tbuckley/cabot-search huggingface dataset:
EPID-02. EFFECTS OF TREATMENT AND SOCIAL DEMOGRAPHICS ON ADULT MEDULLOBLASTOMA SURVIVAL
Authors: Nikita Pradhan, David Piccioni
Journal: Neuro-Oncology (2018)

Medulloblastoma in adults is exceedingly rare, and treatment strategies are largely derived from data in the pediatric medulloblastoma population. The aim of this study was to evaluate treatment patterns and survival in adults with medulloblastoma. We performed a retrospective study of the California Cancer Registry (CCR), to evaluate the effect of treatment variables and social demographics on survival in adults. Treatment and demographic data were extracted from the CCR for adult patients (18 years and older) with medulloblastoma. Patients were diagnosed from January 1, 1988 through December 31, 2010. We restricted the data to patients who had complete records for extent of resection, radiation, chemotherapy and demographic variables. Surgery was dichotomized to Gross Total Resection (GTR) and Subtotal Resection/Biopsy (STR/B). A total of 292 patients were included. Kaplan Meier (KM) survival curves were performed for OS. Bivariate and multivariate analyses were done by cox proportional hazard regression model for all variables. There were 245 cases of classic adult medulloblastoma, 40 desmoplastic, 6 large cell and 1 medullomyoblastoma. 37% underwent GTR and 63% had STR/B. 82% received radiation and 42% of the patients underwent some form of chemotherapy (single agent or multiagent). Median OS for patients undergoing GTR was not reached, vs 115 months for STR/biopsy (HR 0.585). Median OS for patients with radiation was significantly associated with improved OS (211 months vs 56 months, (HR 0.450). There was no survival advantage for patients who received chemotherapy (155 months with chemotherapy vs 180 months without, (HR 1.081). Multivariate analysis again showed GTR and radiation to be significant predictors of OS, but not chemotherapy. Marital status and age were significant predictors of OS, but not race or gender. Radiation and GTR were significantly associated with longer OS. Chemotherapy was not associated with an improvement in OS.
PATH-05. IMPLEMENTATION OF A TARGETED NEXT-GENERATION SEQUENCING PANEL FOR THE DIAGNOSIS AND PRECISION MEDICINE TREATMENT OF ADULT PATIENTS WITH WHO GRADE IV DIFFUSE GLIOMAS
Authors: Yalan Zhang, Annette Molinaro, Jennifer Clarke, Nancy Ann Oberheim Bush, Jennie Taylor, Nicholas Butowski, Susan Chang, Manish Aghi, Michael McDermott, Philip Theodosopoulos, Shawn Hervey-Jumper, Mitchel Berger, Arie Perry, Joanna J Phillips, Andrew Bollen, Tarik Tihan, Melike Pekmezci, David Solomon
Journal: Neuro-Oncology (2018)

Analysis of tumors via next-generation sequencing is now routinely used in clinical practice. The UCSF500 NGS panel became available starting in June 2015. In Dec 2017, a glioblastoma precision medicine initiative started at our institution to sequence all newly-diagnosed WHO grade IV diffuse gliomas. We review our experience over a 3-year period. The UCSF500 Cancer Panel assesses approximately 500 cancer-associated genes for mutations, copy number alterations, and structural rearrangements, including fusions. The test can be run on tumor DNA alone or compared with normal DNA, allowing for discrimination of germline variants. Sequencing results are analyzed by a neuropathologist with genomics expertise (D.A.S.). Results from the 165 adult WHO grade IV diffuse glioma cases sequenced to date were analyzed, including 136 glioblastomas, IDH-wildtype; 19 glioblastomas, IDH-mutant; and 10 diffuse midline gliomas, H3 K27M-mutant. Among the 136 IDH-wildtype glioblastomas, the most common alterations were in TERT, EGFR, CDKN2A, PTEN, NF1, TP53, PIK3R1, PDGFRA, CDK4, MDM2, LZTR1, and STAG2. Among the 19 IDH-mutant glioblastomas, the most common additional alterations were in TP53, ATRX, CDKN2A, and PDGFRA. Paired germline sequencing was performed on 71 patients, ten of which were found to harbor a germline mutation associated with increased cancer risk, including the CHEK2, MSH2, and NF1 genes. Somatic hypermutation was present in nine cases, four at initial resection and five at recurrence with a temozolomide-associated mutational signature. Among the four treatment-naïve glioblastomas with hypermutation, two were Lynch syndrome-associated in patients with damaging germline mutations in MSH2, and two were sporadic tumors that harbored somatic mutations in mismatch repair genes. CONCLUSIONS: Genomic profiling in adult glioblastoma patients results in identification of potentially actionable genetic alterations and also previously unknown germline mutations associated with increased cancer risk. A subset of glioblastomas (approximately 5%) harbor somatic hypermutation, indicating potential utility of immune checkpoint inhibition.
RTHP-28. REPEAT SALVAGE GAMMA KNIFE RADIOSURGERY FOR RECURRENT GLIOBLASTOMA
Authors: Gregory Hermann, Mujtaba Soniwala, Andrew Goraj, Kavitha Prezzano, Dheerendra Prasad
Journal: Neuro-Oncology (2018)

