Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.

Glioblastoma Multiforme is the most common malignant primary brain tumor, having a mean overall survival <2 years. The lack of an efficient immune response against the tumor have been attributed to its immunosuppressive capabilities and an immunosuppressing local environment. Aim: We set out to design a chimeric molecule that recognizes and binds tissue inducible metalloproteinase known to be induced in GBM cells (MMP-2) on one end. Its other end, the effector domain, mobilizes and recruits cytotoxic T-cells to mount an effective anti-tumor reaction. Methods: The targeting moiety is the small 36-amino acids Chlorotoxin, derived from the venom of the Israeli Yellow scorpion. The effector end is a single chain HLA-A2 (Human leukocyte antigen subtype A2) covalently bound to phosphoprotein-65 derived from the cytomegalovirus, to which most of the human population has developed a specific immune response. Results: The molecular construct was cloned and expressed in E.coli. The protein product was isolated, purified, and then folded in vitro. Various activity assays employed demonstrated retained activity of each domain, including flow-cytometry, intracellular staining, fluorescence immunohistochemistry, radiolabeled toxicity assays etc. Initial in-vivo studies show great promise. Conclusions: We present a proof of concept study for a new immunotherapy approach to battle GBM. A molecular construct which contains a non-antibody compact and highly specific targeting domain, combined with the ability to recruit anti-CMV T-cell lymphocyte population. The recruitment of potent memory CTL’s to the tumor’s milieu may prove resistant to the previously described local immunosuppressive environment brought about by the tumor.

The radiological detection of BMs is essential for optimizing a patient’s treatment. This statement is even more valid when stereotactic radiosurgery (SRS), a non-invasive image guided treatment that can target BM as small as 1-2 mm, is delivered as part of that care. The timing of image acquisition after contrast administration can influence the diagnostic sensitivity of contrast enhanced MRI for BM. Objective: Investigate the effect of time delayed acquisition after administration of intravenous Atavist® (Gadobutrol 1mmol/ml) on the detection of BM. Methods: This is a prospective IRB approved study of 50 patients with BM who underwent post-contrast MRI sequences immediately after injection of 0.1 mmol/kg Gadavist® as part of clinical care (t0), followed by axial T1 sequences after a 10 minutes (t1) and 20 minute delay (t2). MRI studies were blindly compared by 3 neuro-radiologists. Results: Single measure intraclass correlation coefficients were very high (0.914, 0.904 and 0.905 for t0, t1 and t2 respectively), corresponding to a reliable inter-observer correlation. The t2 delayed sequences showed a significant and consistently higher diagnostic sensitivity for BM by every participating neuroradiologist as well as for the entire cohort (p=0.016, p=0.035 and 0.034 respectively). A disproportionately high representation of BM detected on the delayed studies was located within posterior circulation territories (compared to predictions based on tissue volume and blood-flow volumes). Conclusion: Considering the safe and potentially high yield nature of delayed MRI sequences, it should supplement the basic MRI sequences in all patients in need of precise delineation of their intracranial disease.

Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.

Radiation necrosis occurs in 5-25% of patients who undergo stereotactic radiosurgery (SRS) for brain metastases. Intravoxel incoherent motion (IVIM) uses MRI diffusion-weighted imaging (DWI) to assess regional perfusion. We investigated the utility of IVIM to differentiate recurrent tumor from radionecrosis after SRS. Patients who had SRS and subsequent surgical resection of what was thought to be either tumor progression or necrosis were included. ROIs were contoured on the pre-operative post-Gd T1-weighted images and transferred to DWI images using automated co-registration. The perfusion fraction (f) was calculated using asymptotic fitting and the mean f (fmean), 90th percentile for f (f90), mean ADC (ADCmean) and 10th percentile for ADC (ADC10) were calculated. Pathology reports were used to identify the predominant feature (necrosis versus tumor). Nine patients with ten lesions were included. One lesion exhibited pure necrosis while the other nine were mixed; three were predominantly (>75%) tumor, three predominantly necrosis, and three were equal parts of both. The perfusion fraction was significantly higher in cases with predominantly tumor compared to those with predominantly necrosis (fmean 0.10±0.01 vs 0.08±0.01, p=0.02 and f90 0.22±0.01 vs 0.14±0.02, p<0.001). ADC did not differentiate tumor from necrosis (ADCmean 0.97±0.23 vs 1.02±0.36, p=0.8 and ADC10 0.53±0.29 vs 0.76±0.29, p=0.33). The IVIM perfusion fraction is useful in differentiating recurrent tumor from radionecrosis in brain metastases treated with SRS. This is the first study to evaluate IVIM against the gold standard (histopathology).

