Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over-expressed in the malignant brain tumour glioblastoma (GBM). It has been previously shown that epidermal growth factor receptors (EGFR) up-regulate Mcl-1 expression contributing to a cell survival response. Hypoxia is a poor prognostic marker in glioblastoma despite the fact that hypoxic regions have areas of necrosis. Hypoxic regions of GBM also highly express the pro-cell death Bcl-2 family member BNIP3, yet when BNIP3 is over-expressed in glioma cells, it induces cell death. The reasons for this discrepancy are unclear. METHODS: Using malignant glioma cell lines +/- hypoxia, gain and/or loss of function assays of BNIP3 or Mcl-1 were performed. BNIP3 and MCL-1 expression was assessed in GBM tumours from adult patients and human gliomas grown as xenografts in immunocompromised mice. RESULTS: Mcl-1 expression is reduced under hypoxia due to degradation by the E3 ligase FBW7 leading to increased hypoxia-induced cell death. This cell death is augmented by EGFR activation leading to increased Mcl-1 expression under hypoxia. Conversely, BNIP3 is over-expressed in hypoxia at times when Mcl-1 expression is decreased. Knocking down BNIP3 expression reduces hypoxia cell death and Mcl-1 expression effectively blocks BNIP3-induced cell death. Of significance, BNIP3 and Mcl-1 are co-localized under hypoxia in glioma cells, GBM tumours and in xenograft glioma tumours expressing mutant EGFR (EGFRvIII). CONCLUSION: These results support that Mcl-1 can block the ability of BNIP3 to induce cell death under hypoxia in GBM tumours

The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently down-regulated in a variety of malignancies. We characterized the role of Dicer in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells to form tumors in a mouse model of GB. DICER silencing in glioma stem-like cells (GSCs) reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER affects the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB.

Ionizing radiation (IR) is one of the conventional post-surgical treatments for Glioblastoma Multiforme (GBM). Mesenchymal stem cells (MSCs) constitute a subpopulation of bone marrow derived cells which are actively recruited to the site of radiation and/or tumour microenvironment (TME), both of which have important implications for neovascularization and tumor progression. The goal of this project is to investigate the functional contribution of MSCs in the TME. We postulate that Bone Marrow-MSCs promote radio-resistance in GBM via cell cycle arrest. We tested the effect of MSC on U87 glioblastoma cell line in response to IR. We found that MSC co-culture, MSC-conditioned media (MSCCM) and irradiated MSC-conditioned media (MSCIRCM) did not reduce IR-induced p53 (ser15) phosphorylation, signifying intact p53-dependent DNA damage pathway in all conditions. However, both MSCCM and MSCIRCM temporally increased phospho-Chk2, a kinase involved in ATM-dependent cascade and cell cycle arrest. This increase occurred at 24 hours and reverted to baseline levels by 48 hours. Interestingly, IR (15Gy) caused transiently heightened metabolic rate under MSC and MSC IRCM as opposed to IR-null treatment at 48 hours elevated cell proliferation. MSCCM, but not MSCIRCM, marginally reduced caspase 3/7-dependent apoptotic levels. The combination of IR and MSCCM as well as MSCIRCM first increased protein level of phospho-Chk2 at 24 hours; followed by increased metabolic rate at 48 hours; and lastly, boosted proliferation at 72 hours. This data combined proposes plausible machinery for BM-MSC mediated radio-resistance by initiating cell cycle arrest in tumour cells for DNA damage repair.

