tbuckley/cabot-search huggingface dataset:
AB1139 Rituximab for scleritis and peripheral ulcerative keratitis associated with rheumatologic disease
Authors: E. Valls Pascual, I. Benítez Hurtado, L. Martínez-Costa Pérez, C. Vergara Dangond, M. Aguilar Zamora, L. Montolio Chiva, A.V. Orenes Vera, A. Ybáñez García, À. Martínez. Ferrer, J.J. Alegre Sancho
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Some types of ocular surface inflammatory diseases are often related to rheumatic conditions: 37% of scleritis (especially diffuse and necrotizing forms) and 60% of peripheral ulcerative keratitis (PUK). Rheumatoid arthritis (RA) and ANCA-associated vasculitis are the most frequently related conditions. Significant loss of visual acuity can be observed if these ocular diseases are not properly treated. To date, no approved therapies are available. Consequently, the management of these ocular diseases are based on published evidence coming from clinical trials (scarce and often with a low sample size), observational studies and case reports. There are positive efficacy data of rituximab (RTX) for ocular surface inflammatory disease.<sup>1–4</sup> <h3>Objectives</h3> To describe our experience with RTX as a therapy for severe ocular surface inflammatory diseases associated to rheumatic conditions. <h3>Methods</h3> This is a retrospective observational study. It includes patients with severe scleritis or PUK associated to rheumatic diseases diagnosed and managed at our <sup>Multidisciplinary Uveitis Clinic between January 2006</sup> and November 2017. We recorded demographic and clinical variables. As outcome variables we used the change in visual acuity and the presence of inflammatory activity by biomicroscopy. <h3>Results</h3> VA: visual acuity, AE: advers events, RA: rheumatoid arthritis, GPA: granulomatosis with polyangiitis, RP: relapsing polychondritis, LTI: latent tuberculous infection, DM: diabetes mellitus, CSC: central serous choroidopathy, MPLN: metilprednisolone, PDN: prednisone, DXM: dexametasone, MTX:methotrexate, CS-A: cyclosporine, LFN: leflunomide, IFX: infliximab, ETN: etanercept, AKR: anakinra TCZ: tocilizumab. <h3>Conclusions</h3> As previously described we consider rituximab as an effective therapy for severe ocular surface inflammatory diseases related to rheumatic conditions when other immunosuppressant drugs fail or are contraindicated. <h3>References</h3> [1] - Albert M, Beltrán E, Martínez-Costa L. Rituximab in rheumatoid arthritis-associated peripheral ulcerative keratitis. Arch Soc Esp Oftalmol. 2011; 86(4):118–20. [2] - Sims J. Scleritis: presentations, disease associations and management. Postgrad Med J. 2012;88(1046):713–8. [3] - Jabs DA, Mudun A, Dunn JP, Mardsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Opthalmol2000;130:469. [4] - Suhler EB, Lim LL, Beardsley RM, Giles TR, Pasadhika S, Lee ST, et al. Rituximab therapy for refractory scleritis: results of a phase I/II dose-ranging, randomized, clinical trial. Ophthalmology. 2014;121(10):1885–91. <h3>Disclosure of Interest</h3> None declared
STEM-05. IDENTIFICATION OF PATIENT-DERIVED GLIOBLASTOMA STEM CELL (GSC) LINES WITH THE ALTERNATIVE LENGTHENING OF TELOMERES PHENOTYPE
Authors: Ahsan Farooqi, Jie Yang, Vladislav Sharin, Jason T Huse, Erik Sulman
Journal: Neuro-Oncology (2018)