Brain tumours represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumour. Current molecular Nsubgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumour through selective targeting by small molecule Wnt agonists (Wnt3A), GSK3 inhibitors (CHIR99021), and transgenic lines containing a stabilized beta-catenin mutant. Activated Wnt signaling resulted in decreased in vitro self-renewal and promoted differentiation within primary human MB stem cells. The clinical relevance of these findings were demonstrated with an in vivo survival advantage in mice containing orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling. Xenografts generated from Wnt-activated tumours were much smaller in size, maintained a much lower rate of proliferation, and reduction in key MB stem cell self-renewal genes (Bmi1, Sox2, Msi1, FoxG1). Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, while providing evidence for the context-specific tumour suppressive function of the canonical Wnt pathway.

Medulloblastoma and neuroblastoma are aggressive solid pediatric tumors, with 5 year survival rates lower than 50-60%. In addition, more than 80% of the survivors develop permanent neurological impairments. Hence, there is a dire need to identify and validate novel, more effective and less toxic therapeutic approaches. Tumors are continually exposed to acute changes in the micro-environment, including nutrient availability. We previously showed that eukaryotic Elongation Factor-2 Kinase (eEF2K) is a critical regulator of cellular adaptation to acute metabolic stress. Based on those findings, we hypothesize that eEF2K is a marker of outcome and mediates medulloblastoma and neuroblastoma adaptation to acute stress. METHODS – Proprietary gene expression datasets (for medulloblastoma) and the R2 genomic analysis platform (for neuroblastoma) were analyzed for links between eEF2K expression and outcome. Effects of eEF2K knockdown on cell survival were evaluated in BE(2)C neuroblastoma cells. Immunoblotting and immunohistochemistry were performed on neuroblastoma cell lines and tissue microarrays (TMAs) for key molecules in the pathway. Similar studies are underway in medulloblastoma cell lines and TMAs. RESULTS - Low eEF2K mRNA expression is predictive of improved survival in medulloblastoma and neuroblastoma. Low p-eEF2 protein expression, indicative of low eEF2K activity, improves survival in human neuroblastoma. Neuroblastoma cell lines with eEF2K knockdown are more sensitive than controls to nutrient deprivation. CONCLUSIONS - eEF2K may represent a critical mechanism for adaptation to acute metabolic stress in neuroblastoma and medulloblastoma, and is therefore a promising therapeutic target. We are currently exploring the pharmacological inhibition of eEF2K in xenograft tumor models.

A point mutation resulting in a specific amino acid change(K27M) in either one of the genes encoding histone H3, H3F3A (H3.3) or HIST1H3B/C/I (H3.1)is present in most pediatric intrinsic pontine gliomas, and has been described in other midline locations. The objective of the present study was to determine the frequency and location of this mutation in diffuse infiltrating gliomas in young adults. The study group consisted of 22 consecutive diffuse gliomas in patients under the age of 40 treated at St. Michael’s Hospital, an adult hospital in the University of Toronto system. Ultra-sensitive digital droplet PCR, a method capable of highly sensitive and specific mutation detection affecting either H3.3 or H3.1, was performed on sample DNA to determine H3K27M status. The H3K27M mutation was detected in the gliomas of five patients, aged 17 to 34 years. The male: female ratio was 3:2. The allele frequency ranged from 26% to 44%, reflecting the infiltrating character of the tumors. Three of the tumors where located in the thalamus, one in the medulla, and one was intraventricular. In terms of grading, one tumor was considered WHO grade II, two III, and two IV. In contrast, most tumors in patients with gliomas lacking the K27M mutation (17 subjects, age 19 to 39 years) were located in the lobes of the cerebral hemispheres, with the following exceptions: 1 in the thalamus, 1 in the hypothalamus, 1 in the cerebellum, and 1 periventricular. WHO grades were 1 II, 9 III, 7 IV. Correlation with patient outcome is ongoing. We conclude that the H3K27M is common in thalamic gliomas in young adult patients, and rare or absent in lobar hemispheric gliomas.

