tbuckley/cabot-search huggingface dataset:
QOLP-03. END OF LIFE PHASE IN GLIOBLASTOMA: PROSPECTIVE ASSESSMENT OF SYMPTOM BURDEN AND SYMPTOM INTERFERENCE IN THE END OF LIFE PHASE- FINAL ANALYSIS
Authors: Tobias Walbert, Lonni Schultz
Journal: Neuro-Oncology (2018)

PURPOSE: To prospectively study symptoms and quality of life in terminal stage Glioblastoma (GBM) patients. End-of-life (EoL) symptoms of patients with GBM are poorly understood and have not been prospectively assessed in larger outpatient cohorts. The aim of this study was to assess prominent EoL symptoms in GBM to guide future treatment decisions and palliative care guidelines. Prospective single-center study assessing symptoms and QoL of GBM patients with low performance status (Karnofsky Performance Status 3rd line therapy with bevacizumab and showing clinical and radiological progression. The MD Anderson Symptom Inventory Brain Tumor Module and neurological assessments were used upon enrollment and during bi-weekly phone calls with patients and caregivers. Mixed models were used to assess changes over time for symptoms and interferences over the last 14 weeks prior to death. Data from 50 patient-caregiver dyads was available for interpretation. The highest reported symptoms during the EoL phase with significant progression (p‹0.01) were: Drowsiness, concentration, fatigue, speaking and understanding. High symptoms that did not progress significantly were remembering and weakness. 24% of all patients reported seizures, but the overall reported impact on symptom burden was low and did not increase in the EoL phase. Pain and GI symptoms were rated low and without significant progression. Interference scores for activity, work, relations, walking, enjoyment of life and decision making were high and increased significantly during the EoL phase. This is the final analysis of a large prospective study assessing EoL symptoms in GBM outpatients. Patients have severe symptom burden affecting decision making in the last weeks of life. Traditional cancer symptoms such as nausea, vomiting and pain were low. Palliative care should focus on early advance care planning and decision making.
HOUT-02. VARIATION IN POST-OPERATIVE LENGTH OF STAY IN NEURO-ONCOLOGIC SURGERY
Authors: Saksham Gupta, Blake Hauser, Lisa Caulley, Ian Dunn, Wenya (Linda) Bi
Journal: Neuro-Oncology (2018)

Little is known about the predictors of post-operative length of stay (LOS) following brain tumor resection or the influence of LOS on post-operative outcomes. We assessed associations between LOS and 30-day post-operative morbidity, mortality, and readmission in a nationwide retrospective cohort study of Americans who underwent resection of an intracranial tumor. The analysis included data collected from the NSQIP 2006–2015 and NHDS 1970–2010 registries in a multivariable logistic regression. 16,101 craniotomy for tumor cases were identified in NSQIP with a median age of 58 years (IQR 47–67). Median post-operative length of stay was 3 days (IQR 2–6). Patients with LOS of 1–2 days after craniotomy were deemed early discharge (26%), 3–5 days was considered an intermediate LOS (46%), while 6+ days of LOS was considered late discharge (28%). Predictors of early discharge included male sex, white race, young age, functional independence, low chronic disease burden, low ASA score, shorter operative length, supratentorial location, and cranial nerve tumor histology (p Early discharge following craniotomy for tumor resection was associated with decreased likelihood of post-operative medical complications, readmission, and death as compared to late discharge. Select patients may benefit from personalized discharge planning that prioritizes shorter LOS.
CSIG-14. ALPHA-CARDIAC ACTIN 1 IS EXPRESSED IN MEDULLOBLASTOMA AND MAY PLAY A ROLE IN CELL SURVIVAL DURING MITOTIC INHIBITION
Authors: Rahul Suresh, Rita Lo, Daniel Picard, Marc Remke, Roberto Diaz
Journal: Neuro-Oncology (2018)