Telomeres are terminal DNA elements found at chromosomal ends consisting of hexagonal repeats of (TTAGGG)n, which are essential for maintaining genomic stability. In glioblastoma, TERT promoter mutations occur in approximately 60–80% of cases, leading to increased telomerase activity and enabling replicative immortality. The remaining tumors, instead, activate a telomerase-independent alternative lengthening of telomeres (ALT) mechanism, driven by homologous recombination machinery. ALT+ gliomas are enriched in tumors harboring mutations in ATRX and IDH, and mutually exclusive with TERT promoter mutations. A novel quantitative PCR (qPCR) method that measures both telomere content (TC) and extra-chromosomal telomeric DNA C-Circles (CCs) was used to screen a panel of 24 human GSC cell lines for potential ALT lines. mRNA expression of TERT (which encodes the catalytic component of telomerase) was measured via whole transcriptome sequencing. ATRX protein expression was assessed by immunoblotting. We identified 2 ALT+ GSC cell lines: GSC-522 and GSC-818. These 2 cell lines have significantly elevated DNA CC content (p<0.001) and telomere content (p<0.001) relative to the other GSCs, consistent with the ALT phenotype. Furthermore, whole transcriptome sequencing identified mRNA expression of TERT to be negligible in these two cell lines relative to the others (p=0.0023), suggesting absence of telomerase activity. Both GSC-522 and GSC 8–18 were found to lack detectable full length ATRX protein upon immunoblot analysis, suggesting loss of function of this pathway. CONCLUSIONS: Identification of ALT+ GSCs will enable future explorations of the mechanisms and biology of the ALT phenotype in the context of glioma, and will also help define radiation sensitivity and resistance patterns in ALT vs. telomerase-positive gliomas. Furthermore, these cell lines will serve as pre-clinical models to test novel chemotherapeutic agents in an effort to improve outcomes in a subset of high-grade gliomas.
Abstract P207: Gene-by-Psychosocial Factor Interactions on Blood Pressure in Older Non-hispanic Whites and African Americans: A Genomic Region-level Analysis
Authors: Jennifer A Smith, Erin B Ware, Wei Zhao, Jessica D Faul, Sharon L Kardia
Journal: Circulation (2016)

Introduction: Hypertension is a major risk factor for cardiovascular disease, stroke, kidney disease, and vascular dementia. Nearly two out of three Americans develop hypertension by age 70, and African Americans are disproportionately affected compared to non-Hispanic whites. The etiology of hypertension is complex, but there is an emerging consensus that both biological and social/psychosocial factors contribute to increases in blood pressure. Hypothesis: In this study, we assess whether the relationship between genetic factors and systolic and/or diastolic blood pressure is modified by social or psychosocial factors in up to 12,000 non-Hispanic whites and 3,000 African Americans from the Health and Retirement Study (mean age = 68). Methods: We conducted genomic region-level analysis using the Sequence Kernel Association Test (SKAT) to evaluate whether genetic variation at 34 known blood pressure loci (29 from published GWAS of European Ancestry, and 5 from trans-ethnic meta-analysis) were associated with systolic and/or diastolic blood pressure in each ethnic group, separately. Illumina HumanExome BeadChip data was used to evaluate the effects of rare exonic variants, while 1000 Genomes imputed data was used to evaluate common variants across the entire genomic region. For genomic regions that demonstrated a marginally significant effect on blood pressure (p&lt;0.2), we used the Gene-Environment Set Association Test (GESAT) to evaluate whether social factors (education, parental education) or psychosocial factors (anger, stressful life events, social isolation, and depression) interacted with the genomic region to influence blood pressure. Results: Preliminary results indicate genomic region-level influences on blood pressure in non-Hispanic whites (ATP2B1, C10orf107, CACNB2, FES, MTHFR, ZNF652, and regions around rs1173711 and rs4373814) and African Americans (ATP2B1, FES) at p&lt;0.05. Genomic region had a significant interaction with anger (C10orf107, PLCE1) in non-Hispanic whites, and both education (region around rs1458038) and anger (ULK4) in African Americans at p&lt;0.001. Interaction analysis results for stressful life events, social isolation, and depression are forthcoming. Conclusions: New methods for integrating data on biological and social/psychosocial exposures are needed to more fully characterize the determinants of cardiovascular disease and elucidate potential mechanisms for cardiovascular disparities across ethnic groups.
EPID-17. PRIMARY LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM. CLINICAL AND THERAPEUTIC EXPERIENCE
Authors: Enrique Gomez-Figueroa, Michele Breda-Yepes, Gerardo Arellano-Flores, Alberto Gonzalez-Aguilar
Journal: Neuro-Oncology (2018)

