Background: Brain tumors present unique challenges to patient and family quality of life (QOL). Cognitive dysfunction is common and functionally limiting, with no established treatments. These studies evaluate feasibility and preliminary efficacy of behavioral interventions developed for neuro-oncology patients. Study 1: A randomized controlled trial (N=25 primary brain tumor patients) compared an adapted version of Goal Management Training (GMT, a neuroscience-based integration of mindfulness and strategy training) and a newly-designed supportive psychoeducational intervention (Brain Health Program, BHP) to standard of care. Each intervention comprised 8 individual sessions and at-home practice between sessions. GMT patients’ executive functions improved immediately (p=.077, d=1.13), with maintenance at 4-month follow-up (p=.046, d=1.09). Both intervention groups reported improvements in everyday cognitive functioning immediately (p=.049; d’s GMT=0.43, BHP=0.79) and at follow-up (p=.001; d’s GMT=0.22, BHP=1.01). BHP patients also reported improved mood (p’s=.026 & .012, d’s=0.61 & 0.62). Study 2: Following a needs assessment about cognitive concerns and QOL in brain metastases patients (N=109) and caregivers (N=31), we developed a novel, brief (3 sessions + homework) Cognitive Support Program to provide education and strategy-training in key areas of concern: executive functions, memory, and communication. Options include caregiver co-training, and in-person or web-based delivery. Preliminary data from a pilot trial in progress demonstrate objective and subjective improvements. Conclusions: Cognitive rehabilitation may be a feasible and effective option for primary or metastatic brain tumor patients, addressing a need that is largely unmet in standard cancer care. Further development and larger trials appear warranted, with capacity for remote delivery recommended.

Background: A will, power of attorney and advanced healthcare directive are critical to guide decision-making in people with cognitive decline. We identified characteristics that are associated with the existence of these documents in patients who presented to a rural and remote memory clinic (RRMC). Methods: 95 consecutive patients were included in this study. Patients and caregivers completed questionnaires on initial presentation to the RRMC and patients were asked if they have legal documents. Patients also completed neuropsychological testing. Statistical analysis (t-test and χ2 test) was performed to identify significant variables. Results: 70 patients had a will, 62 had a power of attorney and 21 had an advanced healthcare directive. Having a will was associated with good quality of life (p=0.001), living alone (p=0.034), poor verbal fluency (p=0.055) and European ethnicity (p=0.028). Factors associated with having a power of attorney included good quality of life (p=0.031), living alone (p=0.053) and poor verbal fluency (p=0.015). Old age (p=0.015), poor verbal fluency (p=0.023) and severity of cognitive and functional impairment (p=0.023) were associated with having an advanced healthcare directive. Conclusions: Our results indicate that poor quality of life, good verbal fluency, non-European ethnicity and living with others are associated with a lower likelihood of creating legal documents in patients with cognitive decline

Despite decades of trials, the prognosis for diffuse intrinsic pontine gliomas (DIPG) remains dismal. DIPG is inoperable and standard treatment is radiation alone, as the addition of chemotherapeutic agents, such as temozolomide, have not improved survival. In addition to inherent chemoresistance, treatment of DIPG is impeded by an intact blood-brain barrier (BBB). VAL-083 is a structurally unique bi-functional DNA-targeting agent that readily crosses the BBB. VAL-083 forms interstrand DNA crosslinks at N7-guanine, resulting in DNA double-strand breaks (DSB), S/G2-phase cell-cycle arrest, and ultimately cancer cell death. We have previously demonstrated that VAL-083 is able to overcome temozolomide-resistance in vitro and in vivo, and that its cytotoxicity is independent of the DNA-repair enzyme O6-methylguanine DNA-methyltransferase (MGMT). MGMT is almost universally expressed in DIPG and its expression is strongly correlated with temozolomide-resistance. VAL-083’s distinct mechanism-of-action suggests the potential for combination with inhibitors of DNA DSB repair or S/G2 cell-cycle progression (e.g. Wee1 inhibitor AZD1775). Here, we investigated the effects of VAL-083 in combination with radiation, AZD1775 or irinotecan (topoisomerase inhibitor) in three DIPG cell-lines: SF10693 (H3.1), SF8628 (H3.3) and NEM157 (H3.3). VAL-083 showed activity at low uM-concentration in all three cell-lines. In addition, VAL-083 showed synergy with AZD1775 in all three cell-lines. Combined with its ability to cross the BBB, accumulate in brain tumor tissue and overcome MGMT-related chemoresistance, these results suggest VAL-083 as a potentially attractive treatment option for DIPG as single agent or in combination with AZD1775. Combination studies with radiation are ongoing and will be presented at the meeting.