Our institutional practice has been to treat recurrent glioblastoma (GB) with gamma knife radiosurgery (GK). We evaluated survival outcomes in these patients. This was a single institution review of patients with GB who underwent a definitive course of postoperative external beam radiotherapy (EBRT) with concurrent chemotherapy and subsequently treated with GK for recurrence or progression between 2006 and 2017. Overall survival (OS) was determined using Kaplan-Meier statistics. 87 patients were identified with median age of 55 years. Median follow-up was 21.1 months. The majority of patients underwent gross total (57%) or subtotal resection (38%). 23 (26%) underwent surgery for recurrence. The median marginal dose for first GK was 17 Gy and 14 Gy for patients with 1 target or >1 target, respectively. 4 patients underwent fractionated GK treatment with 18–25 Gy in 3–5 fractions. 20 patients underwent a second GK treatment and 1 patient was treated three times. Time from first to second GK was 6 months, with a median marginal dose for second or third GK of 15 Gy. 10 patients underwent a second course of EBRT ranging from 30–59.4 Gy in 10–33 fractions; 2 patients received stereotactic body radiation therapy with 25 Gy in 5 fractions. Median OS was 21.4 months. 2- and 5-year OS was 41.8% and 9.9%, respectively. Median survival after first and second GK was 9.6 months and 4.7 months, respectively. There was a trend towards improved OS for patients treated with both EBRT and GK compared to GK alone (Median OS: 2.85 years vs 1.75 years, p=0.14). DISCUSSION: To our knowledge, this study reports on the largest cohort of patients treated with salvage GK for recurrent GB. The survival outcomes compare favorably to contemporary trials. Future studies will include an analysis of toxicity and patterns of failure.
RBTT-09. THE EFFICACY OF KETOGENIC DIET WITH CONCOMITANT INTRANASAL PERILLYL ALCOHOL AS A NOVEL STRATEGY FOR THERAPY OF RECURRENT GLIOBLASTOMA
Authors: Clovis Fonseca, Juliana Santos, Thereza Santos, Wanise Cruz
Journal: Neuro-Oncology (2018)

It has been hypothesized that persistent ketotic hypoglycemia might represent a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against TMZ-resistant glioma cells, regardless of MGMT promoter methylation status. This study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH administered with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. Thirty-two patients were divided into two groups - KD or standard diet, both associated with intranasal POH (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, while receiving inhalation of POH (55 mg, four times daily) in an uninterrupted administration schedule for three months. Neurological examination and imaging analysis were used to monitor disease progression. Clinical toxicity and overall survival following treatment were correlated with tumor size, topography, extent of peritumoral edema, and frequency of seizures. In the KD patient, strict compliance with the KD was confirmed by measuring the levels of ketone bodies in the urine (9/17 patients) at three times a week. After three months of well tolerated treatment, we observed a partial response in 77.8% (7/9 patients), stable disease in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease. Among the patients assigned to the standard diet (control group), the partial response was 25% (2/8 patients), stable disease was 25% (2/8), and progressive disease was 50% (4/8 patients). The patients assigned to the KD group presented: reduced frequency of seizures; a slight increase in lean muscle mass; reduced serum lipid levels; and decreased low-density lipoprotein cholesterol (LDL-C) levels. Our results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM
Hypercalcaemia with undetectable parathormone levels
Authors: Ilaria Muller, Lakdasa D Premawardhana
Journal: BMJ (2018)

A 54 year old woman had unintentional weight loss of 12-19 kg with nausea, abdominal discomfort, and constipation over 2-3 months.She presented acutely with profuse vomiting for three days.She was taking venlafaxine 150 mg/day for bipolar disorder, she smoked (40 pack years), consumed little alcohol, and had no family history of disease.On examination, she was dehydrated, her blood pressure was 106/74 mm Hg, pulse 122 beats/min and regular, and her
CSIG-01. GLYCOPHOSPHATIDYLINOSITOL TRANSAMIDASE (GPIT) SUBUNIT GPAA1 IS OVEREXPRESSED IN GLIOBLASTOMA MULTIFORME (GBM) CELL LINES AND CONTRIBUTES TO TUMOR CELL MIGRATION
Authors: Blake Johnson, Martin Tremwell, Sheldon McCown, Zhongpeng Lu, Karen Abbott
Journal: Neuro-Oncology (2018)