Primary lymphoma of the central nervous system (PCNSL) is a non-Hodgkin lymphoma variety representing 4–5% of intracranial tumors and 5% of all lymphomas. It originates in the encephalon, eyes, leptomeninges and spinal cord without evidence of lymphomatoid activity at the systemic level; the subtype of lymphoma is mostly type B cells. MATERIAL AND A descriptive study was carried out on patients diagnosed with PCNSL who were treated in 3rd level centers in Mexico between the years 1980–2016. We included patients with scrutiny for the search for systemic lymphoma. The results were analyzed by simple frequencies and in the case of disease free time (DFT) and Global survival (GS) was analyzed by Kaplan Meier curves and the differences between curves by Log Rank. In a total of 215 cases only 74 cases had PCNSL. 45% were women and 55% were men. 36.7% were over 60 years old. All the patients were HIV negative. The most frequent clinical manifestations were motor deficit (60%) and cognitive alterations (52%). The majority of patients received some form of chemotherapy (89%). The treatment was mostly based on Metrotexate at High doses. The DFT was: Palliative 2 months, Chemotherapy alone 16 months, Radiation therapy alone 27 months and Radiochemotheraphy 35 months. Of the patients receiving chemotherapy alone, 7 patients received CHOP, 7 patients MTX, TMZ and Cytarabine (META protocol), 21 patients only MTX, and 9 as a combination of MTX and cytarabine, with the META protocol having the longest survival. The only significant factor for radiological response and clinical prognosis was the combined use of radiochemotherapy (p = 0.044). Lymphoma represents a tumor pathology with a high clinical radiological response to treatment, although the response is not durable. Its early identification and multidisciplinary management is fundamental for the best outcome in these patients.
Inulin-type fructans improve active ulcerative colitis associated with microbiota changes and increased short-chain fatty acids levels
Authors: Rosica Valcheva, Petya Koleva, Inés Martínez, Jens Walter, Michael G. Gänzle, Levinus A. Dieleman
Journal: Gut Microbes (2018)

The intestinal microbiota is involved in ulcerative colitis (UC) pathogenesis. Prebiotics are hypothesized to improve health through alterations to gut microbiota composition and/or activity. Our aim was therefore to determine if inulin-type fructans induce clinical benefits in UC, and identify if benefits are linked to compositional and/or functional shifts of the luminal (fecal) and mucosal (biopsy) bacterial communities. Patients (n = 25) with mild/moderately active UC received 7.5 g (n = 12) or 15 g (n = 13) daily oral oligofructose-enriched inulin (Orafti®Synergy1) for 9 weeks. Total Mayo score, endoscopic activity and fecal calprotectin were assessed. Fecal and mucosal bacterial communities were characterized by 16S rRNA tag sequencing, and short chain fatty acids (SCFA) production were measured in fecal samples. Fructans significantly reduced colitis in the high-dose group, with 77% of patients showing a clinical response versus 33% in the low-dose group (P = 0.04). Fructans increased colonic butyrate production in the 15 g/d dose, and fecal butyrate levels were negatively correlated with Mayo score (r = −0.50; P = 0.036). The high fructan dose led to an increased Bifidobacteriaceae and Lachnospiraceae abundance but these shifts were not correlated with improved disease scores. In summary, this pilot study revealed that 15 g/d dose inulin type fructans in UC produced functional but not compositional shifts of the gut microbiota, suggesting that prebiotic-induced alterations of gut microbiota metabolism are more important than compositional changes for the benefits in UC. The findings warrant future well-powered controlled studies for the use of β-fructans as adjunct therapy in patients with active UC.
Guidelines for palliative care in urology
Authors: Joon-Ha Ok, Fredrick J. Meyers, Christopher P. Evans
Journal: Cancer Research (2004)

