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Introduction: This study aimed to investigate long-term neurocognitive, psychological, and return to work (RTW) outcomes in meningioma patients, and to explore whether neurocognitive and psychological factors influence RTW outcomes in this population., Methods: In this retrospective study, 61 meningioma patients completed in-depth clinical neuropsychological assessments. Of these participants, 42 were of working-age and had RTW information available following neuropsychological assessment. Seventy-one percent and 80% of patients received radiation and surgery, respectively, with 49% receiving both radiation and surgery. Associations between demographic, medical, neurocognitive, psychological, and RTW data were analyzed using multivariable logistic regression analyses., Results: In our sample, 68% of patients exhibited global neurocognitive impairment, with the largest effect sizes found on tests of visual memory (d = 0.73), executive function (d = 0.61), and attention (d = 0.54). Twenty-seven percent exhibited moderate to severe levels of depressive symptoms. In addition, 23% and 30% exhibited clinically significant state and trait anxiety, respectively. Forty-eight percent of patients were unable to RTW. Younger age, faster visuomotor processing speed, and, unexpectedly, higher trait anxiety scores were associated with an increased likelihood of returning to work., Conclusions: Meningioma patients are at risk of experiencing neurocognitive deficits, psychological symptoms, and difficulties returning to work. Our results suggest that neurocognitive and psychological factors contribute to RTW status in meningioma patients. Prospective research studies are necessary to increase our understanding of the complexity of functional disability in this growing population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although radiation (RT) is standard treatment for many brain tumors, it may contribute to neurocognitive decline. The objective of this study was to investigate associations between RT dose to circumscribed brain regions and specific neurocognitive domains in patients with meningioma., Methods: We undertook a retrospective study of 40 patients with meningioma who received RT and underwent an in-depth clinical neurocognitive assessment. Radiation dosimetry characteristics were delineated based on treatment planning computerized tomography co-registered with contrast-enhanced 3D T1-weighted magnetic resonance imaging. Principal components analysis was applied to organize neurocognitive test scores into factors, and multivariate multiple linear regression models were undertaken to examine if RT dose to circumscribed brain regions is associated with specific neurocognitive outcomes., Results: Radiation dose to brain regions was associated with neurocognitive functions across a number of domains. High dose to the parietal-occipital region was associated with slower visuomotor processing speed (mean dose, β = -1.100, P = .017; dose to 50% of the region [D50], β = -0.697, P = .049). In contrast, high dose to the dorsal frontal region was associated with faster visuomotor processing speed (mean dose, β = 0.001, P = .036)., Conclusions: These findings suggest that RT delivered to brain regions (ie, parietal-occipital areas) may contribute to poor neurocognitive outcomes. Given that modern radiotherapy techniques allow for precise targeting of dose delivered to brain regions, prospective trials examining relations between dose and neurocognitive functions are warranted to confirm these preliminary results., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: High-quality radiotherapy (RT) planning for children and young adults with primary brain tumours is essential to minimize the risk of late treatment effects. The feasibility of using automated machine-learning (ML) to aid RT planning in this population has not previously been studied., Methods and Materials: We developed a ML model that identifies learned relationships between image features and expected dose in a training set of 95 patients with a primary brain tumour treated with focal radiotherapy to a dose of 54 Gy in 30 fractions. This ML method was then used to create predicted dose distributions for 15 previously-treated brain tumour patients across two institutions, as a testing set. Dosimetry to target volumes and organs-at-risk (OARs) were compared between the clinically-delivered (human-generated) plans versus the ML plans., Results: The ML method was able to create deliverable plans in all 15 patients in the testing set. All ML plans were generated within 30 min of initiating planning. Planning target volume coverage with 95% of the prescription dose was attained in all plans. OAR doses were similar across most structures evaluated; mean doses to brain and left temporal lobe were lower in ML plans than manual plans (mean difference to left temporal, - 2.3 Gy, p = 0.006; mean differences to brain, - 1.3 Gy, p = 0.017), whereas mean doses to right cochlea and lenses were higher in ML plans (+ 1.6-2.2 Gy, p < 0.05 for each)., Conclusions: Use of an automated ML method to aid RT planning for children and young adults with primary brain tumours is dosimetrically feasible and can be successfully used to create high-quality 54 Gy RT plans. Further evaluation after clinical implementation is planned., (© 2022. The Author(s).)

Background: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion., Methods: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery., Results: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation., Conclusions: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement., (© 2021. The Author(s).)

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., (© 2022. The Author(s).)

Background: Radiosurgery dose rate and biologically effective dose (BED) are associated with outcomes after stereotactic radiosurgery (SRS) for functional neurosurgical conditions and some benign tumors. It is not known if these factors affect the efficacy of SRS for meningioma., Objective: To determine the association between cobalt-60 dose rate and BED on outcomes in patients with meningioma treated with SRS., Methods: A single-institution cohort of 336 patients treated between 2005 and 2018 with cobalt-based SRS for 414 separate meningioma lesions was assembled. BED was calculated using an SRS-specific monoexponential model accounting for treatment time per lesion, assuming α/β = 2.47 Gy. Cumulative incidences of local failure (LF) were reported after considering the competing risk of death, on a per-lesion basis. Multivariable analysis of LF was performed using a proportional hazards model., Results: The most common SRS dose was 12 Gy (n = 227); 140 lesions received 14 Gy. Five-year LF was 15.6% (95% confidence interval 10.4-21.9) and 4.3% (1.4-9.8) in patients who had a dose rate of <2.95 and ≥2.95 Gy/min, respectively (P = .0375). Among 354 grade I or unresected lesions treated with SRS, BED >50 Gy2.47 was associated with a lower incidence of LF (P = .0030). Each 1 Gy/min increase in dose rate was associated with an adjusted hazard ratio of 0.53 (95% confidence interval, 0.29-0.97, P = .041) for LF. Prescription dose >12 Gy was not associated with a lower incidence of LF., Conclusion: Patients with meningiomas treated with lower dose rates experienced a higher incidence of LF than those treated with higher dose rates., (Copyright © Congress of Neurological Surgeons 2021. All rights reserved.)