We have previously demonstrated that Myc-overexpressing medulloblastoma cells are sensitive to apoptosis induction in response to mitotic inhibition with an Aurora kinase B inhibitor. Profiling of differential mRNA expression by microarray and RT-PCR revealed that alpha cardiac actin 1 (ACTC1) mRNA expression is upregulated in cells resistant to apoptosis triggered by Aurora kinase B inhibition and this upregulation is absent in Myc-overexpressing cells. We confirmed expression of ACTC1 protein by Western blot in SHH subgroup (DAOY, UW228, UW426) and Group 3 subgroup cell lines (D458, D425) and observed that expression is lower in Group 3 cells. These findings were further validated by analysis of ACTC1 mRNA expression among all four medulloblastoma subgroups by microarray in a set of 763 medulloblastomas which revealed increased expression of ACTC1 in SHH and WNT subgroups compared to Group 3 and Group 4. Inhibition of Aurora kinase B in SHH cells that overexpress Myc results in a reduction in ACTC1 protein level after 96 hours and this is not observed in the isotype control cells with basal Myc expression. Reduction in ACTC1 protein levels in SHH cells overexpressing Myc is associated with Caspase 3 cleavage. ACTC1 may play a role in blocking apoptosis triggered by mitotic inhibition in medulloblastoma. Further experiments to test this hypothesis are planned. These finding could potentially impact on chemotherapy choice in the treatment of SHH and WNT tumours, which demonstrate increased ACTC1 expression.
Effect of pre-existing Hepatitis C NS3 Q80K variant in Genotype la and NS5A Y93H variant in Genotype 3 for interferon-free treatment combinations with direct antiviral agents (DAAs) : Real-life experience from a multicenter study in Sweden and Norway
Authors: Hege Kileng, Midori Kjellin, Assar Bergfors, Ann-Sofi Duberg, Lars Wesslen, Astrid Danielsson, Magnhild G. Kristiansen, Tore Gutteberg, Anders Lannergard, Johan Lennerstrand
Journal: Hepatology (2016)

Effect of pre-existing Hepatitis C NS3 Q80K variant in Genotype la and NS5A Y93H variant in Genotype 3 for interferon-free treatment combinations with direct antiviral agents (DAAs) : Real-life experience from a multicenter study in Sweden and Norway
Abstract 14033: Clinical and Molecular Evidence of a Gene Dosage Effect in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Related to Multiple Genetic Mutations: A Report From the PACES CPVT Registry
Authors: Thomas M Roston, Martin J LaPage, Zhiguang Yuchi, Anjan S Batra, Yaniv Bar-Cohen, Chris Anderson, Yung R Lau, Kathleen Maginot, Lynn Kimlicka, Roman A Gebauer, Susan Etheridge, James E Potts, Filip Van Petegem, Shubhayan Sanatani
Journal: Circulation (2017)

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare genetic arrhythmia disorder with variable penetrance and expressivity. The double gene dosage effect, whereby ≥2...
Want Fries With That?
Authors: Peter Louis Loper
Journal: Annals of Internal Medicine (2018)

On Being a Doctor6 November 2018Want Fries With That?Peter Louis Loper Jr., MDPeter Louis Loper Jr., MDPalmetto Health–University of South Carolina Medical Group, Columbia, South Carolina (P.L.L.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-2250 Audio Reading - “Want Fries With That?” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Want Fries With That?," by P.L. Loper Jr. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Motivated purely by curiosity, I wandered into a fast-food franchise the other day. I stood there, fascinated, amid the swirl of activity, the efficiency of service, the long lines of customers, and I listened, observed, and imagined. The provider greeted the customer with an enchanting smile and without hesitation served up to the hungry customer fats, grease, and calories that would ultimately be transformed into obesity, diabetes, and heart disease. The time for each encounter between provider and customer was, all told, about 10 minutes. The provider, head down, staring into the computer monitor, entered the data necessary for swift ... Author, Article, and Disclosure InformationAffiliations: Palmetto Health–University of South Carolina Medical Group, Columbia, South Carolina (P.L.L.)Corresponding Author: Peter Louis Loper Jr., MD, Palmetto Health–University of South Carolina Medical Group, 3555 Harden Street Extension, 15 Medical Park, Suite 141, Columbia, SC 29203; e-mail, peter.[email protected]org. PreviousarticleNextarticle Advertisement Audio Reading - “Want Fries With That?” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Want Fries With That?," by P.L. Loper Jr. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 6 November 2018Volume 169, Issue 9Page: 656KeywordsChildrenComputersFatsHealth careObesityOpioidsOverweightQuality of lifeSleepSodium ePublished: 6 November 2018 Issue Published: 6 November 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
PDTM-41. SUPER ELONGATION COMPLEX-MEDIATED TRANSCRIPTIONAL DEPENDENCY IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: Nathan Dahl, Sujatha Venkataraman, Ilango Balakrishnan, Krishna Madhavan, Susan Fosmire, Dong Wang, Rajeev Vibhakar
Journal: Neuro-Oncology (2018)

