Survivors of adolescent and young adult (AYA) central nervous system (CNS) neoplasms are at risk for late effects (LE) - treatment-related health problems occurring more than 5 years after therapy). Since, in Canada, AYA survivors are usually followed in the community, information must be conveyed to primary care providers to guide risk-based follow-up care. Objective: To assess documentation of LE risks and screening recommendations (SR) in medical records of AYA CNS tumor survivors treated with radiation therapy. Methods: The medical records of all patients diagnosed with a CNS neoplasm (benign or malignant) at ages 15-39 years, treated between 1985 and 2010 in the province of British Columbia, surviving >5 years and discharged to the community were assessed. Documentation of LE and SR were extracted, and analyzed descriptively. Results: Among 132 survivors (52% female), treated with radiation therapy (95% partial brain, 10% craniospinal, 8% partial spine, and 4% whole brain) and chemotherapy (17%), 19% of charts included no documentation of LE risks, 26% included only non-specific documentation, and 55% had minimal documentation (1 or 2 LE). Documentation of at least one specific LE increased from 24% in 1980-1989, to 54% in 1990-1999, to 86% in 2000 – 2010. Based on treatment information, all survivors were at high-risk for LE, such as radiation induced neoplasm, meningioma and cerebrovascular events. Yet, SR were documented in only 25% of charts. Conclusions: The documentation of LE risks and screening recommendations has been limited, highlighting the need to improve written communication with primary care providers.

PURPOSE: To investigate health-related quality of life (HRQOL ) in survivors of intracranial germ cell tumors (IGCT). METHODS: Survivors of IGCT were invited to complete the 36-Item Short Form Survey Instrument (SF-36). The SF-36 is scored from 0-100, with a higher number representing a more favorable HRQOL. RESULTS: The study cohort consisted of 12 survivors of IGCT, 6 males and 6 females. Median age was 13 years at diagnosis, and 26 years at time of study. Median follow-up was 11 years. Five patients had germinomas, and 7 had non-germinomatous germ cell tumors. All 12 patients received radiation therapy (RT), 10 to the craniospinal axis, 1 to the whole ventricles and 1 to the tumor bed alone. Nine patients received chemotherapy. Mean SF-36 scores were 67.9 (standard deviation [SD] 33.2) for physical functioning, 58.3 (SD 37.4) for role limitations due to physical health, 77.8 (SD 32.8) for role limitations due to emotional problems, 43.1 (SD 18.4) for vitality, 74.3 (SD 15.3) for mental health; 62.5 (SD 32.0) for social functioning, 74.2 (SD 33.4) for pain, and 57.1 (SD 24.0) for general health; mean scores were >1 SD lower than that of Canadian normative data for vitality, social functioning and general health. Physical component score was 43.6 (SD 13.9) and mental component score was 47.6 (SD 11.2), normalized to a US population with mean of 50 and SD of 10. CONCLUSIONS: Long-term HRQOL for survivors of IGCT is lower than that of the overall population, particularly in vitality, social functioning and general health.

BACKGROUND: Adult medulloblastomas account for less than 1% of adult neoplasms. They are challenging to treat due to their rarity and the heterogeneity of treatment options, all of which have limited evidence. In this retrospective review, we examined cases of adult medulloblastoma diagnosed in Alberta during a 70-year period. METHODS: We reviewed the charts of patients diagnosed with medulloblastoma between 1944 and 2014. We performed Cox and logistic regression analysis to elucidate features that may influence recurrence risk and survival. RESULTS: We found 86 and analyzed 78 cases. The median age at diagnosis was 27 (range 16 to 71). Most were male (68%). Most had surgery (92%). By COG risk stratification, 54% were standard risk while 21% were poor risk. RT was administered to 85% of patients, and craniospinal irradiation (CSI) to 81%. Chemotherapy was administered to 48%. Median survival was 4.4 years from diagnosis (range 0 to 20). At last follow-up, 39% were alive and recurrence-free. Patients who had CSI and posterior fossa boost had longer survival (p=0.047 and<0.01, respectively) and were less likely to recur (p=0.041 and<0.01). Chemotherapy was also associated with decreased recurrence (p=0.025). CONCLUSIONS: Medulloblastomas carry a significant recurrence risk, especially for patients who had subtotal resection. CSI and posterior fossa boost were associated with fewer recurrences and improved survival. COG risk stratification, Chang staging, desmoplastic histology, vermian location, 4th ventricle involvement, tumor enhancement, presence of hydrocephalus and cerebrospinal fluid (CSF) involvement are not significantly prognostic.

