tbuckley/cabot-search huggingface dataset:
PATH-17. CORRELATION OF COMMERCIALLY-AVAILABLE QUANTITATIVE MGMT (O-6-METHYLGUANINE-DNA METHYLTRANSFERASE) METHYLATION SCORES AND OVERALL GBM PATIENT SURVIVAL
Authors: Laura Dovek, Nhung Nguyen, Byram Ozer, Linda Liau, Phioanh Nghiemphu, Timothy Cloughesy, Albert Lai
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. One of the most robust clinically-obtained biomarkers available for GBM is MGMT promoter methylation, which predicts improved outcome to standard of care alkylating chemotherapy. MGMT promoter leads to gene silencing of MGMT resulting in reduced DNA repair activity. Current commercial MGMT testing-such as available through LabCorp-use quantitative methylation-specific-PCR with a single threshold value to distinguish methylated from unmethylated MGMT tumors. In this study, we sought to determine whether the magnitude of MGMT methylation as determined by LabCorp testing correlates with outcome in our GBM patients. We identified 243 newly-diagnosed GBM patients with LabCorp-derived MGMT scores performed on pre-treatment tissue samples. In addition, we further required that patients’ samples were IDH1 wild-type and were treated with temozolomide. This resulted in a cohort of 202 patients that were eligible for inclusion in this study. We used both Kaplan-Meier and multivariate analysis of overall survival to determine whether unmethylated and methylated groups could be further stratified. First, we validated that the standard LabCorp threshold of 2 could separate our cohort by survival. We then sub-stratified the <2 (unmethylated) group and found that patients with scores 3 0.1 had higher survival than those with methylation scores < 0.1. Lastly, when we sub-stratified the 3 2 (methylated) group, we found that patient with scores 3 30 trended towards improved survival. In our large single institution cohort, our results suggest the use of 4 (instead of 2) clinically-relevant methylation categories in which unmethylated can be subdivided into unmethylated and partially methylated groups and methylated can be subdivided into methylated and super-methylated groups. Our results suggest a ‘dose-dependent’ relationship of quantitative MGMT methylation to outcome that is obscured by current binary stratification.
QLIF-06. DESIGN AND IMPLEMENTATION OF A SURVIVORSHIP PROGRAMME IN AN UNSELECTED COHORT OF NEWLY DIAGNOSED BRAIN TUMOUR PATIENTS: FEASIBILITY AND APPLICATION OF ROUTINE HOLISTIC NEEDS ASSESSMENT
Authors: Catherine McBain, Julie Emerson, Elizabeth Molloy, Sara Robson, Sarah Cundliffe, Alison Gilston-Hope, Charlotte Smith, Andrea Wadeson
Journal: Neuro-Oncology (2017)

The importance of survivorship in oncology care is increasingly recognised. This project aimed to evaluate the feasibility and utility of routine holistic needs assessment (HNA) and use concerns identified to inform the design of health and well-being events. A 48-item neuro-oncology HNA was offered to all new brain tumour patients diagnosed January-June 2016. HNA was repeated at routine clinic visits at treatment completion and 1-year post-diagnosis. Patients ranked each item from 1(low) to 10(high). Two thresholds >4 and >7 were used to identify percentage patients’ specific concerns. 104/154 newly-diagnosed patients completed HNA at diagnosis (1st HNA), 48/104 post-treatment (2nd HNA). 32/48 remain potentially eligible at 12 months (3rd HNA). Total:1st HNA:2nd HNA numbers by diagnostic groups were: Grade IV:85:55:36; Grade III:11:8:4, Low grade:18:12:4, Meningioma:33:26:5, other:6:3:0. Staff time required for each HNA completion was 15 minutes preparation and 20-90 minutes with the patient. Highest ranking concerns (scored>7/10) at 1st HNA were common to all groups and included fatigue (26% of all patients), worry/anxiety (23%) fear of recurrence (22%), transport (21%). At 2nd HNA, fatigue and fear of recurrence were reported as >7/10 by 35% and 27% of patients respectively; 21% and 19% now also identified mobility and appearance as areas of high concern. No significant differences were seen in nature of concerns between different diagnostic groups. Longitudinally, fatigue remained the most frequently reported concern, followed by fear/worry/anxiety and loss of memory/concentration. Results were used to inform the content of a highly successful all-day survivorship event in November 2016. Concerns identified were common to all diagnoses indicating that a common survivorship programme may be appropriate early in the pathway for patients with tumours of all grades. Fatigue was the most commonly reported concern; the value of 3 different fatigue interventions is to be compared in a randomised-controlled trial.
Screening for Chronic Obstructive Pulmonary Disease
Authors: Valerie G. Press, Adam S. Cifu, Steven R. White
Journal: JAMA (2017)