As the central component of heightened vascularization in glioblastoma (GBM), endothelial cells (EC) are arguably the most responsive stromal cells in the tumour microenvironment during conventional treatment using ionizing radiation (IR). Although the inherent tumor tropism and angiogenic property of mesenchymal stem cells (MSC) has been documented in many cancer types including GBM, little is known about the function of MSC that are recruited to the GBM tumor microenvironment. The purpose of this study was to elucidate the effect of MSC on irradiated EC. Here we studied the influence of IR, MSC or MSC condition media (CM) on human umbilical vein endothelial cells (HUVECs). IR was found to up-regulate mRNA levels of CXCL5, CXCL10, ICAM1, VCAM1, VEGF-c and tissue factor (TF) in a dose-dependent manner whereas MSC co-culture boosted the expression of ICAM1, VCAM1, VEGF-c, TF, and MCP3. An additive effect of IR and MSC-culture was most detected with respect to ICAM1, TF and CXCL5 under 2Gy. MSC co-culture decreased IR-induced phospho-p53 in HUVECs at 15Gy. In addition, IR decreased the level of phospho-Akt in HUVECs as well as cell proliferation. Notably, both effects were countered by MSC CM. Interestingly, up-regulation of the same set of IR-driven genes in GBM was positively correlated with poor survival in the TCGA GBM database, a correlation that was lost if using gene list that was obtained from IR and MSC combine. These findings suggest that MSC promotes angiogenesis in GBM by overturning the IR-induced active state of endothelial cells and rendering them radio-resistant.

We identified the G protein coupled relaxin receptor RXFP1 in glioblastoma (GB) and discovered C1q-tumor necrosis factor related protein 8 (CTRP8) as a novel ligand of RXFP1 in this common and most aggressive form of brain tumor. The known RXFP1 ligand relaxin isoform 2 (RLN2) is not expressed in the brain indicating that RXFP1 signaling in GB is activated by auto-/paracrine secretion of CTRP8. In GB, RXFP1 signaling included PI3K and PKC activation and resulted in the increased production and secretion of lysosomal protease cathepsin B, a known prognostic marker of GB. In the present study, we have investigated the potential role of RXFP1 in chemoresistance to the commonly used DNA alkylating drug temozolomide (TMZ) in human GB. Upon TMZ treatment, CTRP8/RLN2 mediated activation of RXFP1 was able to mitigate DNA damage in human primary GB cells and enhanced their survival. Activation of RXFP1 resulted in STAT3 pathway activation and the RXFP1- and STAT3-dependent up-regulation of proteins and their activity deemed important for TMZ-induced DNA damage repair. Furthermore, RXFP1 activation resulted in the up-regulation of key anti-apoptotic factors in human GB cells. Our results indicate a novel role for the CTRP8-RXFP1 ligand-receptor system in STAT3-dependent cell invasion, TMZ chemoresistance, and survival and identify RXFP1 as a new protective G protein coupled receptor in GB cells.

The most common brain cancer, glioblastoma (GBM), also has the worst five-year survival rates of all cancers. This is due in part to cancer stem cells, known as brain tumor initiating cells (BTICs), which initiate GBM and are resistant to current therapies. Thus, it is important to study therapeutics targeting BTICs. Innate immune cells, microglia and macrophages (MMs), are also important GBM-associated cells. GBM influences MMs to promote tumor growth. However, my research group discovered that an old drug, amphotericin B, re-stimulates MMs to secrete cytokines that inhibit BTIC self-renewal (Nature Neurosci 17:46-55, 2014). Hence, I hypothesize these cytokines are potential GBM treatments. Methods: Twenty genetically diverse BTIC lines were exposed to interleukin-8 (IL8), monocyte chemoattractant protein-1 (MCP1), and tumor necrosis factor-alpha (TNF), the cytokines secreted most abundantly by amphotericin-stimulated MMs. Assays for proliferation, differentiation, apoptosis, and cell cycle arrest were performed. BTICs were then co-cultured with human GBM-derived MMs stimulated with TNF. Lastly, the relationship between TNF receptors (TNFR1/2) and presumed BTICs was determined in frozen human GBM sections by immunofluorescence. Results: TNF had the most potent inhibitory effect on BTIC proliferation. Also, TNF was able to increase BTIC differentiation, and induce apoptosis and G1 cell cycle arrest. In MM-BTIC co-culture, TNF stimulated MMs to decrease sphere formation. Interestingly, in human GBM tissue TNFR1 co-labeled with OLIG2, a major transcription factor expressed in presumed BTICs, implicating TNF as a BTIC-specific treatment. Conclusion: TNF is a promising candidate for the treatment of GBM.