Objective: Maximal safe resection is the standard-of-care treatment for adults with intracranial ependymoma. The value of adjuvant radiotherapy remains unclear as these tumors are rare and current data are limited to a few retrospective cohort studies. In this study, the authors assembled a cohort of patients across multiple international institutions to assess the utility of adjuvant radiotherapy in this patient population., Methods: Adults with intracranial ependymoma managed surgically at the University Health Network in Toronto, Canada, the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma, and The Ottawa Hospital in Ottawa, Canada, were included in this study. The primary end points were progression-free survival (PFS) and overall survival (OS). Clinicopathological variables were assessed in univariate and multivariate Cox proportional hazard models for prognostic significance of PFS and OS., Results: A total of 122 patients diagnosed between 1968 and 2019 were identified for inclusion. The majority of patients had grade II ependymomas on histopathology (78%) that were infratentorially located (71%), underwent gross-total (GTR) or near-total resection (NTR; 55%), and were treated with adjuvant radiotherapy (67%). A volumetric analysis of the extent of resection in 49 patients with available tumor volume data supported the accuracy of the categorical GTR, NTR, and subtotal resection (STR) groups utilized. Independent statistically significant predictors of poorer PFS in the multivariate analysis included STR or biopsy (vs GTR/NTR; HR 5.4, 95% confidence interval [CI] 2.4-11.0, p < 0.0001) and not receiving adjuvant radiotherapy; cranial (HR 0.5, 95% CI 0.2-1.1) and craniospinal (HR 0.2, 95% CI 0.04-0.5) adjuvant radiotherapy regimens improved PFS (p = 0.0147). Predictors of poorer OS in the multivariate analysis were grade III histopathology (vs grade II: HR 5.7, 95% CI 1.6-20.2, p = 0.0064) and undergoing a biopsy/STR (vs GTR/NTR: HR 9.8, 95% CI 3.2-30.1, p = 0.0001)., Conclusions: The results of this 50-year experience in treating adult intracranial ependymomas confirm an important role for maximal safe resection (ideally GTR or NTR) and demonstrate that adjuvant radiotherapy improves PFS. This work will guide future studies as testing for molecular ependymoma alterations become incorporated into routine clinical practice.

Purpose: Hearing loss (HL) is a serious secondary effect of treatment for CNS and head-and-neck tumors in children. The goal of this study was to evaluate incidence and risk factors for HL in patients with multiple ototoxic exposures., Patients and Methods: We evaluated 340 ears from 171 patients with CNS or head-and-neck tumors treated with radiation, with or without chemotherapy, who had longitudinal audiologic evaluation. International Society of Pediatric Oncology-Boston grades were assigned to 2,420 hearing assessments. Multivariable weighted ordinal logistic regression was fitted to evaluate the effect of clinicopathologic features on HL., Results: Mean cochlea dose (odds ratio [OR] 1.04 per Gy, P < .001), time since radiotherapy (RT; OR 1.21 per year, P < .001), cisplatin dose (OR 1.48 per 100 mg/m 2 , P < .001), and carboplatin dose (OR 1.41 per 1,000 mg/m 2 , P = .002) were associated with increasing International Society of Pediatric Oncology-Boston grade of HL. There was no synergistic effect of RT and cisplatin (interaction term, P = .53) or RT and carboplatin (interaction term, P = .85). Cumulative incidence of high-frequency HL (> 4 kHz) was 50% or greater at 5 years after RT if mean cochlea dose was > 30 Gy, while incidence of HL across all frequencies continued to increase beyond 5 years after RT., Conclusion: Children treated with radiation and chemotherapy experience a high incidence of HL over time, with associations found between more severe HL and cisplatin or carboplatin dose as well as mean cochlea dose. Mean cochlea dose of ≤ 30 Gy is proposed as a goal to reduce the risk of HL; a lower threshold (20-25 Gy) may be considered in patients receiving platinum chemotherapy to reduce cumulative HL burden., Competing Interests: Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst) Sharon CushingConsulting or Advisory Role: DecibelSpeakers' Bureau: Interacoustics, Cochlear CorporationResearch Funding: Cochlear Corporation (Inst)Patents, Royalties, Other Intellectual Property: Systems and Methods for Balance Stabilization. Applied Patents No.: 7041-0. Joint Holder Name(s), Royalties—Plural Publishing—Editor of Manual of Pediatric Balance DisordersTravel, Accommodations, Expenses: Interacoustics, Cochlear Corporation Vijay RamaswamyHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca CanadaNo other potential conflicts of interest were reported.

Abstract: A 24-year-old man presented with a 2-month history of progressive, painless vision loss in the right eye, with no history of headache, nasal congestion, rhinorrhea, or epistaxis. His visual acuity was counting fingers at 1 ft in the right eye and 20 of 20 in the left eye with a right relative afferent pupillary defect and mild temporal optic disc pallor. MRI of the brain and orbits showed a mass involving bilateral ethmoid and sphenoid sinuses and right nasal cavity. He underwent urgent extended endoscopic endonasal transsphenoidal approach for resection of the sinonasal skull base tumor and photon radiation therapy. Pathology revealed a well-differentiated cartilaginous neoplasm with focal areas of entrapped native bone, consistent with a chondrosarcoma WHO grade I/III. At 6-month follow-up after surgery, he had a visual acuity of 20/40 in the right eye and 20/20 in the left eye. Malignant tumors from the sinonasal area should be kept in the differential diagnosis for compressive optic neuropathies and may present with vision loss even in the absence of nasal or sinus symptoms., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by North American Neuro-Ophthalmology Society.)