Glioblastoma multiforme (GBM) is the deadliest brain tumor with an approximate 14 month survival rate after diagnosis and treatment. Temozolomide (TMZ), the chemotherapeutic drug of choice for GBM, is an alkylating agent that causes DNA damage. TMZ treatment results in the induction of apoptosis in GBM cells, however, it induces autophagy and consequently chemoresistance. Statins are mevalonate (MEV) cascade inhibitors with beneficial effects on the enhancement of the survival rate of patients with different types of cancer. Here, we determined the effect of simvastatin (Simva), a blood brain barrier permeable statin, on the sensitization of GBM cells to TMZ induced apoptosis through inhibition of autophagy flux. We pretreated two GMB cell lines, U251 and U87 cells, with low doses of Simva (1 and 2.5 M, respectively) with or without different intermediates of the mevalonate cascade and then treated cells with TMZ (100 M) for 48-96 hrs. A signficiantly reduced viability and increased in the population of apoptotic dead cells were observed in GBM cells treated with the Simva-TMZ compared to cells treated with TMZ alone. Addition of MEV, Farnesyl pyrophosphate, Geranylgeranyl pyrophosphate and cholesterol did not attenuate these effects significantly. Sima-TMZ treatment did not alter the total cholesterol pool in U87 and U251 cells compared to controls. Western blot analysis, immunocytochemistry and transmission electron microscopy revealed that Simva-TMZ inhibited autophagic flux. Overall, the results suggest that sensitization of GBM cells to TMZ-induced apoptosis by Simva is independent on the cholesterol biosynthetic pathway but may involve inhibition of autophagy.

Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to innate and adaptive immune response defects in cancers that allow virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized yeast cytosine deaminase gene that converts the prodrug Toca FC (investigational, extended-release 5-FC) into 5-FU within the tumor microenvironment. 5-FU kills infected dividing cancer cells and surrounding tumor, myeloid derived suppressor cells, and tumor associated macrophages, resulting in long-term tumor immunity in preclinical models. Data from a Phase 1 resection trial showed six durable CRs and extended mOS compared to historical controls. The FDA granted Breakthrough Therapy Designation for Toca 511 & Toca FC in the treatment of patients with rHGG. Toca 5 is an international, randomized, open-label Phase 3 trial (NCT02414165) of Toca 511 & Toca FC versus SOC in patients undergoing resection for first or second recurrence of rHGG. Patients will be stratified by IDH1 status, KPS, and geographic region. Primary endpoint is OS, and secondary endpoints are durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. Key inclusion criteria are histologically proven GBM or AA, tumor size ≥1cm and ≤5cm, and KPS ≥70. Immune monitoring and molecular profiling will be performed. Approximately 380 patients will be randomized. An IDMC is commissioned to review the safety and efficacy data which includes 2 interim analyses. Enrollment is ongoing.