Background: To determine whether exosomal microRNAs (miRNAs) in CSF of patients with FTD can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic FTD Initiative (GENFI) cohort and in sporadic FTD. Methods: GENFI participants were either carriers of a pathogenic mutation or at risk of carrying a mutation because a first-degree relative was a symptomatic mutation carrier. Exosomes were isolated from CSF of 23 -pre-symptomatic and 15 symptomatic mutation carriers, and 11 healthy non-mutation carriers. Expression of miRNAs was measured using qPCR arrays. MiRNAs differentially expressed in symptomatic compared to pre-symptomatic mutation carriers were evaluated in 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD), and 10 healthy controls (HCs). Results: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared to pre-symptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 [90% CI: 0.79-0.98] and 0.81 [90% CI: 0.68-0.93], and when combined an area of 0.93 [90% CI: 0.87-0.99]. In sporadic FTD, only miR-632 was significantly decreased compared to sporadic AD and HCs. Decrease of miR-632 revealed an area of 0.89 [90% CI: 0.80-0.98]. Conclusions: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Background: The NIH Toolbox - Cognition Battery (NIHTB-CB) is a computerized cognitive assessment designed for clinical research that is administered in-person. Here, we explored the feasibility and validity of a novel video-conference protocol for administering the NIHTB-CB. Since our protocol required repeated assessments, we further explored the NIHTB-CB’s practice effect. Methods: Twenty-five healthy participants completed the NIHTB-CB under two separate conditions four weeks apart. The standard condition followed the recommended administration protocol, whereas the video-conference condition had the examiner and participant in separate rooms but able to communicate over video-conference. A linear mixed-model analysis was performed to explore the fixed effect of testing condition and time on NIHTB-CB performance. Results: Across all three NIHTB-CB composite scores (total, fluid and crystallized cognition) no significant fixed effect of administration condition was found. A significant practice effect was observed for the fluid and total cognition composite scores over a 29.0 (± 2.1) day test-retest interval. Conclusions: Our novel video-conference protocol for the NIHTB-CB is equivalent to the standard protocol in healthy participants, and may provide a solution for researchers seeking to engage study participants at remote sites. If the NIHTB-CB is used longitudinally to monitor patients, corrections for repeated measures may be required.

Current standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide. Most tumors recur within a year from diagnosis and median survival for recurrent GBM (rGBM) is 3-9 months. Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance, exhibited by most GBM patients. VAL-083 is a DNA-targeting agent with a mechanism-of-action that is independent of MGMT. VAL-083 overcomes temozolomide-resistance in GBM cell-lines, cancer stem cells, and in vivo models. VAL-083 readily crosses the blood-brain barrier and accumulates in brain-tumor tissue. We recently completed a VAL-083 dose-escalation trial in temozolomide- and bevacizumab-refractory rGBM and determined that 40mg/m2/day given intravenously on days 1,2,3 of a 21-day cycle is generally well-tolerated. This dosing regimen was selected for subsequent GBM trials, including an ongoing single-arm, biomarker-driven Phase 2 trial (N=48) in temolozomide-refractory, bevacizumab-naïve rGBM , MGMT-unmethylated (Clinicaltrials.gov:NCT02717962). The primary objective of this study is to determine if VAL-083 improves OS compared to a historical control of 7.15 months for MGMT-unmethylated rGBM patients treated with lomustine (EORTC26101). In addition, another single-arm, biomarker-driven, Phase 2 study (N=25) of VAL-083 in combination with radiotherapy in newly diagnosed GBM, MGMT-unmethylated is ongoing (Clinicaltrials.gov:NCT03050736). This trial aims to determine a dose for further study of VAL-083 in combination with radiotherapy and explore if VAL-083 improves PFS and OS compared to historical results in newly diagnosed GBM. Enrollment and safety data updates will be provided at the meeting. The results of these studies, if successful, may support VAL-083 as part of a new chemotherapeutic treatment paradigm for GBM.

