bluuebunny/crossref_metadata_2025 huggingface dataset:
OS6 - 210 Gliomas in Young Adults: Presence of Mutations in Histone Genes
Authors: Munoz D. G. , Ryall S. , Das S. , Hawkins C.
Published: October 2016

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.
OS7 - 145 Combination Immunotherapy for Glioma: Beyond PD 1 Inhibition
Authors: Curry W.
Published: October 2016

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.
OS13 - 175 Genetic Profiling of Radiation Induced Meningiomas
Authors: Tonge P. , Agnihotri S. , Jalali S. , Aldape K. , Zadeh G.
Published: October 2016

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.
OS14 - 208 The prognostic role of pre-operative complete blood count (CBC) in progression-free survival in patients with meningioma
Authors: Karimi S. , Tonge P.D. , Gonen L. , Tabasinejad R. , Zadeh G. , Aldape K.
Published: October 2016

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.
PS1 - 159 A Case of Intracranial Metastases from Renal Pelvic Carcinoma and Review of Literature
Authors: Ghare A. , Haji F. , Boulton M.
Published: October 2016

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.
PS1 - 188 Rehabilitation Consultation: An Integrated Model for Addressing Rehabilitation Concerns in the Primary Brain Tumor Population
Authors: Lax I. , Daniels M. , Kanter C. , Mason W. , Edelstein K.
Published: October 2016

Individuals with primary brain tumors experience a range of physical, cognitive and psychosocial sequelae which impact their independence, safety and quality of life. These impairments may be addressed through rehabilitation intervention. Despite acknowledgement that timely rehabilitation services over the course of the disease process is of benefit, few outpatient neuro-oncology treatment teams include a rehabilitation professional. Purpose: The aims are: (1) to describe a rehabilitation consultation model of care integrated into outpatient neuro-oncology treatment for individuals with primary brain tumors; and (2) to describe the characteristics of individuals referred for rehabilitation services. Methods: This retrospective descriptive study examined data from 200 individuals that received rehabilitation consultation from January 2015 to March 2016 at Princess Margaret Hospital, Pencer Brain Tumor Centre. Information on patient demographics, referral characteristics, and number of patient care visits was collected. Descriptive statistics were calculated. Preliminary Results: Of all patients, (n=195), the most common diagnosis is glioblastoma, 39% (n=76), and 50% are 50-69 years of age (M=55, SD=15.0). The most common reason for initial referral was decline in physical functioning, strength and balance (41%). In 77% of cases, patients were seen immediately at the time of referral. In total, 540 consultations were completed (face-to-face=230, telephone=310) with 2.78 on average (SD=4.0) per patient. Conclusion: Given the range of symptoms that individuals with primary brain tumors experience coupled with changes in functional status as the disease progresses, integrated and timely rehabilitation consultation is feasible.
PS1 - 186 Needs Assessment for a Pediatric Proton Therapy Program in Canada
Authors: Patel S. , Whitlock J. A. , Olivotto I.A. , Parliament M. , Laperriere N. , Bouffet E. , Eisenstat D.D.
Published: October 2016

Proton therapy enables normal tissue sparing for curative-intent treatment of children with cancer who require radiation therapy. In the USA and elsewhere, proton therapy is being rapidly adopted, and many new proton centres are being established. Without a proton centre in Canada, children and their families must travel abroad for treatment at high cost and has raised the question whether a Canadian proton therapy facility is needed. METHODS: Canadian Pediatric Oncology centres were surveyed to assess current and future clinical practices. Needs were modeled by screening the Alberta Cancer Registry, ascertaining the number of children eligible for proton RT and comparing to the number who actually received this therapy. RESULTS: Most centres (63%) referred children, and 49 children were referred abroad between 2008 and 2013. Referrals were estimated to increase to 36 cases per annum across Canada. Most respondents (75%) supported that proton therapy will reduce late effects in most or selected cases compared to photon therapy. The registry search revealed 37,170 patients irradiated of which 379 children (1.0%) were potentially eligible for proton therapy, accounting for 15.9% of the new cases of childhood cancers diagnosed in Alberta over the interval. CONCLUSIONS: A strong perceived need for a pediatric proton therapy in Canada was identified. Proton therapy utilization was lower than modeled needs. Future referrals are anticipated to increase, with annual estimated cost of approximately $60 million spent outside of Canada that could be invested within the Canadian health care economy. These issues are worthy of further national discussion.
PS2 - 153 Dianhydrogalactitol (VAL-083) Treatment Causes Irreparable DNA Double-Strand Breaks, S/G2 Phase Cell-Cycle Arrest and Cell Death in Cancer Cells
Authors: Zhai B. , Steino A. , Bacha J. , Brown D. , Daugaard M.
Published: October 2016