The enzyme polynucleotide kinase/phosphatase (PNKP) plays a key role in DNA repair by resolving the chemistry at DNA strand breaks. Mutations in PNKP (chromosome 19q13.4) are known to cause MCSZ, a serious neurodevelopmental disorder, but to date there has been no link to cancer initiation or progression. However, a child with MCSZ recently presented at Seattle Children's Hospital with a 3-cm glioblastoma. The child was shown to have two germline mutations in PNKP. To study the effects of the PNKP mutations found in this patient, we generated mutant PNKP cDNAs carrying either the individual mutations or the double mutation using site directed mutagenesis. These cDNAs were incorporated into bacterial and mammalian expression vectors. The bacterially expressed mutant proteins as well as the wild type have been purified and are undergoing testing for PNKP DNA kinase and phosphatase activity. The PNKP cDNAs, fused to GFP, were expressed in Hela and HCT116 human cancer cell lines. High-content analysis and micro-irradiation techniques are being used to determine PNKP localization within the cells and recruitment to damaged DNA. Our preliminary results indicate that the mutations alter the ratio of nuclear to cytoplasmic PNKP compared to the wild-type protein.

BACKGROUND: Exercise has been shown to benefit health-related fitness, psychosocial health, and disease outcomes in cancer survivors. PURPOSE: To review the evidence on exercise for individuals diagnosed with Neurological Cancer (NC); present data on NC participants in the ACE pilot and ongoing implementation study; and propose a framework to incorporate exercise into the care of NC survivors in Alberta. METHODS: The ACE program is open to survivors with any cancer diagnosis at any stage of treatment. Exercise programming consists of two training sessions per week, with the pilot and implementation studies being 8 and 12 weeks in duration respectively. Outcomes are assessed at study baseline, post-exercise intervention, and 24-week follow-up, and include recruitment and follow-up rates, health-related fitness, psychosocial outcomes, and cancer symptoms. RESULTS: NC survivors represented 7 of 80 participants in the ACE pilot; however, only 3 of the 7 (43%) completed the study. Findings suggested a need for consideration of supervised exercise for some survivors with NC. To date, 14 NC survivors have enrolled in the ACE implementation study. Participants are screened and then referred to either supervised clinic-based or community-based exercise. Seven of 9 participants have completed the ACE intervention, and 5 of 5 have completed the 24-week follow-up. NC participants improved or maintained health-related physical fitness, and reported reduced symptom burden and fatigue. CONCLUSION: Preliminary results suggest exercise training is feasible and beneficial for NC survivors. To optimize recruitment and outcomes, efforts are needed to better identify, screen, and refer survivors to appropriate exercise programming.

Malignant gliomas (MG) are highly invasive and aggressive brain tumors. Despite the current standard of care, the prognosis for patients with MG is abysmal– highlighting the need for novel, more effective treatment options to combat this aggressive disease. Oncolytic virus (OV) therapy is an advancing treatment option that harnesses tumor-selective viruses to kill cancer cells while simultaneously facilitating a systemic anti-tumor immune response. Many studies have noted synergistic effects when OV’s are combined with radiotherapy in preclinical cancer models, warranting further investigation of this multi-modal approach. Image-guided radiotherapy (IGRT) uses computer-modulated imaging techniques to precisely deliver ionizing radiation to treat cancer. Despite the precision IGRT offers, cancer cells can still be ‘missed’ due to tumor microextensions or radioresistant cell populations– such as glioma stem cells or therapy-induced senescent cancer cells –and may contribute to recurrence or progression. Here we propose to combine our mCherry-tagged mutant vaccinia virus (deltaF4L-deltaJ2R-mCherry), which exhibits tumor-selectivity due to mutations in key viral nucleotide biosynthesis genes, with IGRT executed using state-of-the-art Small Animal Radiation Research Platform (SARRP) technology. We hypothesize that combining deltaF4L-deltaJ2R-mCherry with IGRT will produce better tumor control than either modality alone, by generating additive or synergistic effects in which IGRT destroys the majority of the tumor mass while our OV seeks out and targets any remaining cancer cells that have been missed or are resistant to radiotherapy.