Background: The goal of this study was to evaluate extent of surgical resection, and timing and volume of re-irradiation, on survival for children with locally recurrent ependymoma., Methods: Children with locally recurrent ependymoma treated with a second course of fractionated radiotherapy (RT2) from 6 North American cancer centers were reviewed. The index time was from the start of RT2 unless otherwise stated., Results: Thirty-five patients were included in the study. The median doses for first radiation (RT1) and RT2 were 55.8 and 54 Gy, respectively. Median follow-up time was 5.6 years. Median overall survival (OS) for all patients from RT2 was 65 months. Gross total resection (GTR) was performed in 46% and 66% of patients prior to RT1 and RT2, respectively. GTR prior to RT2 was independently associated with improved progression-free survival (PFS) for all patients (HR 0.41, P = 0.04), with an OS benefit (HR 0.26, P = 0.03) for infratentorial tumors. Median PFS was superior with craniospinal irradiation (CSI) RT2 (not reached) compared to focal RT2 (56.9 months; log-rank P = 0.03). All distant failures (except one) occurred after focal RT2. Local failures after focal RT2 were predominantly in patients with less than GTR pre-RT2., Conclusions: Patients with locally recurrent pediatric ependymoma should be considered for re-treatment with repeat maximal safe resection (ideally GTR) and CSI re-irradiation, with careful discussion of the potential side effects of these treatments., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Extracranial arteriovenous malformations (AVMs) are rare pathological, benign conditions that are characterized by aberrantly connected arteries and veins without normal intervening capillary vasculature. Although stereotactic radiosurgery is an established, efficacious, safe treatment for intracranial AVMs, there is no known published data on the use of stereotactic body radiotherapy (SBRT) for the treatment of abdominopelvic AVMs. One patient with an extracranial AVM in the pelvis that was only partially responsive to embolization was treated with SBRT to a dose of 21 Gy, delivered in three fractions over six calendar days. At presentation, the patient was non-ambulatory due to neuropathic pain from a sciatic impingement of the AVM. The patient underwent two prior catheter-based embolization procedures that had achieved partial obliteration, but with the persistence of neuropathic pain and symptoms. After SBRT to the pelvic AVM, the patient had marked improvement in pain over 10 months and was able to ambulate again. Follow-up angiography and CT demonstrated the obliteration of previously visualized AVM. We describe the first known report of pelvic AVM successfully treated with a combination of embolization and SBRT. Three-fraction SBRT to a total dose of 21 Gy appears to be safe and effective for extracranial AVMs arising in the pelvis. This strategy may be considered for patients with pelvic AVMs that are refractory to standard interventional therapies. However, these findings should be validated in larger cohorts., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Jooya et al.)

Objective: To evaluate the relationships between calibration dose rate, calculated biologically effective dose (BED), and clinical factors and tumor control after stereotactic radiosurgery (SRS) for acoustic neuroma., Methods: We performed a retrospective study of all patients with acoustic neuromas treated with frame-based cobalt-60 SRS at a single institution between 2005 and 2019. The calibration dose rate and cobalt-60 half-life were used to calculate the nominal dose rate during treatment. An SRS-specific monoexponential model accounting for treatment time per lesion was used to estimate BED., Results: The study included 607 patients with 612 acoustic neuromas. Median follow-up was 5.0 years. There was no association between dose rate or BED with local failure (LF), radiologic edema, or symptomatic edema. Cystic tumors (adjusted hazard ratio 0.26, P = 0.028) were associated with lower LF, while use of SRS as salvage treatment for growing tumors (adjusted hazard ratio 4.9, P < 0.0001) was associated with higher LF. LF occurred more frequently in larger-diameter tumors, while radiologic or symptomatic edema occurred more frequently in larger-volume tumors., Conclusions: Radiosurgery dose rate and BED were not associated with tumor control or radiologic or symptomatic edema. Salvage SRS and larger tumors were associated with a higher LF rate, while cystic tumors were associated with a lower LF rate. Patients with larger tumors should be counseled appropriately about potential side effects and when to seek follow-up care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: Magnetic resonance guided radiotherapy (MRgRT) has been successfully implemented for several routine clinical applications in adult patients. The purpose of this study is to map the potential benefit of MRgRT on toxicity reduction and outcome in pediatric patients treated with curative intent for primary and metastatic sites., Materials and Methods: Between May and August 2020, a survey was distributed among SIOPE- and COG-affiliated radiotherapy departments, treating at least 25 pediatrics patients annually and being (candidate) users of a MRgRT system. The survey consisted of a table with 45 rows (clinical scenarios for primary (n = 28) and metastatic (n = 17) tumors) and 7 columns (toxicity reduction, outcome improvement, PTV margin reduction, target volume daily adaptation, online re-planning, intrafraction motion compensation and on-board functional imaging) and the option to answer by 'yes/no' . Afterwards, the Dutch national radiotherapy cohort was used to estimate the percentage of pediatric treatments that may benefit from MRgRT., Results: The survey was completed by 12/17 (71% response rate) institutions meeting the survey inclusion criteria. Responders indicated an 'expected benefit' from MRgRT for toxicity/outcome in 7% (for thoracic lymphomas and abdominal rhabdomyosarcomas)/0% and 18% (for mediastinal lymph nodes, lymph nodes located in the liver/splenic hilum, and liver metastases)/0% of the considered scenarios for the primary and metastatic tumor sites, respectively, and a 'possible benefit' was estimated in 64%/46% and 47%/59% of the scenarios. When translating the survey outcome into a clinical perspective a toxicity/outcome benefit, either expected or possible, was anticipated for 55%/24% of primary sites and 62%/38% of the metastatic sites., Conclusion: Although the benefit of MRgRT in pediatric radiation oncology is estimated to be modest, the potential role for reducing toxicity and improving clinical outcomes warrants further investigation. This fits best within the context of prospective studies or registration trials., Competing Interests: Dr. Hall reports an Honorarium from Accuray, Inc for Serving on the Scientific Review Committee, AERO 2019 Meeting. All other authors declared that there are no conflict of interest., (© 2021 The Author(s).)

Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past., (© 2020 Wiley Periodicals LLC.)

Radiation therapy (RT) is often used as a palliative treatment for children with recurrent malignant disease to ameliorate or prevent symptoms. However, no guidelines exist regarding the clinical indications or dose fractionation for palliative RT. The goal of this report is to provide guidelines for the use of palliative RT in children with cancer. In this guideline, appropriate indications for palliative RT, recommended dose-fractionation schedules, relevant toxicities, and avenues for future research are explored. RT is an effective palliative treatment for bone, brain, liver, lung, abdominopelvic and head-and-neck metastases, spinal cord compression, superior vena cava syndrome, and bleeding. Single-fraction regimens (8 Gy in one fraction) for children with short life expectancy are recommended for simple, uncomplicated bone metastases and can be considered for some patients with lung or liver metastases. A short, hypofractionated regimen (20 Gy in five fractions) may be used for other indications to minimize overall burden of therapy. There are little data supporting use of more prolonged fractionation regimens, though they may be considered for patients with very good performance status. Future research should focus on response and outcomes data collection, and to rigorously evaluate the role of stereotactic body RT in well-designed, prospective studies., (© 2021 Wiley Periodicals LLC.)