INTRODUCTION: Gangliogliomas (GGs) are neuroepithelial tumours of the central nervous system (CNS) composed of mature ganglion cells or a mixed population of ganglion and glial cells. Microarray data of low grade gliomas (LGG) including GGs revealed overexpression of the Dlx2 gene, a homeobox gene essential for interneuron migration and differentiation. We hypothesized that GGs are arrested in development, and began to explore the role of the Dlx2 gene. BRAF rearrangements and BRAF V600E point mutations have been reported in pediatric LGG. METHODS: DLX2 expression was examined in GGs using immunofluorescence (IF) and immunohistochemistry (IHC) labelling of formalin fixed paraffin embedded (FFPE) tissue sections, along with staining of glial and neuronal markers. BRAF mutations were detected using a commercial antibody and/or sequence verification of the DNA extracted from the FFPE blocks. RESULTS: In the Discovery cohort 10/30 were DLX2+ (33.3%) and in the Validation cohort 15/40 were DLX2+ (37.5%). Of these 15 cases, 15 were GFAP+ (100%), 15 were synaptophysin and/or NeuN+ (100%), and 13 were OLIG2+ (86.7%); 6 had a BRAF V600E mutation (40.0%). For the Validation cohort of 40 GGs, 28 were OLIG2+ (70.0%); 13/28 co-expressed DLX2 (46.4%). 18/40 cases had a BRAF V600 mutation(17 V600E, 1 V600G; 45.0%) and 6/18 were DLX2+ (33.3%). CONCLUSIONS: DLX2 is expressed in GGs in both neuronal and glial marker expressing tumour cells. Our results support that GGs arise from CNS progenitors arrested at the neuronal-glial cell fate “decision” point.

Background: Neurogenic orthostatic hypotension (NOH) is characterized by a reduction in systolic blood pressure of ≥20 mmHg or diastolic blood pressure of ≥10 mmHg within three minutes of upright posture. NOH is prevalent in the elderly population who is at increased risk for cognitive decline, therefore it is imperative to investigate if there is a relationship between NOH and impaired cognition. Methods: Currently, 9 control subjects and 4 NOH patients have been recruited. Cognitive function is assessed using the symbol digit modalities test (SDMT) which assesses information processing speed and the Stroop test which measures response inhibition. SDMT and Stroop test are administered when the table is supine and during tilt. Results: NOH patients scored significantly worse on SDMT when lying (p=0.018) and standing (p=0.004) compared to the control group. Control subjects performed significantly better when standing for both SDMT (p=0.008) and Stroop (p=0.026), whereas NOH patients had similar scores when lying and standing for SDMT and Stroop. Conclusions: Preliminary results show that information processing speed is slower in NOH patients than controls in both the supine and standing positions. NOH patients have a more difficult time inhibiting unwanted responses compared to controls when standing, which is represented by a greater interference score in NOH patients.

Background: Lisdexamfetamine has not heretofore been reported to cause pathological gambling. Such a case is presented. Methods: A middle-aged woman, without past interest in gambling, gaming, or risk taking behavior, with childhood history of attention deficit hyperactivity disorder presented with difficulty focusing and concentrating. Lisdexamfetamine was started at 20 mg daily and gradually escalated due to lack of efficacy. At 70 mg daily, she began binging on sweets and gambling all day, every day at nearby riverboats, which she had never frequented previously. Upon reduction to 60 mg daily, the gambling resolved. Ritalin 20 mg every morning and 50 mg every afternoon was used without gambling reoccurrence. Results: Mental Status Examination: Alert, cooperative and oriented x 3 with good eye contact. Euthymic, without mania, thoughts logical and goal directed. Conclusions: Enhanced dopamine in the nucleus accumbens may induce hedonic activities including gambling, binging on sweets, or sexual activity (Moore et al. 2014). Lisdexamfetamine has been described to induce mania, and pathological gambling may have been an isolated manifestation of early mania. In those who have recently begun lisdexamfetamine, query should be made regarding change in gambling behavior and in those who are pathologically gambling, investigation should be entertained as to whether they are taking lisdexamfetamine.

Glioblastoma is the most common and malignant brain tumor with a median overall survival of 20.5 months. There is an urgent need to develop novel therapeutic strategies. Using a glioblastoma TCGA dataset, we have determined that high NSUN5 mRNA expression is strongly associated with poor survival in glioblastoma patients. NSUN5 is a ribosomal RNA (rRNA) cytosine methyltransferase. Human NSUN5 is located in chromosome 7 and is completely deleted in the Williams-Beurren syndrome, a complex neurodevelopmental disorder. However, RNA targets of NSUN5 in mammals and its role in cancer are unknown. The objective of this project is to determine whether elevated NSUN5 changes rRNA methylation pattern and thereby leads to pro-tumorigenic translational reprogramming and pro-tumorigenic phenotypes in glioblastoma. Western blotting showed that NSUN5 is expressed in 7 out of 9 established glioblastoma cell lines and in 8 out of 12 primary patient-derived glioblastoma cell lines. Bisulfite sequencing confirmed that NSUN5 methylates C3782 of human 28S rRNA in glioblastoma cells. Functionally, overexpression of NSUN5 increases, whereas NSUN5 knockout decreases global protein synthesis and sphere formation in glioblastoma cells. More importantly, mice bearing intracranial NSUN5-expressing U87 tumors survived for a shorter time than mice bearing tumors derived from U87 control cells. Our results suggest that NSUN5 methylates 28S rRNA and may enhance cancer stem cell phenotypes and tumor formation and/or progression in glioblastoma. Experiments are ongoing to determine whether NSUN5 promotes tumor formation and/or progression through translational reprogramming in glioblastoma. This study may help identify novel therapeutic targets for glioblastoma.