Purpose: Exercise has been shown to be beneficial for the physical and psychological health of cancer survivors, however, little research has been conducted on the effects of exercise in the brain tumour population. Survivors with brain tumours present with unique challenges in terms of mobility and function that may compromise their ability to safety take part in community-based exercise. Methods: Three survivors with primary brain tumours will be profiled in this case series presentation. Participants were screened using a cancer specific intake questionnaire and the Physical Activity Readiness Questionnaire, and triaged to supervised clinic-based or community-based exercise. All participants completed the 12-week intervention for the Alberta Cancer Exercise (ACE) study. Measurements were taken at baseline, and post-intervention including measures of body composition, aerobic fitness, musculoskeletal fitness, balance and flexibility. Self-reported measures included questionnaires to assess impact on physical functioning, symptoms and quality of life, and to evaluate satisfaction with programming. Results: One participant was referred to supervised clinic-based exercise programming due to a high risk of falls, and two participants were deemed safe and approved for community-based supported exercise programming at a preferred location closer to their home. Preliminary results suggest high program satisfaction, maintenance and/or benefit of physical fitness, balance, and symptom control. Conclusions: Further efforts are needed to better tailor programming to the needs of the survivor and consideration given to the advantages of the supervised clinic-based environment when compared to the survivor preference for a “closer to home” community-based setting.

Glioblastoma is considered among the most aggressive cancers, dismal prognosis and overall survival is only 14 months, 80% of primary low grade gliomas and seccondary GBMs that progress from low grade to grade II or III WHO classification have isocitrate dehydrogenase, (IDH1) or IDH2, mutations [1]. IDH1 mutant glioma is characterized by impaired glycolysis activity resulting in an abnormal production of 2-hydroxyglutarate (2-HG) [2] resulting in an undifferentiated phenotype with permanent hyper-methylation status and enhanced proliferation and invasion[3]. Interestingly, the IDH1 mutant phenotype of U87MG glioma cells shows resistance to autophagy induced cell death even in starving and low oxygen conditions [4]. Recent evidence has demonstrated increased autophagy activity on IDH1 mt cytotoxic activity when cells are exposed to autophagy inhibitors such as chloroquine [5]. To this date it remains elusive whether increased autophagy phenotype is the result of IDH1 mutation or if it either represents a secondary co-existing condition in the setting of the IDH1 mutation. Autophagy is also a mechanism of detoxification induced by chronic heavy metal exposure in both normal and cancer cells. Thus, we hypothesized that autophagy activity in IDH1 mt glioma is partially induced by chronic heavy metal exposure, leading to increased cell survival and abnormal DNA repair. Our approach included characterization and quantification of metal content on IDH1 mt glioma cell lines and tissues, in addition to correlation analyses of the celullar metallome with autophagy markers, ROS and DNA repair of IDH1 mt glioma cells allowed us to explore targets responsible for cell survival and DNA repair response. Furthermore, we evaluated the potential therapeutic value of Chloroquine (CQ) and bafylomicin for IDH1 mutant gliomas targeting autophagy pathway in combination with TMZ and radiation. We demonstrated that 2-HG induces autophagy activity via LC3B activation, and autophagy inhibiton by beclin gene silencing results in a reduction of 2-HG leading to cell starvation and apoptosis. Remarkably, we observed a positive correlation on at least six different metals with autophagy induced LC3B and beclin1 expression that significantly differed between the mutant and the wt genotype in glioma cell lines. ROS and DNA repair were also positively associated with at least 6 different metals and only seen in the IDH1 mt cell lines, then suggesting a possible explanation for the increase on autophagy, analysis of both LC3B and beclin 1 expression demonstrated a positive correlation with Mo98, Fe54, and Zn 66 on IDH1 mt cell lines and a positively correlation with Mo98 and V concentrations in relation to H2AX expression. Co, SeO Mo, V and Mg were positively correlated to ROS expression. TMZ and CQ induced autophagy pathway activation as measured by LC3B, Beclin, Atg expression. Silencing beclin in IDH1 mutant glioma cell lines induced apoptosis and reduction on 2-HG production after treatment with TMZ and radiation. Overall the results contained in this study 1) identify cellular metal content in relationship to mechanisms leading to increased autophagy on IDH1 mt glioma cells. 2) evaluate the combination of CQ and TMZ to potentially target and inhibit autophagy as a mechanism downstream the 2-HG production in IDH1 mt glioma cells.