The glycophosphatidylinositol (GPI) anchor is a highly conserved lipid and glycan modification added to the C-terminus of substrate proteins in the endoplasmic reticulum via the activity of the multi-subunit GPI transamidase, or GPIT. Several subunits of the GPIT, namely GPAA1, have previously been characterized as oncogenes across a variety of tumor types. Using a C. septicum alpha toxin enrichment strategy pioneered by our lab, we have previously documented significantly elevated plasma levels of GPI anchored proteins occurring in glioblastoma (GBM) patients relative to non-malignant controls. To better understand the biological significance of GPIT expression and subsequent activity in GBM, we have combined the use of qRT-PCR, immunoblot analysis, chemotaxis and clonogenic assays, with targeted alpha toxin glycoproteomics. Using these methods, we have documented significant increases in GPIT subunit expression in human GBM cell lines relative to normal human astrocyte controls. The observed increases in GPIT expression levels corresponded with increases in GPI anchored protein content. In addition, we found GPAA1-targeted knockdown in U87-MG is sufficient to significantly decrease both tumor cell migration and clonogenic cell growth relative to non-targeted control U87-MG. Collectively, these results suggest that GPIT and GPI anchors are involved in the tumorigenicity of GBM and may represent novel therapeutic alternatives in this disease.
PATH-15. MICROGLIA/MACROPHAGES ARE THE MAJOR TUMOR-ASSOCIATED IMMUNE CELLS IN PILOCYTIC ASTROCYTOMA
Authors: Jie Chen, Namita Sinha, Tarik Tihan, Ayca Ersen, Joanna J Phillips, David Gutmann, Sonika Dahiya
Journal: Neuro-Oncology (2018)

Pilocytic astrocytoma is the most common glioma in children. Although most pilocytic astrocytomas are surgically curable, a small subset does recur and demonstrates CSF dissemination. BRAF-targeted therapies have been applied in recurrent pilocytic astrocytomas. However, a small subset of these tumors lack BRAF alterations. More recently, there has been an emerging role of tumor-associated immune cells (including microglia/macrophages) in gliomagenesis with an attempt to find additional targets as standalone or combined adjuvant therapy. In this study, we investigated composition of different tumor-associated immune cells in pilocytic astrocytomas. Tissue microarrays from 55 pilocytic astrocytomas were generated. Immunohistochemistry for CD3, CD20, CD21, CD68, and CD163 was performed to label different tumor-associated immune cells (T-cells, B-cells, dendritic cells, and microglia/macrophages respectively.) Tumor-associated microglia/macrophages were found at moderate to markedly high density in most pilocytic astrocytomas. CD163 and CD68 positive microglia/macrophages comprised >10% of cells in 67% (37/55), and 60% (33/55) cases. These microglia/macrophages presented as either scattered infiltrate and/or perivascular aggregates. In contrast to microglia/macrophages, lymphocytes and dendritic cells were only found at sparse-to-moderate density. In conclusion, our study reveals that microglia/macrophages are the major tumor-associated immune cells in pilocytic astrocytomas, at least in this small cohort, and raises the possibility of extrapolating tumor-associated microglia/macrophages as a potential therapeutic target in pilocytic astrocytomas.
HDP101, a Novel B-Cell Maturation Antigen (BCMA)-Targeted Antibody Conjugated to α-Amanitin, Is Active Against Myeloma with Preferential Efficacy Against Pre-Clinical Models of Deletion 17p
Authors: Ram Kumar Singh, Richard J. Jones, Samuel Hong, Fazal Shirazi, Hua Wang, Isere Kuiatse, Andreas Pahl, Robert Z. Orlowski
Journal: Blood (2018)
Abstract 15754: The Prevalence of Electronic Health Record-Based Clinical Phenotypes in Patients With Pathogenetic Variants Associated With Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Christopher M Haggerty, Sarah A Pendergrass, Marci Barr, Joseph B Leader, Dustin N Hartzel, Marylyn D Ritchie, David J Carey, David H Ledbetter, Marc S Williams, Frederick E Dewey, Alexander Lopez, John Penn, John D Overton, Jeffrey G Reid, Michael F Murray, Brandon K Fornwalt
Journal: Circulation (2015)