Mutations in the histone 3 (H3) gene (H3K27M) are the eponymous driver in diffuse midline gliomas (DMGs), aggressive pediatric brain tumors for which no curative therapy currently exists. Emerging understanding of H3K27M biology suggests that secondary factors are required to promote oncogenesis. In order to identify specific epigenetic co-operators, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DMG cell lines. This identified AFF4, a component of the super elongation complex (SEC), as critical for DMG viability. We hypothesized that AFF4 promotes DMG tumorigenesis by co-operating with the H3K27M mutation to suppress scheduled transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. We found that AFF4 expression is consistently elevated in both DMG patient samples and established cell lines relative to the normal pediatric pons. We interrogated the role of AFF4 in H3K27M-mutant DMG using an shRNA lentiviral approach. Using live cell imaging, we demonstrate a significant decrease in in vitro clonogenicity and stem cell maintenance following AFF4 depletion. We employed RNA-seq-based gene set enrichment analysis to delineate downstream transcriptional changes under AFF4 regulatory control. Finally, we sought to determine whether CDK9, the catalytic subunit of the SEC, represents a therapeutic vulnerability in DMG. Using a combination of CDK9 overexpression and pharmacologic inhibition, we demonstrate that the disordered regulatory input of the SEC in DMG is dependent on the kinase activity of CDK9 and that this may be exploited through small molecule inhibition in both in vitro and in vivo patient-derived xenograft models. These studies represent the first pre-clinical validation of SEC inhibition as a novel therapeutic approach in pediatric DMG.
DDIS-06. AAV TOOLKIT ENABLING PRECISION COMBINATORIAL VIROTHERAPY FOR GLIOBLASTOMA
Authors: Hunter Futch, Adam Grippin, Zino Kuhn, Lan Hoang-Minh, Van Truong, Joshua Nelson, Nicole Hao, Pedro Cruz, Yong Ran, Brent Reynolds, Duane Mitchell, Todd Golde
Journal: Neuro-Oncology (2018)

Glioblastoma represents the most common and deadly type of brain tumor in adults. Although it is widely recognized that combinatorial therapeutic approaches may be necessary to achieve lasting remission or cure, identification of novel combinatorial therapies is challenging. Despite the availability of a number of potent and intuitively combined biologic monotherapies, the cost of performing studies using multiple biologic agents is prohibitive, and delivery of therapeutics within the brain is often difficult. Recombinant Adeno Associated Viral (rAAV) vectors have become the preferred vector for human gene therapy applications because of their flexibility, ease of production, and translatability from mouse to human studies. We developed a method for rapid screening of cell lines for rAAV transduction efficiency using 29 different capsid serotypes. In addition, we created a large array of rAAV-encoded transgenes that are designed to enhance immune recognition or to have anti-proliferative, anti-invasive, or direct cytotoxic effects on brain tumor cells. The transgenes were engineered with a novel multimerization domain that increases expression several fold compared to unmodified transgenes. Our methods allow for high expression of transgene products that are secreted into the brain tumor microenvironment and act in a non cell-autonomous manner, while potentially avoiding the systemic toxicities associated with such therapeutic cocktails. We screened 14 primary human glioblastoma cell lines and several murine glioma cell lines, identifying AAV capsid serotypes that are capable of high efficiency transduction in vitro. This in vitro screen was reflective for the transduction of tumor and brain microenvironment seen by the serotypes in vivo. Efficacy studies of cocktails of anti-tumor transgenes delivered via rAAV in vivo are under way. We present the use of rAAV vectors encoding biologic agents as a technology accelerator for the preclinical identification of novel combinatorial therapy regimens for glioblastoma.
DRES-16. HYPOXIC MICROENVIRONMENT DETECTED BY FRP-170 PET MAY INDUCE THE EXPRESSION OF DRUG RESISTANCE GENES IN THE PATIENT WITH GLIOBLASTOMA
Authors: Tatsuya Abe, Ikuko Morisaki, Yasutomo Momii, Takahiro Fudaba, Minoru Fujiki, Motofumi Kouguchi, Hiroshi Ito, Tomihiro Wakamiya, Yukiko Nakahara
Journal: Neuro-Oncology (2018)