Background: Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults. Recent efforts have elucidated genetic features of tumor cells and thus enhanced our knowledge of GBM pathophysiology. The most recent clinical trials report median overall survival between 14 and 20 months. However, real-world outcomes are quite variable and there is a paucity of data within the literature. Methods: Three hundred seventy two GBM patients were diagnosed in the province of British Columbia between January 2013 and January 2015. We have performed a retrospective review on the survival outcomes of the 278 patients who underwent surgical resection as part of the initial treatment. Results: Our results indicate a median age of 61.8y at time of diagnosis with a slight preponderance of males. The median overall survival was 10 months for patients who underwent surgery. As expected, patients over the age of 65 and those with worse initial Karnofsy Performance Status (KPS) scores had a poorer prognosis. Moreover, we have found extent of resection (EOR), treatment strategies and treatment location affect overall survival. Conclusion: The present study highlights factors which affect patient survival after surgery in British Columbia. Our outcomes are slightly worse than survival reported in the US. Variability in pathologic classification and in treatment strategy likely contribute to this difference. Further efforts should ensure access to the gold-standard of care.

Adult Glioblastomas (GBMs) remain one of the least curable brain cancers despite the discovery and use of DNA alkylating agent Temozolomide (TMZ). TMZ provides a moderate survival benefit to sensitive patients whose O6-methylguanine-methyltransferase (MGMT) gene is silenced by promoter methylation. Unfortunately, TMZ potential is stunted because of the rapid onset of tumour recurrence and acquired resistance believed to result from the upregulation of DNA damage repair by the base excision repair (BER), mismatch repair (MMR), or homologous recombination (HR) systems. Our laboratory previously demonstrated that cell lines obtained from recurrent, TMZ-resistant GBMs could be re-sensitized to TMZ when treated with an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) – a protein instrumental in the recruitment of BER machinery. From this preliminary research, we postulate that PARP-1 inhibition may not only be used to overcome established resistance in GBM but may also be used to prevent its emergence altogether. To test this hypothesis, we utilized the MGMT-methylated GBM cell line U251N and developed an in vitro model of inducible TMZ resistance. We verified that prolonged treatment of U251N cells with TMZ resulted in the emergence of resistant colonies that resembled recurrent GBM clinically observed in TMZ-treated patients. However, when the parental U251N line was co-treated with TMZ and PARP-1 inhibitor ABT-888, resistant colonies failed to appear. Therefore, PARP-1 inhibition may possess the potential to maintain tumour sensitivity to TMZ as well as evade the otherwise inevitable development of resistance in GBM.

Purpose: We identified key clinicopathologic features of brain metastasis (BM) patients who are long-term survivors (LTS). Methods: We screened a prospective database of 1892 patients (treated 2006-2017), identified 92 (5%) who lived > 3 years following BM diagnosis, and performed per patient analyses. Results: Median age at diagnosis of BM was 57 years (range 19-77), 77% were women. The most common tumors were lung (50%), breast (26%), thyroid (7%) and skin (5%). 42% had tumors with drug-targetable oncoproteins (e.g. EGFR mutant) and 15% expressed hormonal receptors. ECOG was <2 in 70%. 47% had stage IV disease at diagnosis (75% with brain as the first site). 55% had controlled extracranial disease at the time of BM diagnosis. Median BM diameter was 1.5 cm (range 0.2-7) and 62% had a single lesion. Treatment was with surgery, radiosurgery, whole brain radiation (WBRT), or systemic therapy alone in 38%, 62%, 52%, and 4%, respectively. 53% received targeted- or immuno-therapy. Median follow up was 63 months (range 36-113). 61% failed intracranially at a median 24 months (range 1-99). 5 and 10- year survival (from BM diagnosis) was 82%, and 34%, respectively. Neither upfront WBRT nor other variables tested correlated with improved survival. In patients who died, an MRI was available within 3 months from death in 57%; of those 55% had no active intracranial disease, suggesting that the majority of deaths were non-neurologic. Conclusion: In general, LTS of BM had a limited number of BM, inactive extracranial disease, and drug targetable mutations.