Background: The objective of this study was to evaluate the contribution of radiation dose to different intracranial structures on changes in intellectual function for children with brain tumors., Methods: We evaluated children with brain tumors treated in 2005-2017 who had longitudinal neuropsychological assessments and available photon dosimetric data (if radiation therapy [RT] given). Full Scale Intelligence Quotient (FSIQ) and index scores were evaluated (perceptual reasoning index [PRI], processing speed index [PSI], verbal comprehension index [VCI], and working memory index [WMI]). Multivariable linear mixed effects models were used to model endpoints, with age at RT and dose to different brain regions as fixed effects and patient-specific random intercepts. P-values (P*) were adjusted for multiple comparisons., Results: Sixty-nine patients were included, 56 of whom received RT. Median neuropsychological follow-up was 3.2 years. Right temporal lobe mean dose was strongly associated with decline in FSIQ (P* = 0.005); with each gray increase in mean dose, there was a decrease of 0.052 FSIQ points per year. Dose to 50% (D50) of the supratentorial brain was associated with decline in PSI (P* = 0.006) and WMI (P* = 0.001). Right and left hippocampus D50 were individually strongly associated with declines in VCI (P* = 0.009 for each). Presence of a ventriculoperitoneal shunt decreased FSIQ by 10 points., Conclusions: We reported associations between dosimetry to specific brain regions and intellectual outcomes, with suggested avoidance structures during RT planning. These models can help clinicians anticipate changes in neurocognition post-RT and guide selection of an optimal RT plan., (© 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.)

Objective: There is no consensus on the optimal clinical management of ventriculomegaly and hydrocephalus in patients with diffuse intrinsic pontine glioma (DIPG). To date, the impact on survival in patients with ventriculomegaly and CSF diversion for hydrocephalus in this population remains to be elucidated. Herein, the authors describe their institutional experience., Methods: Patients diagnosed with DIPG and treated with up-front radiation therapy (RT) at The Hospital for Sick Children between 2000 and 2019 were identified. Images at diagnosis and progression were used to determine the frontal/occipital horn ratio (FOR) as a method to measure ventricular size. Patients with ventriculomegaly (FOR ≥ 0.36) were stratified according to the presence of symptoms and categorized as follows: 1) asymptomatic ventriculomegaly and 2) symptomatic hydrocephalus. For patients with ventriculomegaly who did not require CSF diversion, post-RT imaging was also evaluated to assess changes in the FOR after RT. Proportional hazards analyses were used to identify clinical and treatment factors correlated with survival. The Kaplan-Meier method was used to perform survival estimates, and the log-rank method was used to identify survival differences between groups., Results: Eighty-two patients met the inclusion criteria. At diagnosis, 28% (n = 23) of patients presented with ventriculomegaly, including 8 patients who had symptomatic hydrocephalus and underwent CSF diversion. A ventriculoperitoneal shunt was placed in the majority of patients (6/8). Fifteen asymptomatic patients were managed without CSF diversion. Six patients had resolution of ventriculomegaly after RT. Of 66 patients with imaging at the time of progression, 36 (55%) had ventriculomegaly, and 9 of them required CSF diversion. The presence of ventriculomegaly at diagnosis did not correlate with survival on univariate analysis. However, patients with symptomatic hydrocephalus at the time of progression who underwent CSF diversion had a survival advantage (p = 0.0340) when compared to patients with ventriculomegaly managed with conservative approaches., Conclusions: Although ventriculomegaly can be present in up to 55% of patients with DIPG, the majority of patients present with asymptomatic ventriculomegaly and do not require surgical interventions. In some cases ventriculomegaly improved after medical management with steroids and RT. CSF diversion for hydrocephalus at the time of diagnosis does not impact survival. In contrast, our results suggest a survival advantage in patients who undergo CSF diversion for hydrocephalus at the time of progression, albeit that advantage is likely to be confounded by biological and individual patient factors. Further research in this area is needed to understand the best timing and type of interventions in this population.

Purpose: Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological impact. This survey study aimed to characterize these methods., Methods and Materials: A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children., Results: Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6 years (range: ≤3 years to ≥8 years). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (P = .04) and <10 years of pediatric radiation oncology experience (P = .04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality., Conclusions: Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The purpose of our study was to characterize clinical features among brain metastasis (BM) patients who were long term survivors (LTS)., Methods: We reviewed a registry of BM patients referred to our multidisciplinary BM clinic between 2006 and 2014 and identified 97 who lived ≥ 3 years following BM diagnosis. The clinical and treatment characteristics were obtained from a prospectively maintained database, and additional information was obtained through review of electronic medical records and radiologic images. Survival analyses were performed using the Kaplan-Meier method., Results: Median follow up for LTS was 67 months (range 36-181). Median age was 54 years, 65% had single BM, 39% had stable extracranial disease at the time of BM treatment, and brain was the first site of metastasis in 76%. Targetable mutations were present in 39% of patients and 66% received treatment with targeted-, hormonal-, or immuno-therapy. Brain surgery at the time of diagnosis was performed in 40% and stereotactic radiosurgery (SRS) or whole brain radiotherapy (alone or combination) in 52% and 56%, respectively. Following initial BM treatment, 5-year intracranial disease-free survival was 39%, and the cumulative incidence of symptomatic radio-necrosis was 16%. Five and ten-year overall survival was 72% and 26%, respectively., Conclusion: Most LTS were younger than 60 years old and had a single BM. Many received treatment with surgery or targeted, immune, or hormonal therapy.

Primary CNS tumors are the leading cause of cancer-related death in pediatrics. It is essential to understand treatment trends to interpret national survival data. In Canada, children with CNS tumors are treated at one of 16 tertiary care centers. We surveyed pediatric neuro-oncologists to create a national standard of practice to be used in the absence of a clinical trial for seven of the most prevalent brain tumors in children. This allowed description of practice across the country, along with a consensus. This had a multitude of benefits, including understanding practice patterns, allowing for a basis to compare in future research and informing Health Canada of the current management of patients. This also allows all children in Canada to receive equivalent care, regardless of location., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SL declared a past co-authorship with the authors to the handling Editor., (Copyright © 2020 Bennett, Erker, Lafay-Cousin, Ramaswamy, Hukin, Vanan, Cheng, Coltin, Fonseca, Johnston, Lo, Zelcer, Alvi, Bowes, Brossard, Charlebois, Eisenstat, Felton, Fleming, Jabado, Larouche, Legault, Mpofu, Perreault, Silva, Sinha, Strother, Tsang, Wilson, Crooks and Bartels.)