Tumours of the central nervous system are currently classified based on the 2007 WHO Classification of Tumours, which uses histological features to classify and grade these heterogeneous tumors. With recent advances in the development of clinically relevant molecular signatures, there is an interest to incorporate appropriate molecular markers in to the classification. The views of the neuro-oncology community on such changes would be informative for advising this process. METHODS A survey with 8 questions regarding molecular markers in tumor classification was sent to an email list of Society of Neuro-Oncology members and attendees of prior meetings (n=5065). There were 403 respondents. Analysis was performed using whole group response and based on self-reported sub-specialty. RESULTS Survey results among all respondents show support for incorporating our molecular knowledge of brain tumors into the WHO classification (>80%). As one example, 96% of respondents responded that the integration of 1p/19q co-deletion into the molecular classification of oligodendroglioma was “very” or “critically” important for the management of grade III gliomas. While 30% of all respondents believe that IDH mutation status should affect overall management of GBM. Interestingly, there was some variability among sub-specialties for certain aspects, and as one example neuropathologists were slightly more inclined to disagree that molecular markers should be included in the WHO classification (25% for neuropathologists versus 13% overall). CONCLUSION Based on a survey provided to the neuro-oncology community, we report strong support for the integration of molecular markers into the WHO classification of brain tumors, as well as for using an integrated “layered” diagnostic format.

In the current practice of pathology, the identification of cell markers and their respective distribution represents an indispensable dialogue for diagnostic, predictive, therapeutic, and research purposes. Early immunohistochemical protocols were limited to direct, fluorescent labeled antibodies, yielding quick results but lacking sensitivity. More recently, the use of indirect techniques –utilization of enzyme labels–and various detection systems have continued to advance the complexity of IHC, increasing both its specificity and sensitivity of detecting one or multiple antigen(s) (Ag) simultaneously. As such, IHC has become an affordable, powerful, and readily available means for the identification of candidate biomarkers (mostly lineage markers) in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Pathologists are now asked to “quantify” expression levels of differential prognostic markers–at microscopic level–using this arguably “non-quantitative” technique. Conventionally, histological grading relies mainly on manual counting of positively immunostained cells, a labour intensive protocol that may be associated with subjectivity, intra- and inter- observer variation and reproducibility issues. The subjectivity and lack of reproducibility has prompted the use of computer-assisted or fully automated image analysis technologies. Digital image acquisition systems are becoming commonplace and as such, the demand for complex assessments of digital images of histological slides must be matched with quantitative platforms. In this study, we aim to introduce a computer-assisted image-computing platform that is both accurate and efficient in quantification of isolated and heterogeneous candidate biomarkers in glioblastoma.

Pre-operative functional magnetic resonance imaging (fMRI) has emerged as valuable clinical tool to help surgically manage patients diagnosed with brain tumours. Surgical decision-making may be significantly improved through the provision of fMRI, however its clinical usage is contingent on the level of agreement with direct cortical stimulation (DCS). While previous studies have been undertaken to investigate the spatial agreement between fMRI and DCS, the influence that various factors may have on fMRI sensitivity and specificity is not fully clear. Thus, in a group of eight brain tumour patients who underwent pre-operative fMRI followed intra-operative DCS during an awake craniotomy procedure, we measured the agreement between the two brain mapping techniques looking at the influence of behavioural task, statistical threshold, and task standardization. Results: There were significant differences between motor and language mapping, where agreement was better for the former. Sensitivity and specificity shared an inverse relationship with increasing fMRI threshold, and were significantly reduced in the case where tasks were not standardized. Lastly, false positive occurrences were identified as the dominate source of error in comparison to false negative occurrences. Conclusion: Thus, the results from this work suggest that fMRI can predict intraoperative findings with good accuracy, however, sources of variability may significantly reduce the quality of fMRI data at the single-subject level. Neurosurgeons should carefully evaluate fMRI data with these considerations prior to its inclusion in the surgical-decision making process.