Dianhydrogalactitol (VAL-083) is a unique bi-functional alkylating agent causing N7-guanine-methylation and inter-strand DNA crosslinks. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tumor tissue and has shown activity in prior NCI-sponsored clinical trials against various cancers, including glioblastoma (GBM) and medulloblastoma. VAL-083 is also active against GBM cancer stem cells and acts as a radiosensitizer independent of O6-methylguanine-DNA methyltransferase activity (in contrast to e.g. temozolomide and BCNU). Here we report new insights into VAL-083 mechanism of action by showing that VAL-083 induces irreversible cell-cycle arrest and cell death caused by replication-dependent DNA damage. In lung (H2122, H1792, H23, A549) and prostate (PC3, LNCaP) cancer cell lines VAL-083 treatment caused irreversible S/G2 cell-cycle arrest and cell death (IC50 range 3.06-25.7 µM). VAL-083 pulse-treatment led to persistent phosphorylation of DNA double-strand breaks (DSB) sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X, suggesting persistent DNA lesions. After 10 months in culture with increasing VAL-083 concentrations, H1792 and LNCaP cells survive at concentrations up to 9.4 µM and 7.4 µM, respectively, suggesting that efficient resistance mechanisms are not easily acquired by the cancer cells. Taken together with previous results showing that VAL-083 circumvents cisplatin-resistance and is less dependent on p53 activity than cisplatin, these results suggest a molecular mechanism for VAL-083 that differs from both TMZ, BCNU and cisplatin. They further suggest that irreparable DNA damage induced by VAL-083 is impervious to common strategies employed by cancer cells to escape effects of alkylating drugs used in GBM treatment.
PS2 - 171 Bmi1 Identifies Treatment-Refractory Stem Cells in Human Glioblastoma
Authors: Vora P. , Qazi M. , Venugopal C. , Subapanditha M. , Mahendram S. , Chokshi C. , Singh M. , Bakhshinyan D. , McFarlane N. , Singh S.
Published: October 2016

Glioblastoma (GBM) is an aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. We hypothesize that brain tumor initiating cells (BTICs), a subpopulation of treatment-resistant cells with stem cell properties cause tumor relapse and a subset of neural stem cell genes regulate BTIC self-renewal, driving GBM recurrence. We adapted the existing treatment protocol for adults with primary GBM for in vivo treatment of immunocompromised mice engrafted with GBMs. Post-chemoradiotherapy, the recovered GFP+GBMs were profiled for self-renewal and expression of critical stem cell genes. Using invitro and invivo gain-of-function/loss-of-function experiments, we investigated the regulatory functions of Bmi1 in primary neural stem & progenitor cells (NSPCs) and GBM tumor formation. Finally, global RNA-Seq profiling was performed to understand the consequences of Bmi1 dysregulation on target gene expression. GBM cells showed an increase in Bmi1 levels post-chemoradiotherapy, suggesting the presence of a treatment-refractory BTICs. GFP+cells extracted from treated xenografts had higher self-renewal and BTIC marker expression. Although treated mice responded to therapy, we observed tumor relapse with increased Bmi1 expression. Knockdown of Bmi1 diminished self-renewal and proliferation of GBM cells and delayed tumorigenesis, highlighting a critical role for Bmi1 in tumor maintenance. Conversely, over-expressing Bmi1 in NSPCs failed to initiate tumor formation in vivo. Using high-throughput sequencing data, we generated a map of signaling pathways dysregulated in GBM that may lead to tumor recurrence. Our data confirms the existence of a rare treatment-refractory BTIC population with enhanced self-renewal capacity that escapes therapy and drives tumor relapse.
PS2 - 174 Hexokinase 2 Drives Radio-Resistance through ERK Signaling and Sensitizes Cells to Azole Compounds
Authors: Agnihotri S. , Li M. , Wilson M.R. , Burrell K. , Alamsahebpour A. , Aldape K. , Zadeh G.
Published: October 2016