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RTHP-14. TO STUDY THE ROLE OF REIRRADIATION IN RECURRENT GLIOBLASTOMA
Authors: Vikas Roshan
Journal: Neuro-Oncology (2017)

Clinical Outcomes after primary treatment in case of recurrent glioblastoma (GBM) are dismal. One of the treatment options left after brain tumors recurrence is reirradiation. To study the feasibility of reirradiation in recurrent glioblastoma. We have analyzed 11 patients at our institute that came with progression after primary treatment of GBM. Patients were treated with surgery followed by postoperative concurrent chemo radiotherapy and then adjuvant temozolomide. All patients were received 60Gy/30# with concurrent temozolomide. In adjuvant settings, four patients (44%) received 12 cycles of TMZ, and seven (77%) patients received six cycles of TMZ. All patients with recurrent brain tumor underwent planning CT/MRI scan with Double shell positioning system. Images are fused MONACO FOCAL SIM Version 5.11.01. Software. The residual volume on T1 contrast and T2 flair on MRI was contoured and transferred to primary CT scan for treatment planning. Median PTV Volume was 350 cc. All patients were planned for 45Gy/25# to tumor and edema and 9Gy/5# to tumors only. Median time of presentation to hospital after primary treatment was 7 months. The patients who present within one year of primary treatment with recurrence are two (22%) in no and started on dose dense temozolamide 14 days on, and one week off regimen, Five (55%) of patients underwent second surgery and rest four patients (44%) refused surgery and were planned for radiotherapy with concurrent temozolamide. All patient completed treatment. All patients were given steroids during radiation, but three patients (33%) needed increased dose of steroids. Median progression-free survival noted was 4.2 months. Re-irradiation was a well-tolerated procedure with no grade 3-4 toxicities even in recurrent settings. Favorable outcomes of re-irradiation after primary failure in patients with recurrent GBM suggest its role as a treatment option for small volume recurrences.
GENE-46. COMPARISON OF MATCHED GLIOBLASTOMA TUMOR AND MARGIN SAMPLES USING SINGLE BASE RESOLUTION MAPS REVEALS ACQUIRED, EARLY EPIGENETIC CHANGES THAT PREDISPOSE TO MUTATIONS DURING TUMOURIGENESIS
Authors: Eun-Ang Raiber, Dario Beraldi, Sergio Martinez Cuesta, Gordon McInroy, Zoya Kingsbury, Jennifer Becq, Terena James, Margarida Lopes, Kieren Allinson, Sarah Field, Sean Humphray, Thomas Santarius, Colin Watts, David Bentley, Shankar Balasubramanian
Journal: Neuro-Oncology (2017)

Aberrant genetic and epigenetic changes drive malignant transformation and are hallmarks of cancer. Methylation patterns of 5-methylcytosine (5mC) and its intermediate metabolite 5-hydroxymethylcytosine (5hmC) become aberrant in cancer. These epigenetic changes have been associated with aberrant cellular function, genomic instability and remodeling of DNA methylation in several solid tumors but data in brain cancer is limited. We performed whole genome sequencing (100x coverage) and total RNA sequencing of blood, tumor and margin samples from a patient with de-novo glioblastoma (GB). Oxidative bisulfite sequencing and bisulfite sequencing were employed on PCR-free DNA libraries to generate high-depth (80x) coverage and build single base resolution maps that distinguished 5mC and 5hmC modifications. Enhanced (hydroxyl)-methylome sequencing reveals global hypermethylation in the tumor with average levels of 60% 5mC and drastic loss of 5hmC to 1.6%. In the margin we found levels of 50% 5mC and 20% for 5hmC integrated over all CpGs in the genome. CpGs with high levels of 5hmC in the margin had correspondingly higher levels of 5mC in the tumor. We analysed the mutational landscape by identifying single nucleotide variants (SNVs) in the tumor and margin using the blood sample as a reference. In the margin SNV sites were significantly more methylated and significantly less hydroxymethylated compared to non-SNV sites. The majority of SNVs were C>T deamination products within CpG context, where cytosine was preferentially methylated in the margin. Cells neighboring tumor cells displayed epigenetic alterations characteristic of the tumor itself despite appearing genetically “normal” themselves. Epigenetic information may transfer between cells contributing to intratumour heterogeneity of GB. 5mCPG sites are predisposed to mutations whereas 5hmCpG are protected from mutations during tumourigenesis. This is the first report of acquired, early changes in 5hmC in proximal cells.
MNGI-10. SURVIVAL BENEFIT ASSOCIATED WITH ADJUVANT RADIOTHERAPY IN ELDERLY PATIENTS WITH WHO GRADE lll MENINGIOMA
Authors: Hao Zhou, Raymond Huang, Giogos Karakousis, Paul Zhang, Lilian Chan, Harrison Bai, Bo Xiao, Li Yang
Journal: Neuro-Oncology (2017)