Recurrent GBM and AA have a dismal prognosis and a high unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that encodes the transgene cytosine deaminase (CD). Toca 511 selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) by CD within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. Clinical data from phase 1 trials are consistent with this mechanism of action, and show extended survival compared to historical controls. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care administered to patients undergoing resection for first or second recurrence of GBM or AA. Phase 2 will enroll 170 patients. Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven GBM or AA, measurable disease preoperatively of less than 5cm, candidate for equal or greater 80% resection of enhancing tumor based on pre-operative evaluation, and KPS equal or greater to 70. Assays for immune monitoring will be performed and molecular profiling of resected tumor samples will be correlated efficacy.

For decades, debate has persisted regarding the role of surgical resection in newly diagnosed glioblastoma. There is increasing evidence that extent of resection (EoR) is an independent prognostic factor. Previous work has proposed the inclusion of EoR in a risk stratification algorithm but does not incorporate account recent advances in the molecular characterization of tumours. We set out to investigate the effect of EoR on overall survival (OS), and to develop a stratification algorithm incorporating both EoR and modern molecular markers for prognostication. HYPOTHESIS: Greater EoR is independently associated with improved OS. METHODS: We examined 190 consecutive cases of histopathologically confirmed newly-diagnosed glioblastoma who were operated upon between January 1, 2012 and December 31, 2014. Variables including age, sex, postal code, KPS, tumour location, presenting symptoms, treatment history, date of progression, date of reoperation, as well as MGMT, IDH, 1p/19q codeletion, and ATRX status were recorded. Preoperative and postoperative MRIs were reviewed and volumetric tumour burden will be analyzed and EoR will be calculated. RESULTS: Preliminary EoR calculations (n=18) show a positive correlation between EoR and OS. CONCLUSION: A correlation exists between EoR and OS, although multivariable analysis is planned to exclude potential confounders. MRI review, chart review including molecular marker analysis and EoR calculations are ongoing.

Glioblastoma (GBM) is the most common brain cancer. Resistance to front-line systemic therapy with temozolomide (TMZ) is correlated with O6-methylguanine-DNA-methyltransferase (MGMT) expression. Second-line treatment with bevacizumab has not improved overall survival. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that has MGMT-independent cell-kill activity against GBM cell-lines and cancer stem cells in vitro. VAL-083 crosses the blood-brain barrier and showed promise against CNS tumors in prior NCI-sponsored clinical trials. The goal of this clinical trial is to determine appropriate VAL-083 dosing for advancement to Phase III trials as a new treatment for recurrent GBM. METHODS: Patients must have recurrent GBM following surgery, radiation, TMZ and bevacizumab. Phase I: Open-label, single-arm, dose-escalation study. Patients received VAL-083 on days 1,2,3 of a 21-day cycle, until reaching MTD. Phase II: Additional patients enrolled at MTD to further assess safety and outcomes. RESULTS: Phase I: 29 patients were enrolled across 9 dose cohorts (1.5-50 mg/m2/d). 40mg/m2/d was confirmed as MTD. Myelosuppression was mild; no drug-related serious adverse events were reported at doses up to 40mg/m2/d. Dose limiting G4 thrombocytopenia was observed at higher doses. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. A dose-related survival improvement was observed. Pharmacokinetic analyses show 1-2h plasma terminal half-life; average Cmax 781ng/mL at 40mg/m2/d. Phase II: 14 patients were enrolled at 40mg/m2/d. To date, safety observations in Phase II are consistent with Phase I. CONCLUSIONS: VAL-083 at 40mg/m2/d exhibits a favorable safety profile and dose-related trend toward clinically meaningful improved survival in refractory GBM patient