The brain tumor cells can survive regardless of hypoxia and undernutrition. Hypoxia is known to be causes of resistance to radio-chemotherapy, increased recurrent and poor prognosis. Recent reports demonstrated that cancer stem cells (CSCs) exist in hypoxic lesion of the tumor. In this study, we examined the mechanism of drug resistance under hypoxic condition in vitro and in vivo. Most of brain tumor patients are treated by temozolomide (TMZ) as chemotherapy. The efficiency and resistance of TMZ are associated with the O6-methylguanine-DNA methyltransferase (MGMT) gene. In addition, MGMT expression is induced by hypoxia, and regulated by N-myc downstream regulated gene 1 (NDRG1). We investigated the expression of these genes in glioma cell lines (GCs), glioma stem cells (GSCs), and clinical specimens detected by molecular hypoxia imaging, 18F-FRP170 PET. Some hypoxic clinical specimens showed the increased expression of MGMT and NDGR1 genes. However, GBM cell lines and GSCs showed increased expression of NDRG1 and decreased expression of MGMT. These data suggest that a hypoxic microenvironment in vivo might play an important role in molecular and phenotypic profile of tumor cells including cancer stem cells.
ACTR-17. EVOPHOSPHAMIDE (TH-302) FOR RECURRENT GBM FOLLOWING BEVACIZUMAB FAILURE, FINAL RESULTS OF A MULTICENTER PHASE II STUDY
Authors: Andrew J Brenner, David Reardon, Patrick Wen, Shiliang Huang, Peter Fox, Mark Muzi, Eudocia Lee
Journal: Neuro-Oncology (2018)

INTRODUCTION: Evophosphamide is a hypoxia-activated prodrug that, when activated in hypoxic conditions, (<0.5% O2), releases the bis-alkylating agent bromo-isophosphoramide mustard (Br-IPM). Our prior phase 1 study in recurrent GBM (rGBM) with dose expansion showed preliminary activity with a 24% objective response rate and a 26% PFS rate at 4 months. A multicenter, single-arm, two-stage prospective study, non-blinded with combination therapy with bevacizumab at 10 mg/kg intravenously (IV) every 2 weeks and TH-302 at 670 mg/m2 IV every 2 weeks, in 6 week cycles, until disease progression. The primary endpoint was progression free survival at 4 months (PFS4). Patients underwent baseline assessment for hypoxic burden by 18F-misonidazole PET, dynamic susceptibility contrast (DSC) perfusion imaging, and serum sampling for biomarker analysis. 36 patients received study drug. Treatment was well tolerated, with adverse events as expected and the most common toxicity rash along the perineum. The PFS4 rate was 25% which met the primary endpoint and compares favorably with historical controls (10%). Biomarker analysis revealed progression to be correlated with Tmax on DSC perfusion (HR=0.8, 95% CI 0.66 to 9.96, p=0.02), ratio of enhancement on anatomic MRI Ratio (HR=9.37, 95% CI 1.18 to 74.5, p=0.03) and survival was most closely correlated with hypoxic volume on FMISO PET (HR=1.02, 95% CI 1 to 1.04, p=0.01). CONCLUSION: Evofosfamide has modest activity in bevacizumab refractory glioblastoma, with progression and survival correlated with radiographic features at baseline.
QOLP-26. PATIENT REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM (PROMIS) SCREENING FOR ANXIETY &amp; DEPRESSION IN CENTRAL NERVOUS SYSTEM(CNS) CANCER: LARGE COHORT REPORT FROM THE NEURO-ONCOLOGY BRANCH NATURAL HISTORY STUDY (NOB-NHS).
Authors: Nancy Garren, Elizabeth Vera, Orwa Aboud, Alvina Acquaye, Lisa Boris, Miranda Brown, Sonja Crandon, Ming Ji, Jason Levine, Jennifer Reyes, Carlos Romo, Christine Siegel, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2018)