Background: Stereotactic radiosurgery (SRS) is an effective option in the management of brain metastases, offering improved overall survival to whole-brain radiation therapy (WBRT). However, given the need for active surveillance and the possibility of repeated interventions for local/distant brain recurrences, the balance between clinical benefit and economic impact must be evaluated., Objective: To conduct a systematic review of health-economic analyses of SRS for brain metastases, compared with other existing intervention options, to determine the cost-effectiveness of this treatment across different clinical scenarios., Methods: The MEDLINE, EMBASE, Cochrane, CRD, and EconLit databases were searched for health-economic analyses, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, using terms relevant to brain metastases and radiation-based therapies. Simple cost analysis studies were excluded. Quality analysis was based on BMJ Consolidated Health Economics Reporting Standards (CHEERS) checklist., Results: Eleven eligible studies were identified. For lesions with limited mass effect, SRS was more cost-effective than surgical resection (6 studies). In patients with Karnofsky performance scale (KPS) >70 and good predicted survival, SRS was cost-effective compared to WBRT (7 studies); WBRT became cost-effective with poor performance status or low anticipated life span. Following SRS, routine magnetic resonance imaging surveillance saved $1326/patient compared to symptomatic imaging due to reduced surgical salvage and hospital stay (1 study)., Conclusion: Based on our findings, SRS is cost-effective in the management of brain metastases, particularly in high-functioning patients with longer expected survival. However, before an optimal care pathway can be proposed, emerging factors such as tumor molecular subtype, diagnosis-specific graded prognostic assessment, neuroprognostic score, tailored surveillance imaging, and patient utilities need to be studied in greater detail., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Purpose: Reirradiation is rarely administered to patients with recurrent craniopharyngioma owing to concerns regarding visual and endocrine side effects. The purpose of this case series was to evaluate our institutional experience of patients with craniopharyngioma treated with 2 courses of fractionated radiation therapy., Methods and Materials: A retrospective study was performed of all patients with craniopharyngioma treated with 2 courses of fractionated radiation therapy at a single institution. Electronic medical records and radiation therapy records were reviewed., Results: We identified 4 eligible patients with recurrent craniopharyngioma. With a median follow-up of 33 months after reirradiation, 3 patients attained disease control; 1 patient developed progressive disease, 27 months after reirradiation. In 3 evaluable patients, vision remained stable or improved after reirradiation; one patient had no light perception before reirradiation. None of the patients experienced additional endocrine toxicities after reirradiation, apart from one patient who had low serum thyroid stimulating hormone before reirradiation and later developed hypothyroidism after treatment., Conclusions: Reirradiation may represent a safe and effective therapeutic option for selected patients with recurrent, refractory craniopharyngioma and without other salvage treatment options. Larger studies with longer-term follow up are warranted to better understand outcomes in these patients., (© 2020 The Authors.)

Background: Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described., Methods: We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation., Results: We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients., Conclusions: Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose/Objective(s) The incidence of intracranial meningiomas increases with age. The standard of care treatment is complete surgical excision, followed by radiation therapy (RT) if indicated. However, six weeks of RT can be challenging for elderly or frail patients. The purpose of this study was to determine if short course RT is safe and effective in elderly patients with meningioma. Materials/Methods We performed a retrospective analysis of patients with meningioma treated with short course beam RT (5-15 fractions) at a single institution. Seventeen patients (94%) received 4005 cGy over 15 fractions and one patient (6%) received 2500 cGy over five fractions. Study endpoints were treatment toxicity (edema), progression-free (PFS) and overall survival (OS). Results Eighteen patients with histologically proven (n = 12) or radiologically presumed meningioma (n = 6, presumed grade I) were identified. Median age at treatment was 85 years (66-95 years). There were eight, eight and two patients with grade I, II and III tumours, respectively. Eight patients (44%) had radiologic edema prior to RT. Six (33%) required dexamethasone treatment during RT and the dose was increased during RT for two patients. Fourteen patients had reduced or no edema post-RT and 13 patients had stable or improving symptoms post-RT. Six patients had disease progression (five in-field, one out-of-field). Median PFS was 3.3 and 0.9 years for grade I and II/III tumours, respectively (p = 0.014). Median OS was 3.3 and 2.5 years for grade I and II/III tumours, respectively (p = 0.12). Conclusion Short course RT for elderly patients with meningioma is well-tolerated and can offer disease control for some patients, particularly those with grade I tumours., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Sarhan et al.)

Purpose: Stereotactic radiosurgery is an established treatment option for sporadic meningiomas, though limited data exists for radiation-induced lesions., Methods: Patients treated with cobalt-60 radiosurgery between October 2005 and December 2018 in an institutional registry were reviewed. Single fraction treatments were prescribed to the 50% isodose line. Lesions were deemed to be radiation-induced according to standard criteria previously established by Cahan et al. RESULTS: A total of 37 patients with 72 lesions were analysed. Median follow up per patient was 44 months (range, 1.4-150.7 months). Median age at initial radiotherapy was 5 years (4 months-48 years), and at radiosurgery was 38 years. Of the 72 lesions, 62 were grade 1 (n = 4) or radiologically-diagnosed (n = 58), six were grade 2 and four were grade 3. Median lesion volume was 2.13 cc (0.04-13.8 cc), while the median radiosurgery margin dose was 13 Gy. Local control, on a per lesion basis, was 88.6% at 5 years (95% confidence interval [CI] 72.3-95.6). For grade 1 or radiologically-diagnosed lesions, local control was 96.6% at 5 years (95% CI 77.9-99.5), whereas those with grade 2 or higher lesions had a local control of 40% at 5 years (95% CI 5.2-75.3, p = 0.005). Radiologic oedema developed in 17 lesions (23.6%) and was symptomatic in 12 patients (16.7%). Doses above 12 Gy were not associated with local control probability (p = 0.292)., Conclusion: Radiosurgery is an effective treatment option for grade 1 or radiologically-diagnosed radiation-induced meningiomas, with 12 Gy appearing to be a sufficient dose.