Our ongoing work has demonstrated that hexokinase 2 (HK2) but not HK1 or HK3 is a critical mediator of tumour glycolysis and mitochondrial metabolism in Glioblastoma (GB). Furthermore, HK2 is highly expressed in GB but not in normal brain making it an attractive therapeutic target. Our current findings now support that loss of HK2 alters tumor vasculature, increases sensitivity to radiation, and confers a significant survival benefit in several GB xenograft-bearing mice. Using a genome wide transcript analysis, we identified that loss of HK2 attenuates several pro-growth signaling pathways in GB including ERK signaling. Mechanistically, ERK rescue experiments in HK2 depleted cells rescues cell sensitivity to radiation and reduces DNA damage. Furthermore using a systems biology approach and a rationale drug screen we identified several antifungal agents in the azole class as to inhibit tumor metabolism and growth in HK2 expressing GB cells. Loss of HK2 in GB cells dampened the effect of several azoles suggesting that the mechanism of action is mediated in part through HK2. Furthermore, we tested several azole compounds known to cross the blood brain barrier in vivo. Clinically achievable doses of azoles as single agents increased survival in several orthotopic xenograft GB mouse models. In summary, HK2 drives several oncogenic pathways associated with GB including ERK signaling and sensitizes tumour cells to the azole class of antifungals. Future work will determine whether azoles work synergistically with radiation and temozolomide and elucidate the mechanisms by which they inhibit GB growth in HK2 expressing cells.
PS2 - 201 Bone Marrow-Derived Mesenchymal Stem Cells-Mediated Radioresistance in Glioma
Authors: Zhao T. , Zadeh G.
Published: October 2016

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.
PS2 - 203 Bone Marrow-Derived Mesenchymal Stem Cells Reverse Ionizing Radiation-Induced Active State of Endothelial Cells in Glioblastoma
Authors: Zhao T. , Metcalf J. , Zadeh G.
Published: October 2016

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.
PS2 - 195 Integrating Molecular Workings into the World Health Organization (WHO) Classification of Tumours of the Central Nervous System: A Survey from the Neuro-Oncology Community
Authors: Nejad R. , Louis D.N. , Aldape K. , Zadeh G.
Published: October 2016

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.
PC3 - 155 Phase II Study of Dianhydrogalactitol in Patients with MGMT-Unmethylated, Bevacizumab-Naïve Recurrent Glioblastoma
Authors: O'Brien B.J. , Bacha J.A. , Brown D.M. , Steino A. , Schwartz R. , Kanekal S. , Lopez L.M. , Penas-Prado M.
Published: October 2016

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.
PC3 - 179 Analysis of Glioblastoma Physical Characteristics in Patients Benefiting from Tumor Treating Electric Fields Therapy
Authors: San P.P. , Timmons J. , Lok E. , Swanson K.D. , Wong E.T.
Published: October 2016

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.
PC3 - 128 Clinical Profile and Treatment Outcomes of Patients with Primary CNS Lymphoma in a Tertiary Hospital in the Philippines: An Eight-Year Retrospective Review
Authors: Concepcion Sales M.C.
Published: October 2016

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.
PC3 - 129 Primary Intracranial Round Cell Sarcoma in an HIV Patient: A Case Report and a Review of Literature
Authors: Concepcion Sales M.C.
Published: October 2016

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.
PC3 - 142 Gamma Knife Radiosurgery in Patients with Persistent Acromegaly or Cushing’s Disease: Long-Term Risk of Hypopituitarism
Authors: Cohen-Inbar O.
Published: October 2016