Background: We present a case of a previously well 71-year-old woman who developed rapidly progressive dementia. She had several prolonged hospital admissions and extensive investigations were performed. Her illness was steroid-responsive with clinical features suggestive of Hashimoto’s Encephalopathy (HE). However, multiple thyroid antibody panels acquired were initially normal, becoming elevated during subsequent relapses that occurred 3 years after initial presentation. The case signifies the importance of repeating antithyroid antibody levels in a patient with a clinical picture suggestive of HE. Methods: Case report. Results: The diagnosis of HE was established because of a compatible clinical picture including a relapsing encephalopathy with motor involvement and steroid responsiveness. In addition, although initial antithyroid antibody testing was negative, subsequent attacks were associated with significant elevations and reverted to normal with resolution of the attacks. Conclusions: In a patient with normal levels of antithyroid antibodies and a clinical presentation suggestive of HE, we recommend repeat antithyroid antibody testing to confirm diagnosis. Further studies are necessary to clarify the pathogenic role of elevated antithyroid antibodies in the mechanism of HE.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare genetic condition caused by mutations in the Merlin gene on chromosome 22. It results in acoustic neuromas (schwannomas) and other CNS tumors including meningiomas and ependymomas. Most patients develop hearing loss as a result of neuroma-driven destruction of auditory nerves. Surgery and radiation therapy remain the two most commonly recommended treatment options. However, there is a risk of further hearing loss with these procedures. There is emerging evidence that bevacizumab, a monoclonal antibody against VEGF-A, can shrink acoustic neuromas and mitigate hearing loss. CASE PRESENTATION: A 34-year-old female with bilateral acoustic neuromas from NF2 suffers partial hearing loss in the left ear and total hearing loss in the right ear after removal of the right-sided neuroma. Baseline MRI showed a left-sided acoustic neuroma (15 x 13 mm) and recurrence of the right-sided neuroma (18 x 14 mm). Bevacizumab was initiated at 5 mg/kg IV every 14 days. After 8 cycles, the patient reported marked improvement in hearing. At lower frequencies (< 1,000 Hz, the range of human voice), auditory thresholds improved by up to 60% of baseline, while at higher frequencies, improvements of up to 46% were seen. Repeat imaging showed no disease progression. CONCLUSIONS: Bevacizumab led to hearing improvement and prevention of disease progression after 8 cycles of therapy. This treatment should be considered in patients with NF2 and acoustic neuromas who wish to pursue a less-invasive treatment option with the potential of delaying progression and mitigating hearing loss.

Background: Idiopathic Normal-pressure hydrocephalus (iNPH) is characterized by cognitive impairment, gait disturbance, enlarged ventricles with/without cerebral atrophy, with/without urinary incontinence, and normal cerebrospinal fluid pressure. Familial iNPH is very rarely described in the literature. A Canadian family with more than one generation of iNPH has never been described. Methods: Patient 1: 50-year-old female presented with wide-based and magnetic gait, multiple falls with subsequent freezing. LP with large volume tap was performed. Patient had ventriculo peritoneal (VP) shunt surgery. Patient 2: 52 year male (brother): Presented with long-standing cognitive impairment and fatigue. Montreal Cognitive Assessment (MOCA) was performed. Whole exome sequencing(WES) of both siblings as well as an unaffected first cousin was done. The father and grandmother of both patients was diagnosed with iNPH. Results: Patient 1: Opening pressure on LP was 22 cm-H2O. She responded well to large volume tap. She had VP shunt resulting in improved gait. Patient 2: Opening pressure on LP was 16cm-H2O. CSF flow study was slow for age indicative of NPH. MoCA score was 25/30. WES of patients and unaffected first cousin is underway. Conclusions: We present an undescribed Canadian family with iNPH in more than one generation. WES is underway for better understanding of genetic predesposition and inheritance of familial iNPH

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.