Purpose: Cranial radiotherapy (CRT) was commonly given for childhood leukemia and brain tumors. Survivors are at risk of late effects including radiation induced meningioma (RIM). Surveillance for RIM is not standardized . We aimed to determine the incidence, latency, and screening patterns for RIM. Materials and Methods: Retrospective chart review of all patients aged <18 years at the time of radiation (RT), treated with CRT for leukemia or a brain tumor in BC between 1981-2006. Patient, tumor, and treatment characteristics were collected. Actuarial statistics were calculated with Kaplan-Meier Curves. Patients were censored at the date of last normal cranial imaging, or development of a RIM. Results: 392 patients were identified. Median age (range) at CRT was 9.6 years. Median CRT dose was 28Gy. The original diagnosis was leukemia in 50%, glioma in 13%, medulloblastoma in 8%, ependymoma in 7%, neuroectodermal tumor in 7%, germ cell tumor in 5%, craniopharyngioma in 4%, and other pathologies in 6%. Median (range) of clinical follow-up (FU) was 13.2 (0-37.5) years. Median (range) of cranial imaging FU was 15.5 (0-21.2) years. There was no documented cranial imaging FU in 144 patients. Forty-eight patients developed a RIM. The median age (range) at RT for patients with RIM was 6.7 years. Only 8 of these cases presented with associated symptoms. The earliest RIM in our cohort occurred 10.2 years after CRT. On actuarial analysis, the median (95% CI) time to development of a meningioma was 29.8 (28.9-30.7) years. Incidence (95% CI) of meningioma at 10 years was 0%, 15 years was 5 (2-9)%, 20 years was 12 (6-18)%, 25 years was 33 (23-43)% and 30 years was 47 (37-68)%. Amongst patients with a RIM, the median dose of CRT was 45 Gy. The lowest dose of RT in a patient who developed RIM was 12 Gy. RT was delivered to the whole brain in 58% and partial brain in 42% of patients with a RIM. Conclusions: After CRT in pediatric patients, there is a significant risk of developing a RIM and a steady increase in this risk with ongoing follow-up. We recommend standardization of surveillance for these patients with screening beginning 10 years after completion of CRT.

CIC, or Capicua, encodes a transcriptional repressor that is itself repressed by RAS/MAPK signalling. CIC is a recurrent target of somatic mutation in type 1 low grade gliomas (LGG), with at least half of the alterations predicted to be deleterious. Type 1 LGGs are a cohort of tumours that are molecularly defined by the loss of heterozygosity of chromosome arms 1p and 19q and the presence of neomorphic IDH1/2 mutations. Despite the high frequency of mutations in CIC within this tumour type, CIC’s putative tumour suppressive role remains to be elucidated. It is also unclear how CIC may cooperate with neomorphic IDH1/2 to promote gliomagenesis. To comprehensively characterize the molecular consequences of CIC loss, we performed RNA-seq, Whole Genome Bisulfite Sequencing, and ChIP-seq on 6 different histone modifications on isogenic CIC-wildtype (WT) and CIC-knockout (KO) normal human astrocytes. To also investigate the collective effects of CIC deficiency and neomorphic IDH1 on the transcriptome and epigenome, we generated the same dataset in isogenic CIC-WT and CIC-KO astrocytes possessing the IDH1 R132H mutation. Analysis of differentially expressed genes illustrates the enrichment of oncogenic pathways in specifically the CIC-KO, IDH1-R132H cells, supporting a synergistic relationship between CIC loss and IDH1-R132H in driving tumour progression. Integrative analyses are ongoing to unveil the epigenetic mechanisms underpinning the regulatory changes in these isogenic cell line models.