Programmed Cell Death – 1 (PD1) inhibition activates tumor-specific T-lymphocytes and is an effective clinical therapy against some cancers. Preclinical data regarding immune checkpoint inhibitors against malignant glioma is scant, and interim analyses of clinical trials suggest modest effect in patients as single agents. We examined PD-1 inhibition in murine glioblastoma models in combination with other immunomodulatory agents. Methods – Syngeneic glioma tumors (GL261 and CT2A) were implanted intracranially in C57/Bl6 mice. In separate experiments, PD-1 inhibition was combined with antibody blockade of t-cell immunoglobulin and mucin protein (TIM3), ligation of OX40 on T-lymphocytes, or vaccination with irradiated GM-CSF expressing tumor cells. Systemic antitumor immunity and tumor infiltrating lymphocytes were analyzed by ELISPOT assay and flow cytometry, respectively. Results - In both syngeneic glioma models, day 3,6, and 9 systemic delivery of a monoclonal antibody against PD-1 led to increased survival vs. controls. In animals with GL261 intracranial tumors, survival was improved by combination of PD-1 blockade with subcutaneous injection of irradiated GM-CSF expressing GL261 tumor cells, with antibody blockade of t-cell immunoglobulin and mucin protein 3 (TIM3), or binding of OX40 on T-lymphocytes by an activating antibody. In most cases, ELISPOT analyses demonstrated enhanced Th1 immunity by combination immunotherapies. Vaccination was associated with an increased intratumoral CD8+ T lymphocyte / FoxP3+ T lymphocyte ratio. Conclusion –Blockade of PD-1 on T lymphocytes in glioma-bearing mice is active. Both antitumor immunity and survival can be enhanced by combination of PD-1 inhibition with agents that activate antitumor immunity by complementary mechanisms.

Recurrent glioblastoma (GBM) has an unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector with the transgene cytosine deaminase, selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. In 2 Phase 1 studies, Toca 511 was administered into the cavity wall after surgical resection (NCT01470794) or intratumoral injection by biopsy needle (NCT01156584). To provide context to the results observed, subjects were compared to an external lomustine treated control (Courtesy Denovo Biopharma; Wick 2010). Treatment with Toca 511/Toca FC from 2 Phase I studies showed significant improvement in OS HR equals to 0.48, p less than 0.001, with similar effect in the surgical resection (OS HR 0.45, p equals to 0.003) and intratumoral injection (OS HR 0.56, p equals to 0.060). Fewer related greater or equal to Grade 3 adverse events (AEs) were reported for Toca 511/Toca FC (2.5 percent) vs. lomustine (36.9 percent). There was a virtual absence of hematologic toxicity for Toca 511/Toca FC vs. lomustine (Grade greater or equal to 3 thrombocytopenia 23.8 percent). Discontinuations for AEs occurred in 0percent for Toca 511/Toca FC vs. 4.8 percent for lomustine. Toca 511 is surgically delivered and treatment-emergent AEs regardless of attribution included incision site pain (20 percent), procedural pain (12.5 percent), and wound infection (5 percent) vs. 0percent, 1.2 percent, 1.2 percent respectively for lomustine. Toca 511/Toca FC significantly improved survival and safety relative to lomustine. A Phase 2/3 trial has launched (NCT02414165).

Although genetic mutations are usually responsible for the initial tumor formation and progression, changes in the microenvironment also have a critical role in facilitating this process. Many ''untransformed'' cells infiltrate the tumors, and recent evidence suggests cancer cells can ‘reprogram’ normal cells by miRNAs, which are small, non-coding RNA molecules that regulate several protein targets. One prominent feature of glioma pathology is massive gliosis, an inflammatory response consisting of reactive astrocytes, in and around the tumor. We show that expression of Cx43, a major gap junction protein in astrocytes, is significantly enhanced in astrocytes at the tumor border. Using a mouse model consisting of syngeneic intracranial implantation of GL261 glioma cells into Nestin-Cre:Cx43fl/fl mice in which Cx43 is selectively eliminated in astrocytes, we demonstrate that reduction of astrocytic Cx43 decreases the dissemination of glioma cells from the tumor core. Similarly, knocking down Cx43 in astrocytes also reduces glioma invasion in a co-culture of glioma cells and astrocytes. By comparing the microRNA profiles of the astrocytes before and after co-culture with human glioma cells, we have identified a miR-5096 that appears to reprogram astrocytes to enhance the invasiveness of glioma cells. We are now examining whether we can prevent glioma cells from invading the brain and establishing recurrent secondary tumors by stopping the exchange of materials between glioma cells and astrocytes through eliminating Cx43 channel activity.