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors., Patients and Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries., Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02)., Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Vijay RamaswamyHonoraria: AstraZenecaMiriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmuneDaniel R. BoueStock and Other Ownership Interests: Vertex Pharmaceuticals, Intuitive Surgical, IlluminaAdela CaneteConsulting or Advisory Role: EUSA Pharma, Bayer Speakers’ Bureau: EUSA PHarma Research Funding: EUSA Pharma (Inst) Travel, Accommodations, Expenses: EUSA PharmaIra J. DunkelConsulting or Advisory Role: Bayer, Apexigen, Celgene, Roche/Genentech, AstraZeneca Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Novartis (Inst)Karen GauvainEmployment: Iqvia Biotech Consulting or Advisory Role: Bayer, Axiom Health Care SciencesJordan R. HansfordConsulting or Advisory Role: BayerSarah G. InjacResearch Funding: TakedaMatthias KarajannisConsulting or Advisory Role: Bayer, Recursion Pharma Research Funding: Novartis Travel, Accommodations, Expenses: Bayer Uncompensated Relationships: Debiopharm (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/710370/summaryNormand LaperriereHonoraria: Merck/Schering Plough Consulting or Advisory Role: AbbVieAlvaro LassalettaConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche Travel, Accommodations, Expenses: Shire, Gilead SciencesRoger PackerHonoraria: Novartis Consulting or Advisory Role: Novartis, AstraZenecaJaroslav SterbaResearch Funding: Roche/Genentech (Inst) Travel, Accommodations, Expenses: Bristol-Myers SquibbDerek S. TsangOther Relationship: Varian Medical Systems (Inst), Mevion Medical Systems (Inst), Hitachi (Inst), RaySearch Laboratories (Inst), IBA (Inst), ProTom (Inst)Cornelis M. van TilburgConsulting or Advisory Role: Novartis, BayerOlaf WittConsulting or Advisory Role: Novartis, AstraZeneca, Janssen Research & Development, Bristol-Myers Squibb, Roche, BayerEric BouffetResearch Funding: Roche (Inst), Bristol-Myers Squibb (Inst)Cynthia HawkinsConsulting or Advisory Role: Bayer Patents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Purpose: At our institution, a multifaceted approach is used to reduce general anesthetic (GA) use for children receiving photon radiation therapy (RT) as standard-of-care treatment. The purpose of this study was to evaluate the effectiveness of our methods., Methods and Materials: Patients treated as part of the pediatric radiation therapy program from 2010 to 2018 were retrospectively reviewed. GA use was defined as need for intravenous propofol or inhaled gaseous anesthetic for at least 1 simulation or RT session. Methods to reduce GA use included presence of a dedicated pediatric nurse for procedural preparation, audiovisual distraction (television during RT), and 2-way audio communication with caregivers., Results: There were 779 unique patients who received RT over 14 163 fractions of radiation. GA utilization was 90% in those under age 3, 28% in those age 3 to 6, 1% in those age 7 to 11, and <1% in those ≥12 years of age. Four years of age is a cutoff age at which the majority of patients switch from needing GA (56.6% for those aged 3) to not needing GA (29.8% for those aged 4). Younger age, use of total body irradiation, and craniospinal irradiation were independently associated with requiring GA., Conclusions: Using methods designed to reduce GA use, most children aged 4 years or older were able receive RT awake. Our GA rates compare favorably to other literature reports; thus, pediatric RT centers should consider adopting specific interventions to reduce GA use., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

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.)

Purpose: Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT., Methods: Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups., Results: Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose ( P < .001) and boost margin ( P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed ( P = .003)., Conclusion: To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Introduction: Hyperbaric oxygen therapy (HBOT) shows promising results in treating radionecrosis (RN) but there is limited evidence for its use in brain RN. The purpose of this study is to report the outcomes of using HBOT for symptomatic brain RN at a single institution., Methods: This was a retrospective review of patients with symptomatic brain RN between 2008 and 2018 and was treated with HBOT. Demographic data, steroid use, clinical response, radiologic response and toxicities were collected. The index time for analysis was the first day of HBOT. The primary endpoint was clinical improvement of a presenting symptom, including steroid dose reduction., Results: Thirteen patients who received HBOT for symptomatic RN were included. The median time from last brain radiation therapy to presenting symptoms of brain RN was 6 months. Twelve patients (92%) had clinical improvement with median time to symptom improvement of 33 days (range 1-109 days). One patient had transient improvement after HBOT but had recurrent symptomatic RN at 12 months. Of the eight patients with evaluable follow-up MRI, four patients had radiological improvement while four had stable necrosis appearance. Two patients had subsequent deterioration in MRI appearances, one each in the background of initial radiologic improvement and stability. Median survival was 15 months with median follow-up of 10 months. Seven patients reported side effects attributable to HBOT (54%), four of which were otologic in origin., Conclusions: HBOT is a safe and effective treatment for brain RN. HBOT showed clinical and radiologic improvement or stability in most patients. Prospective studies to further evaluate the effectiveness and side effects of HBOT are needed.

Purpose: Children with recurrent medulloblastoma have a poor prognosis. Re-irradiation is an option for some patients, but has not been well-studied in the era of molecular characterization for pediatric medulloblastoma., Methods: This was a retrospective cohort study of 14 children age 18 years and younger at initial diagnosis with recurrent medulloblastoma, who received two or more courses of radiation therapy (RT). Molecular subgrouping was performed using nanoString and was available for nine patients. The primary study endpoint was overall survival., Results: Re-irradiation (RT2) was directed at the supratentorial brain in six patients, infratentorial brain in one patient, and spine in seven patients. In addition, six patients received stem cell transplant as part of salvage therapy. Median OS for all patients was 12.4 months. One patient with recurrent Wnt-activated medulloblastoma remains alive with 154 months' survival; median survival was not reached for four patients with Group 4 disease, while three with Shh-activated disease had median survival of 2.2 months. A single patient with Group 3 disease died 4.3 months after RT2. Patients treated with RT2 to the spine for diffuse disease had poorer OS (p = 0.02), as compared to focal RT2 for intracranial recurrence. Distant failure, outside RT2 volumes, was the predominant pattern of recurrence after RT2., Conclusions: Re-irradiation for recurrent pediatric medulloblastoma can offer some patients disease control, particularly those with focally recurrent disease in the brain. Prospective studies are needed to confirm subgroups of patients who may benefit most from RT2.

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.)