Objective Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare myocardial disorder. Genetic etiology is ascribed to variants in 8 genes ( PKP2 , DSP , DSC2 , DSG2 , JUP , TMEM43 , TGFβ2 , RYR2 ). We aimed to establish the prevalence and clinical phenotype of individuals with pathogenic variants (PV) in these genes from an unselected cohort. Methods Whole-exome sequences for 31,036 patients in the MyCode™ Biorepository were evaluated for pathogenic or likely pathogenic (P/LP) ARVC variants reported in ClinVar or the ARVC database. Composite ICD-9 data from the electronic health records of PV individuals vs a non-PV control group were analyzed. Results 57 P/LP variants were identified in 240 individuals (0.77%), aged 61 ± 19 years. Characteristics of this PV group versus a non-PV control group are summarized in the table. Zero patients in the PV group had a documented diagnosis of ARVC. Use of implantable cardioverter defibrillators—the primary treatment for ARVC—was rare. Of individuals ≥55 years, 24% with PV had no history of cardiac disease (vs. 22% for non-PV). However, there was a modest increase in the prevalence of cardiac electrical abnormalities (e.g., tachycardia, fibrillation) in PV vs. non-PV. There was also a trend towards increased diagnoses of 'other primary cardiomyopathy'. Conclusions The prevalence of reported pathogenic ARVC variants (0.77%) greatly exceeds the disease prevalence (0.02 - 0.10%). In this cohort of 240 genotype-positive subjects, there was little evidence of overt ARVC disease, suggesting that the positive-predictive value for classic ARVC in individuals with an incidental positive genetic finding is low. The increased risk of certain clinical findings, not specific to ARVC, supports the notion that the spectrum of phenotypes associated with pathogenic variants in these genes is broader than classically described. Targeted “deep phenotyping” is needed to assess subclinical phenotypes in genomically screened populations.
STEM-26. MICROENVIRONMENTAL FGF2 INDUCES GLIOBLASTOMA STEM CELLS THROUGH THE FGFR1-ZEB1 AXIS
Authors: Ana Jimenez-Pascual, Anja Kordowski, Pugh Jamie, Daniel Silver, Karl Holmberg Olausson, Kevin Ashelford, Karin Forsberg Nilsson, Florian Siebzehnrubl
Journal: Neuro-Oncology (2018)

Glioblastoma is the most lethal and aggressive brain cancer in adults. Poor prognosis is due to resilience to therapy and tumour recurrence, which have been linked to glioblastoma stem-like cells (GSCs). FGF2 and its cognate receptors have been linked to malignancy and progression in glioma, and FGF2 is frequently employed in GSC culture paradigms. The specific mechanisms of how this growth factor promotes stemness and malignancy in glioblastoma remain incompletely understood. Therefore, we analysed expression of FGF receptors (FGFRs) and the effects of FGF2 on patient-derived glioblastoma cell lines. We found that FGF2 induces expression of the stemness-associated transcription factor ZEB1, increases sphere formation frequency and cell migration. Analysis of FGF receptor expression and function using knockdown approaches in patient-derived glioblastoma cell lines revealed that FGFR1 is relevant for stem cell maintenance. FGFR1 knockdown reduces sphere and colony formation, and increases survival in a xenograft mouse model. Analysis of large-scale gene-expression datasets revealed association of FGFR1 in mesenchymal glioblastoma, and increased FGFR1 expression in 30–40% of cases. We identify FGFR1 as a potential GSC marker and therapeutic target.
GENE-36. ABERRANT ACTIVE-ENHANCERS ASSOCIATED WITH DOWNREGULATION OF HDAC1-RET FINGER PROTEIN COMPLEX OVERCOME CHEMORESISTANCE IN GLIOBLASTOMA
Authors: Masaki Hirano, Melissa Ranjit, Fumiharu Ohka, Kosuke Aoki, Akane Yamamichi, Takuya Kato, Keitaro Matsuo, Atsushi Enomoto, Masahide Takahashi, Toshihiko Wakabayashi, Atsushi Natsume
Journal: Neuro-Oncology (2018)