Glioblastoma (GBM) is the most common brain cancer. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for MGMT protein-expression and ensuing temozolomide-resistance. Second-line treatment with bevacizumab has not improved overall survival (OS). Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine, thus MGMT-independently inducing interstrand cross-links, DNA double-strand breaks and cell-death in GBM cell-lines and cancer stem cells. VAL-083 is currently in Phase I/II clinical trial for recurrent GBM, post-TMZ and post-bevacizumab. In this Phase II clinical trial, the main goal is to assess the 9-month OS in MGMT-unmethylated, recurrent, bevacizumab-naive GBM. RATIONALE: The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis and median survival after recurrence is 3-9 months. Chemotherapy regimens for these patients are lacking and there is a significant unmet medical need. Given VAL-083’s novel alkylating mechanism, promising clinical benefit, and favorable safety profile, a trial studying VAL-083 in MGMT-unmethylated recurrent GBM is warranted. METHOD: Randomized, non-comparative biomarker-driven Phase II clinical trial in MGMT-unmethylated GBM patients at first recurrence/progression, prior to bevacizumab. 48 patients will be randomized to receive VAL-083 or “standard-of-care” salvage drug lomustine. 32 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. 16 patients will receive lomustine 90 mg/m2/day on day 1 of a 42-day cycle. Patients will be followed until death or for at least 9 months from enrollment, whichever occurs earlier. Survival will be compared to the BELOB trial for recurrent MGMT-unmethylated GBM patients treated with lomustine.

Disparities in cancer survival rates have been identified for rural patients in Canada and are thought to be due to inequities in access to care. The objective was to perform the first examination of urban and rural brain cancer survival in Canada. Methods: A population-based retrospective cohort study was performed using Canadian Cancer Registry data for patients diagnosed with a primary brain cancer from 1996-2008. Seven major brain cancer histology groups used were glioblastoma, diffuse astrocytoma, glioma (not otherwise specified), oligodendroglioma, anaplastic astrocytoma, oligoastrocytic tumours, and anaplastic oligodendroglioma as categorized by the Central Brain Tumor Registry of the United States (CBTRUS). Kaplan-Meier (KM) survival estimates and Cox Proportional Hazards Regression were performed, adjusting for sex, histology, age group, region, and urban-rural residence. Rural residence was defined using Statistics Canada’s “Rural and Small Town” definition of living in a region with a population of less than 10,000 people. Results: No significant difference between urban and rural residence was identified in crude KM survival estimates. Though not significant, 5-year survival was generally better among rural residents than urban residents, except for rural residents with anaplastic astrocytoma. There remained no significant difference for Cox hazard ratios after adjustment for age, sex, or region. Conclusions: This is the first study to examine the effect of urban-rural residence on brain cancer survival. No significant differences for any histology were found, indicating equitable access to care for brain cancer patients in Canada, regardless of their location of residence.

Tumor treating electric fields (TTFields) are an established treatment for glioblastoma patients. But the anatomical and physical characteristics of the brain and tumor contributing to treatment efficacy are unknown. We contoured gross tumor volume (GTV) using ScanIP and measured tumor size according to the RANO criteria on 5 patients with recurrent glioblastomas who benefited from TTFields (cohort 1) and 5 who did not (cohort 2). Tumor surface area and geometric centroid distance (GCD) from the bilateral ventricles were computed. Wilcoxon rank sum test was used to compare these physical parameters between the two cohorts. The results showed that the respective median GTV was 11.6cm3 and 38.1cm3 (P=0.0591), while the respective median GCD was 5.0cm and 5.3cm (P=0.6761), in cohort 1 and 2. The tumor size had a median of 8.2cm2 in cohort 1, as compared to a median of 53.9cm2 in cohort 2 (P=0.0591). The surface area had a median of 56.2cm2 in cohort 1, as compared to a median of 214.0cm2 in cohort 2 (P=0.4034). After removing an outlier from cohort 1 and another from cohort 2, the respective median GTV was 9.7cm3 and 41.3cm3 (P=0.1003), and the respective median surface area was 46.5cm2 and 236.0cm2 (P=0.0304). The respective median surface area/GCD was 13.3cm and 38.9cm (P=0.0304) and the respective median GTV/GCD was 2.7cm2 and 8.5cm2 (P=0.0304). The data suggest that the ratio of surface area/GCD and GTV/GCD, which are proportional to the tissue capacitance, may be an important parameter for optimizing TTFields efficacy in the treatment of glioblastoma.