To investigate patterns of survival and estimate conditional survival rates among brain cancer patients in Canada. METHODS: Canadian Cancer Registry data were obtained for all patients with primary brain cancer diagnosed between 1992 and 2008 (n=38,095). Follow-up ended with patient death or December 31, 2008, whichever occurred first. Crude Kaplan-Meier estimates were calculated at one, two, and five years post-diagnosis and also used to estimate conditional survival (restricted to 2000-2008). Age group, sex, residence and microscopic confirmation were considered in estimating rates for major histology types using multivariate models. RESULTS: The overall five-year survival rate was 27%. Oligodendrogliomas had the highest 5-year survival rate (65%, 95% CI: 62.5-67.4%) and glioblastomas the lowest (4.0%, 95% CI: 3.7-4.3%). Compared to Ontario, the age- and sex-adjusted 5-year glioblastoma survival estimates were lower in British Columbia, Alberta and Manitoba-Saskatchewan, lower in all other regions for diffuse astrocytoma, and lower in Manitoba-Saskatchewan for anaplastic astrocytomas. Estimates were significantly higher for oligodendrogliomas in Alberta, and for anaplastic oligodendrogliomas in Alberta and Quebec (P<0.05). Longer term conditional survival rates (surviving an additional 2 years 1-4 years after diagnosis) varied by histologic group. CONCLUSION: There is a need to further explore the underlying reasons for the observed variation in survival rates by region in an effort to improve the prognosis of brain cancer in the Canadian patient population. Conditional survival information has value for clinicians as they plan the course of treatment and follow-up for individual patients.

Meningiomas are the most common primary benign brain tumor. Radiosurgery (primary or adjuvant) allows excellent local control. The Geriatric scoring system (GSS) for pre-operative risk stratification and outcome prediction of patients with meningiomas has been previously reported. The GSS incorporates eight tumor and patient parameters on admission. A GSS score higher than 16 was previously reported to be associated with a more favorable outcome. We assessed the validity of the GSS score and its influence on outcome in patients treated with gamma-knife radiosurgery (GKRS). Methods: Patients treated with single session GKRS for WHO-1 meningioma during 1989-2013 at the University of Virginia were reviewed. A cohort of 323 patients, 50.2% (n=162) males. Median age was 56 (29-84), and median follow-up was 53.6 (6-235) months. Median tumor volume was 4.5 cm3 (0.2-23). Median margin and maximal doses were 15 Gy (8-36) and 32.3 Gy (20-65), respectively. Results: Tumor volume control was achieved in 87% (n=281), and post-GKRS clinical neurological improvement reported in 66.3% (n=214). The median change in KPS was +10 (range -30 to +40). The most common complication was intermittent headaches (34.1%, n=110) and cranial nerve deficits (14.2%, n=46). The GSS (calculated and grouped as GSS>16 and GSS<=16) was found to correlate with different Post-GKRS functional status (p<0.0001) and tumor control (p=0.028). Conclusion: The GSS, used for risk stratification and outcome prediction in patients with meningiomas seems valid for patients undergoing single session GRKS. GSS score greater than 16 is associated with a better long-term functional status and tumor control.

One-third of all primary central nervous system tumors in adults are meningiomas, which arise from the meninges. Although the majority of meningioma cases are not associated with an environmental risk factor, it is well established that individuals receiving radiation treatment to the CNS are susceptible to radiation-induced meningiomas (RIMs). The genomic integrity of spontaneous meningiomas has been extensively profiled by whole genome sequencing and exome sequencing, providing a well-developed catalogue of meningioma associated mutations. In contrast, a comprehensive understanding of the molecular changes associated with RIMs is not available. Comparative genomic hybridization (CGH) has previously revealed that >90% of RIMs possess multiple regions of DNA copy number alterations, with the most common chromosomal loss being chromosome 1p and 22q. These CGH based studies of gross chromosomal alterations suggest that radiation induced meningiomas show no significant differences to spontaneous meningiomas. We have extensively characterized RIMs through the profiling of their global CpG methylation, gene expression and mutation signatures. The integration of these three platforms at base-pair resolution methylation has facilitated the identification of molecular changes that contribute to RIM. This is the largest cohort of profiled meningiomas to date, providing a robust characterization of unique RIM features that can be exploited for future therapies.