For patient with a recurrent or residual acromegaly or Cushing’s disease (CD) after resection, Gamma knife radiosurgery (GKRS) is often used. Hypopituitarism is the most common adverse effect after GKRS treatment. The paucity of studies with long-term follow up has hampered understanding of the latent risks of hypopituitarism in patients with a Acromegaly or CD. We report the long-term risks of hypopituitarism for patients treated with GKRS for Acromegaly or CD. Methods: From a prospectively created, IRB approved database, we identified all patients with a Acromegaly or CD treated with GKRS at the University of Virginia from 1989 to 2008. Only patients with a minimum endocrine follow up of 60 months were included. The median follow-up is 159.5 months (60.1-278). Thorough radiological and endocrine assessments were performed immediately before GKRS and at regular follow-up intervals. New onset of hypopituitarism was defined as pituitary hormone deficits after GKRS requiring corresponding hormone replacement. Results: 60 patients with either Acromegaly or CD were included. Median tumor volume at time of GKRS was 1.3 cm3 (0.3-13.4), median margin dose was 25 Gy (6-30). GKRS induced new pituitary deficiency occurred in 58.3% (n=35) of patients. Growth Hormone deficiency was most common (28.3%, n=17). The actuarial overall rates of hypopituitarism at 3, 5, and 10 years were 10%, 21.7%, and 53.3%, respectively. The median time to hypopituitarism was 61 months after GKRS (range, 12-160). Cavernous sinus invasion of the tumor was found to correlate with the occurrence of a new or progressive hypopituitarism after GKRS (p=0.018). Conclusions: Delayed hypopituitarism increases as a function of time after radiosurgery. Hormone axes appear to vary in terms of radiosensitivity. Patients with adenoma in the cavernous sinus are more prone to develop loss of pituitary function after GKRS.
PC3 - 157 Subependymal Giant Cell Astrocytoma (SEGA) in Adults without Tuberous Sclerosis
Authors: MacDonald D.R. , MacDonald M.J. , Megyesi J.F. , Hammond R.R.
Published: October 2016

Subependymal giant cell astrocytoma (SEGA) is typically seen in children with tuberous sclerosis (TS), who present with headaches and seizures, and characteristic clinical and cutaneous manifestations of TS. Surgical resection, CSF diversion (for hydrocephalus), radiotherapy, and chemotherapy with a mammalian target of rapamycin (mTOR) inhibitor are treatment options. SEGA can occur in adults without TS, raising diagnostic and therapeutic challenges. A 53 year old man presented with headaches and diplopia. An exophytic, enhancing mass in the left lateral ventricle was resected, confirming SEGA. There was no recurrence on MRI 13 months later. He previously had an “astrocytoma” involving the left frontal horn resected at age 19. Pathology review was SEGA. He had no clinical or cutaneous findings of TS, and no family history of TS. An identical twin was well. A 66 year old man presented with “weakness”, due to diuretic-induced hypokalemia. CT showed a hypodense mass from the right caudate head deforming the frontal horn. MRI showed an exophytic, enhancing mass from the caudate head into the frontal horn. A stereotactic biopsy confirmed SEGA. He had no clinical or cutaneous findings of TS, and negative family history. His mother had a meningioma resected at age 66. Observation is planned. These 2 adult patients had SEGA without clear clinical findings or family history of TS. SEGA should be in the differential diagnosis of tumors involving the lateral ventricle.
Linear stability and weakly nonlinear analysis of the flow past rotating spheres
Authors: Citro V. , Tchoufag J. , Fabre D. , Giannetti F. , Luchini P.
Published: October 2016

We study the flow past a sphere rotating in the transverse direction with respect to the incoming uniform flow, and particularly consider the stability features of the wake as a function of the Reynolds number $Re$ and the sphere dimensionless rotation rate $\unicode[STIX]{x1D6FA}$. Direct numerical simulations and three-dimensional global stability analyses are performed in the ranges $150\leqslant \mathit{Re}\leqslant 300$ and $0\leqslant \unicode[STIX]{x1D6FA}\leqslant 1.2$. We first describe the base flow, computed as the steady solution of the Navier–Stokes equation, with special attention to the structure of the recirculating region and to the lift force exerted on the sphere. The stability analysis of this base flow shows the existence of two different unstable modes, which occur in different regions of the $Re/\unicode[STIX]{x1D6FA}$ parameter plane. Mode I, which exists for weak rotations ($\unicode[STIX]{x1D6FA}<0.4$), is similar to the unsteady mode existing for a non-rotating sphere. Mode II, which exists for larger rotations ($\unicode[STIX]{x1D6FA}>0.7$), is characterized by a larger frequency. Both modes preserve the planar symmetry of the base flow. We detail the structure of these eigenmodes, as well as their structural sensitivity, using adjoint methods. Considering small rotations, we then compare the numerical results with those obtained using weakly nonlinear approaches. We show that the steady bifurcation occurring for $Re>212$ for a non-rotating sphere is changed into an imperfect bifurcation, unveiling the existence of two other base-flow solutions which are always unstable.
Stability of a liquid film flowing down an inclined anisotropic and inhomogeneous porous layer: an analytical description
Authors: Deepu P. , Kallurkar Srinivas , Anand Prateek , Basu Saptarshi
Published: October 2016