1406  Progressive palliative care relieves physical and emotional suffering throughout illness. 75-90% of patients with advanced urologic malignancies experience significant pain and all experience a degree of emotional distress. There are no clear guidelines in the literature for surgical or medical palliative care of patients with advanced urologic malignancies. A review of the available literature for palliative care in urologic oncology was combined with our clinical experience and patient databases to develop rational guidelines for supportive care for urologic oncology patients. Local progression of a primary tumor in the face of incurable metastasis is best treated with renal embolization for renal tumors and radiation therapy or palliative cystoprostatectomy for prostate and bladder cancers. Hematuria from prostate or bladder cancer is best treated with endoscopic resection, intavesical treatments or radiation therapy. Urinary diversion without cystectomy, percutaneous nephrostomy tubes or ureteral stents are all useful modalities to manage renal obstruction. Analgesia and radiation therapy remain the mainstay of advanced palliation for metastatic lesions and pain. Laser therapy of endobronchial metastases provides excellent relief of these lesions. For all patients with advanced disease, hospice team and continued physician support are central to the physical, emotional and spiritual patient and family needs. Interdisciplinary teams that focus on patient and family defined quality of life should be progressively utilized throughout illness.
Phase I/II Trial of Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia
Authors: Clifford G. Robinson, Pamela P. Samson, Kaitlin M.S. Moore, Geoffrey D. Hugo, Nels Knutson, Sasa Mutic, S. Murty Goddu, Adam Lang, Daniel H. Cooper, Mitchell Faddis, Amit Noheria, Timothy W. Smith, Pamela K. Woodard, Robert J. Gropler, Dennis E. Hallahan, Yoram Rudy, Phillip S. Cuculich
Journal: Circulation (2019)

Case studies have suggested the efficacy of catheter-free, electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia (VT) using stereotactic body radiation therapy, although prospective data are lacking.We conducted a prospective phase I/II trial of noninvasive cardiac radioablation in adults with treatment-refractory episodes of VT or cardiomyopathy related to premature ventricular contractions (PVCs). Arrhythmogenic scar regions were targeted by combining noninvasive anatomic and electric cardiac imaging with a standard stereotactic body radiation therapy workflow followed by delivery of a single fraction of 25 Gy to the target. The primary safety end point was treatment-related serious adverse events in the first 90 days. The primary efficacy end point was any reduction in VT episodes (tracked by indwelling implantable cardioverter defibrillators) or any reduction in PVC burden (as measured by a 24-hour Holter monitor) comparing the 6 months before and after treatment (with a 6-week blanking window after treatment). Health-related quality of life was assessed using the Short Form-36 questionnaire.Nineteen patients were enrolled (17 for VT, 2 for PVC cardiomyopathy). Median noninvasive ablation time was 15.3 minutes (range, 5.4-32.3). In the first 90 days, 2/19 patients (10.5%) developed a treatment-related serious adverse event. The median number of VT episodes was reduced from 119 (range, 4-292) to 3 (range, 0-31; P<0.001). Reduction was observed for both implantable cardioverter defibrillator shocks and antitachycardia pacing. VT episodes or PVC burden were reduced in 17/18 evaluable patients (94%). The frequency of VT episodes or PVC burden was reduced by 75% in 89% of patients. Overall survival was 89% at 6 months and 72% at 12 months. Use of dual antiarrhythmic medications decreased from 59% to 12% ( P=0.008). Quality of life improved in 5 of 9 Short Form-36 domains at 6 months.Noninvasive electrophysiology-guided cardiac radioablation is associated with markedly reduced ventricular arrhythmia burden with modest short-term risks, reduction in antiarrhythmic drug use, and improvement in quality of life.URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02919618.
TMOD-21. NEURO-ONCOLOGICAL ANIMAL MODELS AND PERITUMOURAL OEDEMA - IN THE BLIND SPOT?
Authors: Moritz Schramm, Sandeep Solanki, Paul Chumas
Journal: Neuro-Oncology (2018)

Brain tumour associated oedema is a significant contributor to patient morbidity and mortality whilst striving for disease control. Indeed initially, cerebral oedema may result in the signs and symptoms leading to patient presentation rather than the tumour itself. For several decades, Dexamethasone has remained the mainstay in treatment notwithstanding its host of side effects. As such there is growing interest for alternative agents. A prerequisite for the development of novel therapeutic agents would be an animal model with a high degree of validity. Great progress has been made with animal models of brain tumours but a paucity of focus on peritumoural oedema. We sought to investigate animal models of brain tumour that exhibit oedema which can be confirmed on imaging and that manifest clinically. A systematic scoping review of EMBASE, CINAHL, Medline and Pubmed identified 603 reports that matched initial broad inclusion criteria, however as yet, most models did not fully satisfy our search for the ideal model. Further work is required to define an animal model that consistently demonstrates peritumoural oedema that is radiologically quantifiable and clinically manifest to allow effective research into alternative oedema-supressing agents.
PATH-17. INCREASING VALUE OF AUTOPSIES IN PATIENTS WITH BRAIN TUMORS IN THE MOLECULAR ERA
Authors: Jared Ahrendsen, Mariella Filb n, Susan Chi, Peter Manley, Karen Wright, Pratiti Bandopadhayay, Mark Kieran, Robert Jones, Keith Ligon, Sanda Alexandrescu
Journal: Neuro-Oncology (2018)