BACKGROUND: Meningiomas are the most common primary benign brain tumors in adults. Given the extended life expectancy of most meningiomas, consideration of quality of life (QOL) is important when selecting the optimal management strategy. There is currently a dearth of meningioma-specific QOL tools in the literature. OBJECTIVE: In this systematic review, we analyze the prevailing themes and propose toward building a meningioma-specific QOL assessment tool. METHODS: A systematic search was conducted, and only original studies based on adult patients were considered. QOL tools used in the various studies were analyzed for identification of prevailing themes in the qualitative analysis. The quality of the studies was also assessed. RESULTS: Sixteen articles met all inclusion criteria. Fifteen different QOL assessment tools assessed social and physical functioning, psychological, and emotional well-being. Patient perceptions and support networks had a major impact on QOL scores. Surgery negatively affected social functioning in younger patients, while radiation therapy had a variable impact. Any intervention appeared to have a greater negative impact on physical functioning compared to observation. CONCLUSION: Younger patients with meningiomas appear to be more vulnerable within social and physical functioning domains. All of these findings must be interpreted with great caution due to great clinical heterogeneity, limited generalizability, and risk of bias. For meningioma patients, the ideal QOL questionnaire would present outcomes that can be easily measured, presented, and compared across studies. Existing scales can be the foundation upon which a comprehensive, standard, and simple meningioma-specific survey can be prospectively developed and validated.

Background. Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumours that remain relatively asymptomatic for long periods of time before transforming into aggressive high-grade gliomas. Surveillance of tumour stability is performed primarily by serial imaging. Methods. We retrospectively identified LGG patients that were managed by observation with numerous (≥8) serial magnetic resonance imaging (MRI) studies. Tumour volumes were measured by manual segmentation on imaging. Demographic information, tumour histopathological data, and radiological interpretations were collected from electronic medical records. MRI radiology reports of tumour volume stability were classified into "growth" and "no growth" interpretations. Results. Of 74 LGG patients, 10 (13.5%) patients were included in the study. A median of 11 MRIs (range, 8-18) over a median of 79.7 months (range, 39.8-113.8 months) were analyzed per patient. Tumour diameter linearly increased at a median rate of 2.17 mm/year. Cox regression analysis showed that initial tumour volume predicted time to clinical intervention, and Mann-Whitney U test found that tumours of patients diagnosed before age 50 grew more slowly. Radiology interpretations that reported "no growth" (n=66) corresponded to a median measured growth of 3.90 mL and 11.0% compared to the comparison scan. Reports of "growth" (n=36) corresponded to median measured volume increases of 9.36 mL and 20.5%. Conclusion. We retrospectively analyzed the natural history of LGGs in serially-imaged patients at a single institution. Comparisons to the literature suggest that this is a subset of particularly slow-growing and low-risk tumours. We also highlight the clinical value of performing accurate LGG volumetric analyses.