We study the effect of anisotropy and inhomogeneity in the permeability of the porous layer on the stability of surface waves of an inclined fluid–porous double-layer system. The fluid is assumed to be Newtonian and the porous layer to be Darcian. The porous layer is saturated with the same fluid and the two layers are coupled at the interface via the Beavers–Joseph condition. Linear stability analysis is performed based on a long-wave approximation. The resulting eigenvalue problem is exactly solved up to third order in the wavenumber. The anisotropic behaviour of permeability, cross-stream component of permeability, surface tension and porosity are found to have only higher-order effects on the stability characteristics of the system. On the other hand, the inhomogeneous feature in the streamwise component of permeability play a dominant role in determining the stability of the gravity-driven surface waves; as do other system parameters such as the thickness of the fluid layer relative to that of the porous layer and the Beavers–Joseph coefficient.
Reynolds averaged turbulence modelling using deep neural networks with embedded invariance
Authors: Ling Julia , Kurzawski Andrew , Templeton Jeremy
Published: October 2016

There exists significant demand for improved Reynolds-averaged Navier–Stokes (RANS) turbulence models that are informed by and can represent a richer set of turbulence physics. This paper presents a method of using deep neural networks to learn a model for the Reynolds stress anisotropy tensor from high-fidelity simulation data. A novel neural network architecture is proposed which uses a multiplicative layer with an invariant tensor basis to embed Galilean invariance into the predicted anisotropy tensor. It is demonstrated that this neural network architecture provides improved prediction accuracy compared with a generic neural network architecture that does not embed this invariance property. The Reynolds stress anisotropy predictions of this invariant neural network are propagated through to the velocity field for two test cases. For both test cases, significant improvement versus baseline RANS linear eddy viscosity and nonlinear eddy viscosity models is demonstrated.
Robust identification of dynamically distinct regions in stratified turbulence
Authors: Portwood G. D. , de Bruyn Kops S. M. , Taylor J. R. , Salehipour H. , Caulfield C. P.
Published: October 2016

We present a new robust method for identifying three dynamically distinct regions in a stratified turbulent flow, which we characterise as quiescent flow, intermittent layers and turbulent patches. The method uses the cumulative filtered distribution function of the local density gradient to identify each region. We apply it to data from direct numerical simulations of homogeneous stratified turbulence, with unity Prandtl number, resolved on up to $8192\times 8192\times 4096$ grid points. In addition to classifying regions consistently with contour plots of potential enstrophy, our method identifies quiescent regions as regions where $\unicode[STIX]{x1D716}/\unicode[STIX]{x1D708}N^{2}\sim O(1)$, layers as regions where $\unicode[STIX]{x1D716}/\unicode[STIX]{x1D708}N^{2}\sim O(10)$ and patches as regions where $\unicode[STIX]{x1D716}/\unicode[STIX]{x1D708}N^{2}\sim O(100)$. Here, $\unicode[STIX]{x1D716}$ is the dissipation rate of turbulence kinetic energy, $\unicode[STIX]{x1D708}$ is the kinematic viscosity and $N$ is the (overall) buoyancy frequency. By far the highest local dissipation and mixing rates, and the majority of dissipation and mixing, occur in patch regions, even when patch regions occupy only 5 % of the flow volume. We conjecture that treating stratified turbulence as an instantaneous assemblage of these different regions in varying proportions may explain some of the apparently highly scattered flow dynamics and statistics previously reported in the literature.
Englacial latent-heat transfer has limited influence on seaward ice flux in western Greenland
Authors: POINAR KRISTIN , JOUGHIN IAN , LENAERTS JAN T. M. , VAN DEN BROEKE MICHIEL R.
Published: October 2016