New enhancing lesions after surgery and chemoradiation for high grade glioma commonly contain variable proportions of tumor recurrence (TR), tissue necrosis and treatment related changes. Our purpose is to determine whether the pattern of contrast enhancement and perfusion MR parameters correlate with the percentage of TR in these lesions. Methods: We prospectively enrolled 30 patients with high grade gliomas who presented with a new enhancing lesion suspicious for tumor recurrence. Each patient underwent conventional MRI with DCE and DSC perfusion MRI. The pattern of enhancement was classified by a blinded neuroradiologist in 5 different categories (solid, focal nodular, peripheral rim, hazy, punctate). A hot spot region-of-interest analysis was performed for each parametric map (Ktrans, AUC, Vp, corrected CBV). TR percentage was defined histopathologically. The lesions were categorized into predominant TR (=tumor>70%), predominant treatment related changes (T=<35%) and mixed lesions (35 %< T=<70%). Differences between the groups were assessed via Kruskal-Wallis and Mann-Whitney U tests. Results: There were 32 lesions (4 predominantly treatment related lesions,5 mixed lesions,23 predominant tumor recurrence). There is no significant difference in the enhancement pattern between the three groups (p=0.18).Statistically significant difference was only seen for corrected CBV between the three groups (p=0.01), mainly between the mixed and predominant tumor groups. The rest of the perfusion parameters did not show a statistically significant difference between the groups(p>0.05). Conclusion: Corrected CBV might be useful in predicting the proportion of tumor recurrence in post-treatment high grade gliomas.

This study aims to evaluate the impact of preoperative functional magnetic resonance imaging (fMRI) on low grade glioma (LGG) patients’ outcomes and surgical planning. Methods In this retrospective matched cohort study of a single surgeon’s patients, we are comparing two groups of LGG patients (WHO grade II) based on exposure to fMRI. Sixteen LGG patients who underwent fMRI were selected, and 32 control (non-fMRI exposed) patients are being selected through propensity score matching from a pool of 764 brain tumour patients. To assess the impact of fMRI data on clinicians’ decision making process, neurosurgeons within a single centre are completing questionnaires regarding treatment options for each LGG fMRI patient based on clinical data and structural imaging before and after fMRI. Results Within the group of 16 LGG patients who have undergone fMRI studies over a 12-year period, most patients presented with seizures (81 percent), and most lesions were left-sided (81 percent) and frontal (75 percent). Patients underwent either craniotomy (50 percent), stereotactic biopsy (25 percent) or nonsurgically management (25 percent). In surgical patients, between presurgical assessment and eight week post-surgical follow-up, mean modified Rankin scale improved from 1.80 (sd 0.79) to 1.50 (sd 0.97). In our cohort, 5-year mortality was 12.5 percent (mean follow-up duration 5.46 years). Conclusions Data analysis is ongoing with plans to compare relevant patient demographics and outcomes, and to analyse questionnaires to elucidate how surgeons incorporate fMRI data into their therapeutic approach.