Background: Outcomes for patients with melanoma brain metastases (MBM) have been poor. New radiotherapy technologies and systemic agents have improved outcomes. Outcomes have rarely been studied at the population-level. We undertook a population-based study investigating changes in management and outcome for patients with MBM in Ontario from 2007-2016. Methods: This was a retrospective population-based cohort study of patients treated for MBM in Ontario from 2007-2016. Melanoma was identified through the Ontario Cancer Registry. Treatments and outcome were described by era (2007-2009, 2010-2012, 2013-2016). Treatment with cranial radiotherapy and drugs were defined using Cancer Care Ontario data and supplemented by physician billing and drug reimbursement data. Neurosurgery was identified using CIHI hospital records. Time to event was investigated using Kaplan-Meier curves. Results: From January 2007-June 2016, 1096 patients with MBM were treated. Whole brain radiation therapy was the first brain-directed treatment in 75.5% of patients in 2007-2009, dropping to 52.0% for 2013-2016. Patients receiving stereotactic radiation or other conformal techniques as the first brain treatment increased from 3.4% in 2007-2009 to 21.3% 2013-2016. Use of BRAF/MEK inhibitors and immunotherapy increased: <2.0% in 2007-2009 to 40.9% 2013-2016. One-year and two-year overall survival (OS) following first brain-directed treatment was greater in 2013-2016: 21.8% at one year and 13.8% after two years (Wilcoxon p=0.001). This compared to 12.3% and 6.4% 2007-2009, and 10.7% and 5.5% 2010-2012. Conclusion: The advent of new radiation technologies and systemic treatments for MBM was associated with increased survival and greater avoidance of whole brain radiotherapy.

Introduction: Radiation-induced brain necrosis (RN) is a relatively uncommon (5-20%) but potentially severe adverse effect of stereotactic radiosurgery (SRS) for brain metastasis(BM). We attempted to establish the effect of hypo-fractionation on RN rates by reviewing patients having simultaneous multi-fraction and single fraction treatment of BM at our centre. Methods: Patients receiving simultaneous 1 (20-24Gy) or 3 fraction (21-24Gy) SRS treatments were identified in our institution’s database. Serial post-SRS MRIs were reviewed to determine the lesion quotient (LQ), or maximum cross sectional area on T1 plus gadolinium divided by T2 FLAIR sequences. LQ less than 0.3 was considered RN. Result: Twenty-two patients were followed for a median 320 days. Sixteen patients developed radionecrosis in 21 of 62 lesions (33%), four of which were symptomatic (20%). Eleven of these lesions received 3 fractions and ten received one fraction. RN risk increased with increasing tumor volume (log odds ratio=1.12, p=0.04). There was no difference in incidence of RN in patients who received whole brain radiotherapy (WBRT) (p=0.11), hypo-fractionation (p=0.98) or had a higher maximum dose (p=0.71). Radiographic RN, however, did not clear in any patients who developed it. Eight patients developed a local recurrence (12%), six of which occurred in the single fraction group. Conclusion: Radionecrosis was significantly related to tumor volume but not fractionation, WBRT, or maximum dose. Overall, our results indicate patients receiving SRS for multiple brain metastasis have a higher rate of radionecrosis than the literature and poorer survival despite having equivalent local control.

Background: The benefits of increasing extent of resection (EOR) for both overall survival and progression-free survival (PFS) in glioblastoma has been well documented. However, models predicting surgical outcomes have failed to incorporate a patient’s IDH status, a known prognostic factor. We isolate the impact of IDH on surgical outcomes. We determine the effect modification of increasing EOR and decreasing residual tumor volume (RTV) on IDH status. Methods: We performed a retrospective cohort study of 98 patients with glioblastoma who had undergone either biopsy or surgical resection. Tumor volumes were determined by volumetric analysis. Univariable and multivariable Cox PH Regression models were built using overall survival and PFS as endpoints. Results: Increasing EOR and decreasing RTV were both associated with prolonged overall survival and PFS. When IDH status was added to multivariable models, the model utilizing RTV provided a slightly better fit compared to EOR. An interaction term between RTV and IDH status was characterized, such that at low RTVs the prognosis of an IDH mutant is significantly better than that of an IDH wild-type, an effect that is less important as RTV increases. The significance of this term was confirmed by improved fit upon insertion into multivariable models. Conclusion: Minimizing RTV and increasing EOR are important prognostic factors for both IDH wild-type and IDH mutant glioblastoma. The protective benefit of the IDH mutation at lower RTVs suggests these patients are the best candidates for aggressive surgical resection.