Surface meltwater can refreeze within firn layers and crevasses to warm ice through latent-heat transfer on decadal to millennial timescales. Earlier work posited that the consequent softening of the ice might accelerate ice flow, potentially increasing ice-sheet mass loss. Here, we calculate the effect of meltwater refreezing on ice temperature and softness in the Pâkitsoq (near Swiss Camp) and Jakobshavn Isbræ regions of western Greenland using a numeric model and existing borehole measurements. We show that in the Jakobshavn catchment, meltwater percolation within the firn warms the ice at depth by 3–5°C. By contrast, meltwater refreezing in crevasses (cryo-hydrologic warming) at depths of ~300 m warms the ice in Pâkitsoq by up to 10°C, but this causes minimal increase in ice motion (<10 m a−1). Pâkitsoq is representative of western Greenland's land-terminating ice, where the slow movement of ice through a wide ablation zone provides ideal conditions for cryo-hydrologic warming to occur. We find that only ~37% of the western Greenland ice flux, however, travels through such areas. Overall, our findings suggest that cryo-hydrologic warming will likely have only a limited effect on the dynamic evolution of the Greenland ice sheet.
New species of the conodontNeogondolellafrom the Anisian (Middle Triassic) of northeastern British Columbia, Canada, and their importance for regional correlation
Authors: Golding Martyn L. , Orchard Michael J.
Published: October 2016

Eight new species of the conodontNeogondolellaare described from the Anisian (Middle Triassic) of northeastern British Columbia. The subtlety of morphological variation in this conodont genus has hampered biostratigraphical correlation, but large, often independently dated collections have enabled the description ofN.cuneiforme,N.curva,N.hastata,N.dilacerata,N.indicta,N.panlaurentia,N.tenera, andN.vellicatan. spp. Several of these species are widespread, as specimens ofN.curva,N.hastata,N.indicta,N.panlaurentia,N.tenera, andN.vellicataare found in contemporary collections from Nevada, whereasN.panlaurentiahas also been recovered from the Canadian Arctic. This distribution promises to significantly improve correlation among Anisian sections in North America.
Exploration for Late Cretaceous turbidites in the Equatorial African and northeast South American margins
Authors: Kelly J. , Doust H.
Published: October 2016

The Suriname–Guyana and Ghana–Ivorian Basins exhibit strong geological similarities which are of interest from a petroleum exploration point of view. These include (1) a well-developed system of Late Cretaceous erosional canyons allowing coarse-grained shallow-water clastics to enter the deep marine basin to form attractive turbidite exploration targets; (2) a broad shelf with strong longshore currents which sort and transport coarse clastics into the canyon heads; (3) an organic-rich Cenomanian–Turonian hydrocarbon source rock which is thermally mature in the centre of the basin; and (4) a series of extensional fault-networks along the shelf margin that extend upwards from the Rift Sequence into the overlying Drift Sequence and which, along with the canyon geometries, enable migrating oil and gas to accumulate in combination structural and stratigraphic traps. In June 2007, Tullow and its partners made an important discovery in offshore Ghana, at Mahogany, which subsequently became the giant Jubilee field. Tullow is currently applying the same geoscientific technologies in offshore Suriname in the search for analogous subtle combination traps.
Modernity, Islamic Traditions, and the Good Life: An Outline of the Modern Muslim Subjectivities Project
Authors: Jung Dietrich
Published: October 2016

This article provides a brief overview of the heuristic framework of the Modern Muslim Subjectivities Project that is being conducted at the University of Southern Denmark as of the writing of this article. The project explores ways in which Islamic traditions have played a role in the construction of modern Muslim subjectivities. Applying a problem-driven perspective, it selectively borrows from theories of successive modernities, sociology of religion, and poststructuralist approaches to modern subjectivity formation, introducing a novel heuristic framework to the field of Islamic studies. In posing the question as to the ways in which Muslims have constructed modern selfhoods, the project combines studies on Islamic reform, young Muslims in Egypt and Denmark, (post)modern Sufism, Islamic higher education, and changing notions of intimacy in two Egyptian revolutions. In criticizing the alleged exclusivity of Western modernity, the project wants to make original contributions to both conceptual discussions in the humanities and our knowledge of modern Muslim societies.
Revolutions, Crises of Modernities, and the Production of Gender Subjectivities in Egypt
Authors: Hatem Mervat F.
Published: October 2016

A primary concern of this project is to integrate the discussion of gender and gender subjectivities in the discussion of the overall dynamics of revolutions including the conditions that led to them, the understanding of their different actors, and their agendas for change. Another focuses on understanding the way revolutions and the crises of modernity to which they responded influenced the production of gender subjectivities and contributed, in turn, to the development of working subjects who were also private actors shaped by technologies of the self that helped them deal with complex tensions and dilemmas.