Emotional distress, including anxiety and depression, is associated with significant morbidity. Studies in CNS tumor patients have been limited by small non-diverse samples. The NOB-NHS includes screening for depression and anxiety patients undergoing longitudinal care in the NOB. In a previously reported pilot study, anxiety(11%) and depression(15%), and association with performance status and use of psychotropic medications were reported. This report attempts to validate these findings in a larger more diverse cohort. All patients(n= 269) enrolled in the NOB-NHS were screened for depression and anxiety using PROMIS measures. Descriptive statistics and standardized classification of moderate-severe depression and anxiety are used to describe the sample characteristics. Emotional Distress was defined as PROMIS T scores-> 60 on depression, anxiety, or both scales. Chi-square and Fishers exact tests were used to identify associations. Significance level was set at p< 0.05. The sample was primarily white(82%), males(61%), 54 months(0–398) from diagnosis, with a median age of 49(21–81), good performance status(KPS 90, 75%) and a high-grade neoplasm(63%) with glioblastoma(30%) the most common diagnosis. Significant emotional distress was present in 19% of the sample. Poor performance status(28%) and use of psychotropic medications(32%) were both significantly associated with emotional distress(X2(1)= 4.8, p< 0.03 and X2(1)= 7.4,p< 0.01), respectively. Past recurrence(25%), progression/pseudo-progression on MRI(26%), female gender(23%), corticosteroid use(28%) and non-glioblastoma(21%) had higher incidence of distress, although not significant. Tumor location, age and disease status was not associated with emotional distress in this sample. This is one of the largest reported cohorts using screening measures for emotional distress in this population and confirms earlier findings of association with functional status and psychotropic medications. Future studies will investigate longitudinal trends, diagnostic referrals, and emotional distress phenotypes, including genomic predisposition, to improve individual patient/population care.
NIMG-75. WHO 2016 GRADE II GLIOMA MOLECULAR SUBTYPES HAVE A DISTINCT SPATIAL DISTRIBUTION PATTERN
Authors: Maarten Wijnenga, Sebastian van der Voort, Pim French, Stefan Klein, Hendrikus Dubbink, Winand Dinjens, Peggy Atmodimedjo, Joost Schouten, Johan Kros, Clemens Dirven, Arnaud Vincent, Marion Smits, Martin van den Bent
Journal: Neuro-Oncology (2018)

Several studies reported a correlation between the anatomic location of gliomas and the genetic background of the tumor. As such, tumor location may contribute to pre-surgical clinical decision-making. Current evidence is mainly derived from smaller series and report single genes or copy numbers, but not the integrated WHO 2016 classification. Our purpose was to assess the location distribution of different WHO 2016 glioma subgroups in a consecutive series of molecularly defined grade II glioma and to create location heatmaps of the low grade glioma molecular subtypes. 205 adult patients with a grade II supratentorial glioma diagnosed between 2003–2016 were included in this study (100 IDH mutated astrocytoma, 85 IDH mutated and 1p19q co-deleted oligodendroglioma, and 20 IDH wildtype astrocytoma). All patients were classified according to the WHO 2016 criteria using a dedicated Next-Generation-Sequencing panel. Tumor volume and location were assessed with semi-automatic software on T2-weighted images. All volumes of interest were mapped to a standard brain using affine registration. Location heatmaps were created for each WHO 2016 glioma subgroup by overlaying segmentations on a standard brain. Our location maps confirmed earlier observations that different molecular subtypes of grade II glioma have a different spatial distribution: most IDH mutated 1p19q co-deleted oligodendrogliomas were located in the frontal lobes and cortex, while IDH mutated astrocytomas were more frequently located in the frontotemporal and insular region. IDH wildtype astrocytomas were predominantly located in the basal ganglia and temporal lobes. Our observations were significant as confirmed with voxel-based Fisher’s exact tests (figures will be shown at SNO). Each WHO 2016 glioma subgroup displayed a distinct pattern of spatial distribution. Our observations may contribute to pre-surgical clinical decision-making and to radiogenomics.
Abstract 15852: A Low Ankle Brachial Index is Associated With Cardiovascular Events in Patients With Diabetes: The Japan Morning Surge Home Blood Pressure (J-HOP) Study
Authors: Yukako Ogoyama, Tomoyuki Kabutoya, Masahisa Shimpo, Kazuomi Kario
Journal: Circulation (2017)

Introduction: A low ankle brachial index (ABI) is associated with cardiovascular events. The associations among a low ABI, cardiovascular events and diabetes have not been established. Hypothesis: ...