WHO grade III meningiomas are rare but aggressive tumors with high recurrence rate and poor prognosis. The standard care in these patients is maximal surgical resection followed by adjuvant radiotherapy (RT). However, increasing age is associated with decreasing benefit but increasing risk of cognitive side-effects from cranial irradiation. The purpose of this study was to evaluate the benefit of the RT after surgery in elderly patients diagnosed with WHO grade III meningiomas. The US National Cancer Database was used to identify patients with histologically confirmed WHO grade III meningiomas who received either surgery alone or surgery followed by RT from 2004-2013. Demographic and clinicopathologic factors associated with the use of treatment were analyzed using the chi-square test and multivariable logistic regression. Overall survival (OS) was evaluated by Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and propensity score-matched analysis. In total, 830 patients were included, among whom 369 (44.5%) received surgery alone and 461(55.5%) received surgery followed by RT. RT was associated with significantly improved OS when compared with surgery alone on multivariable analysis after adjusting for age at diagnosis, comorbidity, tumor size and extent of resection (adjusted HR,0.709; 95%CI,0.584-0.861;p=0.001). A significant OS benefit for adjuvant RT persisted in a propensity score-matched analysis (HR,0.527;95% CI,0.341-0.816;p=0.004) after matching the two cohorts on age, comorbidity status, year of diagnosis, tumor size and extent of resection. In the subgroup analysis among elderly patients (defined as age over 70), adjuvant RT was identified as an independent predictor of longer OS on both multivariable analysis(adjusted HR,0.708;95% CI,0.530-0.946;p=0.02) and propensity score-matched analysis (log-rank p=0.001). Our results underline the OS benefit associated with adjuvant RT in elderly patients with WHO grade III meningiomas.
P1.01-052 Patient-Reported Outcomes (PROs) in OAK: A Phase III Study of Atezolizumab vs Docetaxel in Non-Small-Cell Lung Cancer (NSCLC)
Authors: R. Bordoni, F. Ciardiello, J. Von Pawel, D. Cortinovis, P. He, T. Karagiannis, M. Ballinger, A. Sandler, W. Yu, F. Felizzi, A. Rittmeyer
Journal: Journal of Thoracic Oncology (2017)
Recomendações europeias sobre a vigilância da resistência aos fármacos anti-tuberculose
Authors: V Schwoebel, C S B Lambregts, M. L. Moro, F Drobniewski, S. E. Hoffner, M. C. Raviglione, H. L. Rieder
Journal: Eurosurveillance (2000)