Many pediatric brain tumors are associated with high morbidity and mortality, which is due to insufficient understanding of tumor biology. Limited tissue allocation for research from small surgical specimens is a key barrier to improved understanding but brain tumor autopsies have been a valuable resource. This study reviews the brain tumor autopsy practice at our institution, and describes emerging research ultilization patterns beyond the clinical autopsy report. Brain tumor autopsies in the interval 2007–2017 were identified, and we analyzed the method of tissue triaging for research and documented its specific uses. Of 1602 deaths at Boston Children’s Hospital (636 with autopsies), 96 had a diagnosis of brain tumor (56 consented for autopsy,). Diffuse intrinsic pontine glioma (DIPG) and other high-grade gliomas accounted for the greatest proportion of diagnoses (52% of brain tumor autopsies). The tumors that resulted in the highest number of autopsies were DIPGs (25 deaths, 21 autopsies). Other frequent diagnoses were atypical teratoid rhabdoid tumors (13 deaths, 8 autopsies) and medulloblastomas (12 deaths, 3 autopsies). Fourteen DIPGs (56%) had tissue samples contributed to the DIPG registry consortium. Mapping was performed on 20 DIPG tumors in order to study heterogeneity; ten underwent whole genome sequencing, RNA expression studies and arrayCGH. Cell lines were successfully generated from 2 DIPGs and 1 ATRT (attempted on 12 autopsies) that had a post-mortem interval of less than 8 hours. CONCLUSIONS: Our institutional pediatric brain tumor autopsy experience demonstrates the increasing utility of autopsy-derived tissue for multiple types of research. Our experience demonstrates a wide utilization of brain tumor autopsy material in translational research, and might encourage research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.
RTHP-30. MANAGEMENT OF GLIOBLASTOMA IN THE ELDERLY - A 10-YEAR ANALYSIS OF THE BC CANCER AGENCY POPULATION
Authors: Jonathan Zeng, Andra Krauze
Journal: Neuro-Oncology (2018)

PURPOSE: Glioblastomas (GBM) are the most common primary tumours of the brain and carry an extremely poor prognosis. Despite recent publications, management of the elderly remains heterogeneous. We investigate the impact of patient characteristics and treatment modalities on the outcome of elderly patients with GBM in British Columbia (BC) from 2005–2015. Using the BC Cancer Agency patient registry, 822 adults diagnosed from 2005–2015, age 60 with histologically confirmed GBM ICD-O-3 codes (9440/3, 9441/3, 9442/3) were identified. Univariate, multivariate and Kaplan-Meier analyses were performed on patient characteristics and treatment modalities for overall survival (OS). Median OS was 6.57 months (0.03–99.93). 60% of the patients were male, mean age at diagnosis was 70 (60–90). Patients were aged 60–64 (26%), 65–69 (27%), 70–74 (20%), 75 (27%). 65% of the cohort was diagnosed between 2011–2015 vs. 35% between 2005–2010. 96% of patients had a diagnosis of glioblastoma with the remainder giant cell glioblastoma and gliosarcoma. MGMT promoter methylation status was available in 11% of patients. Resection status was GTR/STR (72%), biopsy (28%). 41% of patients received chemotherapy, 77% of patients received radiation therapy (RT). 20% of patients did not receive treatment beyond surgical intervention. Patient management involved concurrent chemoirradiation (CRT) (40%), RT alone (37%), chemo alone (1.5%). Younger patients aged 60–69, concurrent CRT and maximal safe resection (GTR/STR) resulted in improved OS (p<0.0001). Year of diagnosis and RT dose fractionation (60/30 (38%) vs. 40/15 (36%)) were not associated with a difference in OS. Elderly patients with GBM treated in BC 2005–2015 achieved similar outcomes to those of existing published data. Younger age, aggressive resection and concurrent CRT were associated with improved OS. Ongoing analysis is directed at further correlation of patient and treatment factors, features of RT and chemotherapy administration, progression-free survival and patterns of failure.