This study aims to evaluate reliability of clinical functional magnetic resonance imaging (fMRI) in identifying language lateralisation index (LI), verified with Edinburgh handedness inventory (EHI), in brain tumour patients. Methods In this retrospective study, 31 of a single surgeon’s brain tumour patients over a 12 year period have been selected. Lesion type varied, 12 (39 percent) were high grade gliomas, 10 (32 percent) low grade gliomas, 3 (10 percent) meningiomas, and 6 (19 percent) other types. Patients underwent language fMRI paradigms for preoperative assessment, and a neuroimaging analyst was able to identify an LI value for at least one Brodmann area (BA). For each paradigm, a neuroimaging analyst attempted to calculate LI for Wernicke’s area (BA 22) and Broca’s area (BA 44 and 45). Results Of 113 total LI values, 66 (58 percent) were concordant to EHI-predicted hemispheric dominance. Reliability of language LI appears dependent upon the type of language task performed. Verb generation correctly identified Broca’s area in 18 patients (64 percent) and Wernicke’s area in 11 patients (61 percent), sentence completion correctly identified Broca’s area in 18 patients (72 percent) and Wernicke’s area in 9 patients (60 percent), and naming correctly identified Broca’s area in 7 patients (47 percent) and Wernicke’s area in 3 patients (27 percent). Conclusions Results show limited correlation between language LI determined by fMRI and EHI. The main limitation of this study is that language LI is being compared to EHI, rather than gold standard measure of hemispheric dominance (e.g. Wada).

Primary CNS Lymphoma (PCNSL) is an unusual extranodal form of Non-Hodgkin’s lymphoma with a locally aggressive course but a rare tendency to disseminate systemically. It has been documented in that the clinical characteristics and response to treatment among Asians is comparable to the Western population yet no studies done locally are available. Objectives: This study aims to determine the clinico-pathologic profile of patients diagnosed with PCNSL seen at Philippine General Hospital (PGH) from January 2006 to September, 2014 and to evaluate the patients’ response to the following treatment modalities: 1) Combination chemotherapy 2) Chemo-RT 3) Single agent chemotherapy and 4) no specific anti-lymphoma treatment. Methodology: This is a descriptive and retrospective study that included all cases of histologically-proven PCNSL seen at the PGH from January 2006 to September, 2014. The clinical profile, imaging studies and biopsy findings were obtained from the patient records. The survival rates at the end of one and two years of diagnosis were computed. Results and Conclusion. Among patients diagnosed with PCNSL at PGH, there is a higher incidence of PCNSL among males with a male to female ratio of 1.4:1 and have a younger onset with a median age of 50.2 years. Most patients presented with signs of increase ICP and majority had solitary cortical lesions with histopathologic diagnosis of diffuse large B cell lymphoma. Patients who did not undergo any form of treatment had a mean survival of 10 months. Immunocompromised patients had a shorter life-span with a mean survival of 7.5 months. Treatment of combination chemotherapy with HD-MTX and Rituximab had the most favorable outcome followed by HD-MTX only with a 2 year survival rate of 100% and 66% respectively while patients who underwent chemo-RT had a 2 year survival rate of 33% with a high incidence of neurocognitive delay.

Primary intracranial sarcoma among patients diagnosed with HIV is rare. Case reports published have shown that there is an increasing number of cases of leiomyosarcoma, hemangiopericytoma and rhabdomyosarcoma among these patients. Further, there are also few reports that sarcomas may present atypically, sometimes mimicking a brain abscess. We report a case of a 26 year old male, newly diagnosed HIV, who presented with bilateral chronic suppurative otitis media associated fever, headache and vomiting. Neuroimaging showed with multiple rim enhancing masses on the left temporal, parietal and occipital areas and bilaterally sclerosed mastoid air cells. Initial impression was an otogenic abscess. Burrhole craniotomy and evacuation of the cystic masses was done. Histopathologic examination revealed a small round blue cell sarcoma. Different immunostains were done to differentiate the various subtypes of sarcomas possible. Patient was discharged improved but did not consent to chemotherapy or radiotherapy.