Purpose: We reviewed the outcomes of a retrospective germinoma cohort and analyzed radiation therapy plans to determine dosimetric differences for critical structures., Methods and Materials: Data from pediatric patients treated with photon radiation for intracranial germinoma were analyzed for clinical outcomes and dosimetry to critical structures, with particular interest in the temporal ventricular horns (TVHs). A consensus contour was generated for TVH-sparing ventricular clinical target volumes (CTVs) via deformable image registration., Results: Twelve and 10 patients had their TVHs included or excluded in their ventricular CTVs, respectively. All patients were living at the time of analysis. One patient relapsed in the fourth ventricle, which had been omitted from the radiation therapy field. Mean dose was significantly lower to the hippocampi (Δ = -578 cGy, P = .0016) and temporal lobes (Δ = -599 cGy, P = .0007) in the TVH-excluded cohort compared with those with TVHs included in the treatment field., Conclusions: Exclusion of the TVHs from the CTV results in significant dose sparing to the hippocampi and temporal lobes. Clinical outcomes remain excellent with no deaths and no TVH failures. Exclusion of TVHs from the ventricular CTV in germinoma requires prospective study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Adult sellar atypical teratoid/rhabdoid tumor (ATRT) is a rare diagnosis that has recently been shown to be a clinicopathologically and genetically distinct variant of ATRT occurring almost exclusively in middle-aged women. Although up to one third of pediatric ATRT is caused by a familial syndrome, no previous cases of a familial adult sellar ATRT have been reported. We present the first case report of a familial germline mutation causing adult sellar ATRT and a literature review of 29 previously reported cases of sporadic adult sellar ATRT., Case Description: A 51-year-old woman with a family history of brain tumors spanning 3 generations presented with visual decline and was diagnosed with an adult sellar ATRT. Genetic studies showed a heterozygous splice-site loss-of-function mutation of the INI1 gene in exon 7. Treatment included endoscopic endonasal biopsy, craniospinal irradiation, and focal tumor boost, followed by adjuvant chemotherapy., Conclusions: This is the first case report of a familial germline mutation causing adult sellar ATRT. This article highlights the importance of a thorough family history and genetic testing in these individuals and reviews the current genetics, histopathology, and multidisciplinary treatment approach in this rare condition., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Radiation-induced meningioma is a known late effect of cranial radiation therapy. Cranial magnetic resonance imaging (MRI) can detect small meningiomas, but its potential value as a screening tool is unknown., Methods and Materials: MRI was used to screen asymptomatic survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy ≥10 years previously. The incidence of radiation-induced meningioma and outcomes of this group were compared with a historical cohort of survivors with the same exposure who underwent imaging only to investigate clinical signs or symptoms., Results: One hundred seventy-six childhood leukemia survivors were included in this study: 70 in the screening group and 106 unscreened. Screening MRI was performed a median of 25 years after radiation therapy and detected meningioma in 15 (21.4%). In the unscreened group, 17 patients (16.0%) had neurologic symptoms leading to an MRI a median interval of 24 years after radiation therapy, 9 of whom (8.5%) were diagnosed with meningioma. There was no significant difference between screened versus unscreened patients in the size of meningioma (mean diameter, 1.6 cm vs 2.6 cm; P = .13), meningioma incidence (7.4% vs 4.0% at 25 years; P = .19), or extent of resection. Three patients had persistent neurologic symptoms in the unscreened group versus none among screened patients (P = .28)., Conclusions: Screening MRI was able to detect small meningiomas that were not clinically apparent; however, we could not demonstrate a significant improvement in the chance of total resection or a significant decrease in morbidity. A larger sample could clarify potential reduction in neurologic sequelae associated with screening., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: The Radiation Medicine Program at the Princess Margaret Cancer Centre received unrestricted educational funds for a symposium in November 2018 from Varian Medical Systems, Mevion Medical Systems, Hitachi, RaySearch Laboratories, IBA and ProTom. Derek Tsang was a co-chair of the symposium and has not received any financial benefits, salaries, honoraria or stipends from any commercial entity related to this work. Samir Patel was an invited faculty speaker at the symposium and has not received any financial benefits, salaries, honoraria or stipends from any commercial entity related to this work. This article has been peer reviewed.

Background: Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years., Methods: Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3)., Results: A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042)., Conclusions: Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time., (© 2019 American Cancer Society.)

Background: The goal of this study was to evaluate outcomes in children with relapsed, molecularly characterized intracranial ependymoma treated with or without craniospinal irradiation (CSI) as part of a course of repeat radiation therapy (re-RT)., Methods: This was a retrospective cohort study of 31 children. Patients with distant relapse received CSI as part of re-RT. For patients with locally recurrent ependymoma, those treated before 2012 were re-irradiated with focal re-RT. In 2012, institutional practice changed to offer CSI, followed by boost re-RT to the site of resected or gross disease., Results: Median follow-up was 5.5 years. Of 9 patients with distant relapse after initial RT, 2-year freedom from progression (FFP) and overall survival (OS) were 12.5% and 62.5%, respectively. There were 22 patients with local failure after initial RT. In these patients, use of CSI during re-RT was associated with improvement in 5-year FFP (83.3% with CSI vs 15.2% with focal re-RT only, P = 0.030). In the subgroup of patients with infratentorial primary disease, CSI during re-RT also improved 5-year FFP (100% with CSI, 10.0% with focal re-RT only, P = 0.036). Twenty-three patients had known molecular status; all had posterior fossa group A tumors (n = 17) or tumors with a RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) fusion (n = 6). No patient developed radiation necrosis after fractionated re-RT, though almost all survivors required assistance throughout formal schooling. Five out of 10 long-term survivors have not developed neuroendocrine deficits., Conclusions: Re-irradiation with CSI is a safe and effective treatment for children with locally recurrent ependymoma and improves disease control compared with focal re-irradiation, with the benefit most apparent for those with infratentorial primary tumors., (© The Author(s) 2018. 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.)