RET finger protein (RFP) plays a pivotal role in the acquisition of chemoresistance via formation of a complex with nuclear transcription factor Y and histone deacetylase 1, producing specific enhancer activity. We hypothesized that chemoresistance mediated by RFP may result from aberrant deacetylation of H3K27 and dysregulation of novel cis-regulatory (active) enhancers. Therefore, we investigated the effects of RFP on active enhancers and gene expression and evaluated the effects of RFP depletion on the growth of glioma cells treated with temozolomide both in vitro and in vivo. We found that the combination of RFP depletion and TMZ treatment markedly suppressed the growth of glioma cells and extended the survival time of intracranial tumor-bearing mice compared to that of TMZ alone. Chromatin immunoprecipitation and whole-transcriptome sequencing revealed that RFP depletion weakened a significant number of enhancers, and diminished RNA with functions related to mitosis, DNA-dependent DNA replication and cell cycle. Further, the transcriptomes of FOXO1 and TBP2 were significantly increased, while that of PARP-binding protein (PARPBP) was decreased, resulting in induction of reactive oxygen species and cell death. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of histone H3K27 and dysregulation of RFP-associated active-enhancers in glioma and that the combination of targeting RFP and TMZ has potential as an effective novel treatment strategy for lethal glioma.
INNV-45. RADIANS: A MULTIDISCIPLINARY CENTRAL NERVOUS SYSTEM CLINIC MODEL FOR RADIATION ONCOLOGY AND NEUROSURGERY PRACTICE
Authors: Shearwood McClelland, Timur Mitin, Jerry Jaboin, Jeremy Ciporen
Journal: Neuro-Oncology (2018)

Radiation therapy for central nervous system disease commonly involves clinical collaboration between the disciplines of Radiation Oncology and Neurological Surgery. Unfortunately such collaboration has been rarely implemented in the outpatient clinic setting. We describe our experience with a multidisciplinary clinic model featuring radiation oncology in tandem with neurosurgery in a community hospital setting. In August 2016, we initiated the novel RADIANS (RADIation oncology And NeuroSurgery) clinic model at a community hospital, with the fundamental idea being to establish a weekly time where patients could receive input from both disciplines during a single clinic visit. Disease and treatment demographics were collected and analyzed. Patient satisfaction was assessed via survey questionnaire, where both radiation oncology and neurosurgery attendings were blinded to both the administration of and patient responses in surveys. The majority of patients were seen for metastatic disease of the brain and/or spine. Of patients receiving radiation, most received stereotactic radiosurgery (SRS)/SBRT rather than conventional fractionation. Survey responses revealed that 86% found that having a consultation with two physicians at the same time in the same room “was a totally new experience”. All responders found that having two physicians at the same time was “a better way to be evaluated than simply having two separate appointments with these two physicians”, while describing the dynamics of the evaluation process as being shared equally between the radiation oncologist and neurosurgeon. The majority of radiation therapy provided through the RADIANS clinic model has been SRS/SBRT rather than conventional fractionation. The model is popular with patients, most of whom present with brain and/or spine metastatic disease. Continued meticulous collection and analysis of outcomes will be needed to rigorously evaluate the long-term impact of RADIANS.
Abstract 17048: Prognostic Implication of Enlarged Left Ventricle in Patients Who Underwent Valve Surgery due to Mitral Valve Prolapse or Flail Mitral Valve: Volume versus Dimension
Authors: Jeong Yoon Jang, Se Hun Kang, Jae Seok Bae, Cheol Hyun Lee, Yu Na Kim, Min Soo Cho, Dae-Hee Kim, Jong-Min Song, Duk-Hyun Kang, Jae-Kwan Song
Journal: Circulation (2015)

Introduction: Left ventricular end-systolic dimension (LVESD) has been being used to guide the optimal timing of surgery in patients with mitral valve prolapse (MVP) or flail mitral valve (FMV). We sought to evaluate whether LVES volume (LVESV) measured by echocardiography can provide additive prognostic information. Methods: Of patients who underwent MV surgery due to MVP or FMV from 2000 to 2014, after exclusion of patients whose rhythm was atrial fibrillation or who needed concomitant maze procedure, aortic valve or coronary bypass surgery, a total of 648 patients (age 51±14 years; ejection fraction 64±7%; LVESD 38±6 mm; LVESV 60±26 mL; repair/replacement = 612/36) was selected. Clinical outcomes included cardiovascular (CV) death, admission due to heart failure (HF) and development of LV dysfunction (EF &lt;45% at the last follow-up). Results: During median follow up of 4.2 years (interquartile range, 1.8-6.6 years), 5 patients died of CV death, 36 admitted for HF, and 38 developed LV dysfunction. Increased LVESD (≥45mm) could not predict CV death. But patients with enlarged LVESV index (LVESV/ body surface area ≥50 ml/m 2 , n=64, 10%) showed higher rate of CV death (p=0.04), HF admission (p=0.04) and composite clinical events (p&lt;0.001). In multivariate regression analysis, enlarged LVESV index was the only independent variable associated with composite clinical events (hazard ratio 2.67, 95% confidence interval 1.39-5.13, p=0.003). Conclusions: In the modern era of MV repair surgery for MVP and FMV, LV volume provides more robust prognostic information than LV dimension.