Factors which might influence outcome in patients with meningioma are not well-understood. Previous studies have examined associations of laboratory blood values including hemoglobin levels with patient outcomes in cancer. We hypothesized those changes in CBC before tumor resection can be used as one of the prognostic factors for tumor recurrence/progression in meningioma. To address this, we gathered the clinical and pre-operative CBC results for final analysis from 226 patients (64 males and 162 females) who underwent craniotomy for primary meningioma (grades: 157 WHO GI, 59 GII, 10 GIII) at our institution between 2001 and 2015.Individual parameters were analyzed for correlation with progression-free survival. The median recurrence free survival (RFS) was not reached and follow-up ranged 0.3-14 years. Fifty-six patients (25%) had anemia and 30% of the patients showed leukocytosis using standard cut-offs. On univariate analyses, low hemoglobin (Hb) level, as well as high leukocytes (Lkc), neutrophil (Neutro) and monocyte counts correlated with worse RFS. As expected, tumor grade was correlated with RFS. Low Hb level, high Lkc and Neutro counts were all significantly associated with RFS after adjusting for grade. Strikingly, 32% of patients with pre-operative anemia experienced a recurrence at 5 years, compared with only 11% of non-anemic patients. Conclusion: In this exploratory study, we find that pre-operative CBC data, which is readily available, may contain prognostic information relevant to subsequent risk of recurrence or progression in meningioma. While the biological mechanism for these associations is not clear, they represent hypotheses for further investigation.

We aimed to investigate the feasibility of delivering stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy with the hybrid MRI-LINAC (MRL) system for patients with single brain metastases, and to characterize the dosimetric impact at tissue-air interfaces resulting from the electron return effect (ERE). Material/Methods: 24 patients treated for intact single brain metastases were selected for analysis. Three optimized radiotherapy plans with the same prescribed dose were generated for each case: 1) standard noncoplanar volumetric modulated arc therapy (VMAT), 2) coplanar step-and-shoot intensity modulated radiotherapy (IMRT) on the MRL in the absence (MRL_B=0), and 3) in the presence of the transverse magnetic field (MRL_B=1.5). The plans were evaluated using cumulative dose-volume histograms (DVHs) and by calculation of Paddick conformity index (PCI), V100%, V12Gy minus gross tumor volume (V12Gy – GTV), and V2Gy. The dosimetric impact of ERE to the skin and air cavities was quantified using a 5 mm rim of tissue around tissue-air boundaries. Results: All plans met the objectives with respective to target coverage and OAR constraints. Differences between all investigated dosimetric parameters significantly favored the VMAT plans as compared to the MRL_B=0 and MRL_B=1.5 plans, except for V2Gy. The VMAT plans showed a higher mean (±standard deviation) PCI compared to the MRL_B=0 and MRL_B=1.5 plans (0.85±0.08 vs. 0.79±0.09 vs. 0.78±0.11). In the presence of the magnetic field, ERE resulted in a statistically significant but small increase in mean dose and D2cc in the skin (0.08 Gy, p < 0.0001 and 0.66 Gy, p < 0.0001, respectively) and around air cavities (0.07 Gy, p = 0.0092 and 0.25 Gy, p = 0.0004, respectively). Conclusions: Stereotactic radiation to single brain metastases is feasible using the MRL Monaco treatment planning system; however, in its current iteration, application to small targets deserve careful consideration given the technical limitations resulting in less favorable plan quality compared to that of a noncoplanar standard VMAT technique. The dosimetric impact of ERE at tissue-air boundaries is minor and does not compromise target conformity or dose gradient.

Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with stage-IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. We report a cohort of patients treated for brain metastasis with immunotherapy and evaluate the effect of SRS timing on the intracranial response. Methods: All consecutively treated melanoma patients receiving Ipilimumab and SRS for their brain metastasis were included in the retrospective analysis. 46 patients harboring 232 brain metastases were reviewed. The median clinical follow-up was 7.9 months (3-42.6). Median age was 63 years (24.3-83.6). 32 patients received SRS before or during ipilimumab cycles (Group-A) whereas 14 patients received SRS after the ipilimumab treatment (Group-B). Radiographic and clinical responses were assessed at approximately 3 months intervals after SRS. Results: The two cohorts were comparable in pertinent pre-treatment aspects with the exception of SRS timing relative to ipilimumab. Local recurrence free duration (LRFD) was significantly longer in Group-A patients (19.6 months, range 1.1-34.7 months) as compared to group-B patients (3 months, range 0.4-20.4 months), respectively (p=0.002). Post-SRS perilesional edema was more significant in Group-A. Conclusions: The effect of SRS and ipilimumab in attaining LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may effect LRFD and post-radiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

Transitional cell carcinoma (TCC) of the renal pelvis is a rare urological malignancy, with only a handful of cases of metastases to the brain reported in literature. We aim to present a case of intracranial metastasis in a female patient with history of renal pelvic carcinoma, and review existing literature of brain metastases from renal pelvic TCC. Methods: We searched PubMed, EMBASE, and MEDLINE from 1966 to January 2016 for published case reports written in English. Results: Five published case reports describe intracranial metastases from renal pelvic TCC. Our case is a 56-year-old woman with known high grade renal pelvic carcinoma and pulmonary metastases, who presented nine years after her initial diagnosis with mild left side weakness and headaches. She was found to have two lesions in the right cerebral hemisphere and underwent surgical resection of the larger right frontal lobe mass. Her neurologic symptoms improved postoperatively. She declined whole brain radiotherapy and remains stable at 6 months’ follow-up. This is the first published case of presentation of brain metastases from pelvic TCC more than 12 months after diagnosis of the primary cancer. Conclusion: There is minimal literature of renal pelvic TCC metastasizing to the brain. However, as systemic chemotherapy leads to improved survival from the primary cancer, it is possible for more cases to appear, necessitating increased awareness from the healthcare team.

Leptomeningeal metastasis is a serious complication of systemic cancer commonly occurring in later disease stages which affects approximately 10% of patients with solid tumors. The risk is highest for patients with lung cancer, melanoma and breast cancer. Survival at one year is in the range of 10%. Cerebrospinal fluid analysis and magnetic resonance imaging are the most important diagnostic measures. Treatment recommendations vary by primary tumor and pattern of disease, that is, e.g., the absence or presence of concurrent systemic or solid brain metastasis. To explore the current practice of diagnosing and treating leptomeningeal metastasis across Europe, a web-based survey was sent to members of the European Association of Neuro-Oncology (EANO) and the Brain Tumor Group of the European Organisation for Research and Treatment of Cancer (EORTC) in April 2016 which contains 24 questions on current practice patterns as well as 8 case presentations. The results of this survey will be presented for the first time. They shall serve as the basis for treatment recommendations for this complication of systemic cancer that reflects current knowledge as well as current practice.

Intracranial metastases from solid tumors are increasingly common, often brain or leptomeningeal metastases. Dural metastases are under-reported, present diagnostic and therapeutic challenges, and may mimic subdural hematoma or meningioma. This report describes 4 recent patients with dural metastases from breast cancer. A 60 year old woman, without known cancer, had 5 months of increasing headaches, left weakness, and focal seizures. Imaging showed an enlarging right frontal extra-axial enhancing mass with edema, initially thought to be a meningioma. At surgery the tumor involved overlying bone, replaced the dura, and invaded brain. Pathology was metastatic adenocarcinoma, ER/PR positive and Her-2 negative. Investigations showed a right breast primary, and lung and bone metastases. She received cranial radiotherapy (RT), letrozole and pamidronate. The tumor remains controlled after 40 months. The 3 other patients all had prior known breast cancer, 2 ER/PR positive and Her-2 negative, and 1 triple negative, ages 45-70 years. Two had known systemic metastases prior to neurological presentation. Presenting symptoms included headache, seizures, focal weakness, and confusion. All had new or progressive systemic metastases, including bone, at diagnosis of dural metastases. Two had resection of dural metastases, 1 with complicated postoperative course, with eventual improvement in both. Two received cranial RT, 1 refused RT, and all received hormonal or chemotherapy, with ongoing clinical or MRI control. These cases illustrate the complexity of dural metastases. Although patients often have extensive metastatic disease, treatment can improve symptoms and prolong survival.