Despite best available therapy, many children with cancer develop recurrence after multimodal treatment, including initial radiation therapy. Re-irradiation is defined as the use of a second course of radiation therapy with a retreatment volume that overlaps substantially with that of a previously delivered course of radiation therapy. Re-irradiation is an important part of salvage treatment for patients with recurrent ependymoma, diffuse intrinsic pontine glioma, medulloblastoma and germinoma. In patients with ependymoma, conventionally fractionated re-irradiation (1.8 Gy/day) can provide long-term disease control with low rates of high-grade toxicity. For children with progressive diffuse intrinsic pontine glioma, re-irradiation provides effective palliation of symptoms and a survival gain as compared with those treated without re-irradiation. Repeat radiation therapy that includes craniospinal irradiation, if safe to deliver, may provide long-term tumour control in patients with medulloblastoma. Patients with recurrent intracranial germinoma can be effectively salvaged with re-irradiation that includes craniospinal irradiation. Finally, the emerging role of re-irradiation in non-brainstem high-grade glioma and extracranial solid tumours requires further study regarding its efficacy and safety. When given, re-irradiation should be delivered with care so that doses to organs at risk are minimised. In all cases, re-irradiation should be considered as an option alongside, or concurrently with, other salvage treatments, including surgery or systemic therapy, to maximise the likelihood of durable disease control., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the ability of a multimodal patient education initiative to improve adherence to healthy bone behaviors (HBBs) in men with prostate cancer receiving androgen deprivation therapy (ADT)., Methods: This was a pilot prospective, single-site, before-and-after clinical trial. The control arm (n = 51) received routine care. The intervention arm (n = 52) received multimodal HBB education which included a healthy bones prescription (BoneRx), focused face-to-face education with an oncology nurse or physician, and customized educational materials. The primary endpoints were feasibility of study methods and self-reported adherence to HBBs (vitamin D intake ≥ 1000 IU/day, calcium intake 1000-1500 mg/day, and exercise ≥ 150 min/week) at 3-month follow-up. Secondary endpoints included receipt of bone mineral density (BMD) testing., Results: Patients were satisfied with the study intervention, found educational materials easy to understand, and felt that it increased their knowledge about osteoporosis. Although the intervention appeared to be associated with trends toward improved levels of vitamin D intake (adjusted odds ratio [OR] 1.8, 95% confidence interval [CI] 0.74-4.5), calcium intake (OR 1.5, 95% CI 0.63-3.4), and exercise (OR 1.7, 0.75-3.9) as compared to the control arm, none of these were statistically significant. Patients who received the study intervention were more likely to receive BMD testing (OR 3.3, 95% CI 1.3-8.8)., Conclusions: Although a brief, tailored educational intervention was feasible to implement and improve BMD test utilization, it did not increase HBB participation. Larger, well-designed trials are needed to clarify the effect of patient education interventions on HBB adherence., Trial Registration: ClinicalTrials.gov ( NCT01973673 ).

Purpose: To determine the long-term outcomes and the optimal dose and volume for reirradiation of recurrent pediatric ependymoma., Methods and Materials: Patients with recurrent ependymoma treated with a second course of fractionated radiation therapy (RT2) were reviewed retrospectively. Eligible patients had localized, intracranial ependymoma at initial diagnosis that was treated with focal radiation (RT1) without craniospinal irradiation (CSI) and were aged ≤21 years at the time of RT2. The median doses of RT1, focal RT2, and CSI-RT2 were 59.4, 54, and 39.6 Gy, respectively. The primary endpoint, overall survival (OS), was measured from the first day of RT2., Results: We included 101 patients in the study. The median interval between RT1 and RT2 was 26.8 months (interquartile range, 18.0-43.1). The median durations of OS and freedom from progression (FFP) were 75.1 and 27.3 months, respectively. Male sex and anaplastic histology at recurrence were associated with decreased OS and FFP on multivariate analysis. Distant-only failure treated with CSI-RT2 was independently associated with improved OS compared with individuals with local failure treated with focal RT2 (hazard ratio 0.37; 95% confidence interval 0.16-0.87). Among individuals experiencing any distant failure after RT1, gain of chromosome 1q was adversely associated with poorer OS (hazard ratio 3.5; 95% confidence interval 1.1-10.6). No distant-only failures were observed in individuals with RT1 local failure who received CSI-RT2 (n=10). The 10-year cumulative incidence of grade ≥3 radiation necrosis after RT2 was 7.9%., Conclusions: Reirradiation for relapsed pediatric ependymoma was well tolerated by most patients and resulted in long-term survival in a subset of patients. The best results were observed in patients who experienced distant-only failure after RT1 and were treated with CSI as part of RT2, without anaplasia at recurrence. The option of reirradiation should be discussed with patients who develop recurrent ependymoma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Elderly glioblastoma (GB) patients are at risk of hospitalizations due to the morbidity of the disease and possible treatment toxicity., Methods: In this observational cohort study, 255 newly diagnosed GB patients age 65 years and older were included. Survival, emergency room visits and admissions to an acute care hospital were determined. Mean and median total health care costs were calculated. Risk factors for Emergency room visits and acute care hospital admissions were determined., Results: Median overall survival was 6 months. The majority of patients (68%) had at least one visit to the emergency department and 77% had at least one admission to acute care. The mean and median total costs (hospital, ambulatory, physician billing, other health care costs) per patient were $162,479.78 (CAN) and $125,511.00 (CAN), respectively. Treatment with radiation or treatment with radio-chemotherapy was associated with a relative risk (RR) of 2.31 (95% CI: 1.44-3.7; P=0.0005) and 2.19 (95% CI: 1.28-3.74; P=0.004), respectively for emergency department visits as compared to patients who were managed with comfort measures only. Patients with a baseline ECOG 0 had a RR of 1.71 (95% CI: 1.06-2.77; P=0.0289) and patients with baseline ECOG 1 had a RR of 1.49 (0.98-2.26; P=0.0623) for hospital admission as compared to patients with ECOG 4., Conclusions: A large proportion of elderly GB patients (particularly those with good baseline performance status who underwent active treatment) presented to the emergency department and had at least one admission to acute care.

Purpose: The long-term survival of pediatric patients with optic pathway or hypothalamic low-grade glioma (LGG) who receive radiation therapy (RT) has not been previously assessed., Methods and Materials: A retrospective study was performed of all patients with optic-hypothalamic pediatric LGG treated with RT at a single institution. Eligible patients were aged ≤21 years at the time of RT and had localized LGG diagnosed by neuroimaging or histology. The median RT dose was 54 Gy, delivered in 30 fractions. Event-free survival (EFS) was defined as survival without progression or secondary high-grade glioma. Days were counted from the first day of RT., Results: Eighty-nine patients were included in the study, with a median follow-up period of 12.5 years. Of the patients, 14 had neurofibromatosis type 1 (NF-1). The 10-year EFS rate was 61.9% (95% confidence interval [CI], 31.2%-82.1%) for patients with NF-1 and 67.5% (95% CI, 54.8%-77.3%) for those without NF-1. The 10-year overall survival rate was 92.3% (95% CI, 56.6%-98.9%) for patients with NF-1 and 98.4% (95% CI, 89.1%-99.8%) for those without NF-1. Pre-RT chemotherapy (which was more commonly given to younger patients) was associated with reduced EFS, whereas younger age was associated with reduced overall survival. Possible RT-induced neoplasms developed in 8 patients, including 4 with NF-1. The 10-year cumulative incidence of clinically significant vasculopathy was 7.1% (95% CI, 2.9%-13.9%); vasculopathy did not develop in any child aged >10 years at the commencement of RT., Conclusions: RT is an effective treatment for optic-hypothalamic LGG. Older children without NF-1 have a low risk of late toxicity. RT can be considered for selected younger patients or individuals with NF-1 as a salvage treatment after progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)