impact upon quality of life are poorly studied. The combination of procarbazine, lomustine, and vincristine (PCV) is not recommended for patients with anaplastic oligodendroglioma and oligoastrocytoma.

Purpose: A systematic review was conducted to develop guidelines for radiotherapy in adult patients with newly diagnosed malignant glioma., Methods: MEDLINE, CANCERLIT, the Cochrane Library, and relevant conference proceedings were searched to identify randomized trials and meta-analyses., Results: Pooling of six randomized trials detected a significant survival benefit favouring post-operative radiotherapy compared with no radiotherapy (risk ratio, 0.81; 95% confidence interval, 0.74 to 0.88, P<0.00001). Two randomized trials demonstrated no significant difference in survival rates for whole brain radiation versus more local fields that encompass the enhancing primary plus a 2 cm margin. A randomized trial detected a small improvement in survival with 60 Gy in 30 fractions over 45 Gy in 20 fractions. Radiation dose intensification and radiation sensitizer approaches have not demonstrated superior survival rates compared with conventionally fractionated doses of 50-60 Gy., Conclusions: Post-operative external beam radiotherapy is recommended as standard therapy for patients with malignant glioma. The high-dose volume should incorporate the enhancing tumour plus a limited margin (e.g. 2 cm) for the planning target volume, and the total dose delivered should be in the range of 50-60 Gy in fraction sizes of 1.8-2.0 Gy. Radiation dose intensification and radiation sensitizer approaches are not recommended as standard care. For patients older than age 70, preliminary data suggest that the same survival benefit can be achieved with less morbidity using a shorter course of radiotherapy. Supportive care alone is a reasonable therapeutic option in patients older than age 70 with a poor performance status.

Except for isolated case reports, blastomycosis has not been identified as a significant problem in immunosuppressed patients. We describe an unusual case with blastomycotic infection of a cerebral glioma in a 56-year-old man who underwent radiotherapy for his tumor and died of fulminant blastomycotic pneumonia. This is believed to be the first reported case of Blastomyces dermatitidis infection of a cerebral glioma. The light microscopic and ultrastructural features of B. dermatitidis, the giant forms of which were encountered in our patient, are described, and thr role of immunosuppression due to steroid therapy in the pathogenesis of this fulminant infection are reviewed.