A resistencia aos farmacos anti-tuberculose, cuja extensao na Europa nao esta bem documentada, constitui uma ameaca grave ao controlo da tuberculose. O objectivo das recentes recomendacoes Europeias sobre a vigilância da resistencia aos farmacos anti-tuberculose, emitidas por um grupo de trabalho constituido por representantes da OMS, IUATLD e de 35 paises da Regiao Europeia da OMS, consiste na melhoria da normalizacao das definicoes e dos metodos. Estas recomendacoes enfatizam a garantia da qualidade e a ligacao dos dados laboratoriais de testes de sensibilidade a farmacos com os dados da notificacao clinica. A vigilância da resistencia aos farmacos anti-tuberculose deve tornar-se um componente integrante da vigilância da tuberculose.
P1.17-014 Platinum Rechallenge in Advanced Thymic Epithelial Tumors: Still an Option in the Age of Target Therapy? A Monocentric Experience
Authors: M. Ottaviano, V. Damiano, P. Perrone, M. Capuano, M. Tortora, C. Forino, G. Palmieri
Journal: Journal of Thoracic Oncology (2017)
TMOD-05. MYCN OVEREXPRESSION AND STABILIZATION DRIVES MEDULLOBLASTOMA FROM HUMAN NEURO-EPITHELIAL STEM CELLS
Authors: Matko Čančer, Sonja Hutter, Gabriela Rosén, Ann-Charlotte Hellström, Magnus Essand, Miller Huang, Jignesh Tailor, Austin Smith, William A Weiss, Anna Falk, Holger Weishaupt, Fredrik Swartling
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) constitutes the most common malignant brain tumor in children. MB is divided into distinct molecular subgroups (WNT, SHH, Group 3 and Group 4) with different associated molecular profiles and prognoses. MYC gene family members are often overexpressed and/or amplified in all MB subgroups. Previously we have shown that a mutationally stabilized MYCN oncoprotein (MYCN-T58A) drives MB formation from mouse cerebellar neural stem cells. Here we report that human MB models can be developed from human hindbrain neuro-epithelial stem (NES) cells and induced pluripotent stem cell-derived NES (iPS-NES) cells via MYCN-T58A overexpression. Immunocompromised mice orthotopically injected with either NES cells overexpressing MYCN-T58A (NES-M) or iPSC-NES cells overexpressing MYCN-T58A (iPS-NES-M) developed tumors with high penetrance. The main features of these tumors clearly mimic those from human MB, with high expression of the proliferation marker Ki67, the neural stem and/or progenitor marker Nestin and the neuronal lineage marker class III beta tubulin (TuJ-1) and very low expression of the glial marker GFAP. Tumors derived from iPS-NES cells developed after 3-4 months, presented with leptomeningeal dissemination and based on RNA-Seq data clustered closest to human SHH MB tumors. By contrast, NES-M tumors developed significantly later (after 5-6 months), rarely showed leptomeningeal spread and were highly immunopositive for OTX2, a marker limited to Group 3 and Group 4 MBs. Taken together, we developed novel but molecularly distinct MB models driven from different hindbrain stem cells of human origin that can be further utilized in studying MB development and as a platform to conduct preclinical drug testing.
Prognostic impact of nutritional support in patients affected by locally advanced or metastatic pancreatic cancer (PC) undergone chemotherapy
Authors: I. Trestini, L. Carbognin, C. Bonaiuto, A. Auriemma, D. Melisi, L. Salvatore, I. Sperduti, E. Bria, G. Tortora
Journal: Annals of Oncology (2017)
Abstract 21196: Low Prevalence of Ideal Cardiovascular Health and Its Association With Job Strain
Authors: Davi D Muniz, Kamile S Siqueira, Cristina T Cornell, Miguel M Fernandes da Silva, Pascoal T Muniz, Odilson M Silvestre
Journal: Circulation (2017)

Introduction: Ideal Cardiovascular (CV) Health is characterized by four ideal lifestyle parameters and absence of cardiovascular risk factors. Hypothesis: The prevalence of ideal CV health is low in the Amazon Basin and it is negatively influenced by job strain. Methods: Job strain was evaluated in 479 employees from a academic center in the Amazon Basin by a validated Portuguese questionnaire that classified the participants as passive (low latitude decision and low job demand), active (high decision latitude and high job demand), low strain (low demand and high latitude decision) or high strain (high demand and low latitude decision). CV health was evaluated according to the AHA by 7 behaviours and risk factors (diet, physical activity, BMI, smoking, hypertension, diabetes and dyslipidemia). Individuals CV health status was classified as: ideal (ideal lifestyle and absence of cardiovascular risk factors), intermediate (intermediate at any parameter) or poor (when any of the seven factors was poor). We used logistic regression adjusted for age, gender, family income and educational level. Results: Mean age 44.3±12 years, 65% men. None participant had ideal CV health. Intermediate CV health was found in 44 (9%) and poor in 434 (91%) individuals. Considering low strain as a reference group, we found that high strain, active and passive had a non-significant (p&gt; 0.05) increase in the chances of having poor CV health. When adjusting for confounders, having a high job strain was associated with poor BMI (&gt; 30 kg/m 2 ), OR 2.11, 95%CI 1.06-4.22; p=0.034) and poor diet OR 2.31, 95%CI 1.29-4.13; p = 0.005. Conclusions: In a population sample with a high prevalence of poor CV health, we found that job strain was associated with obesity and poor diet. Given the lack of participants with ideal CV health, policies focusing on health education and lifestyle interventions are paramount to this population, particularly those with higher job strain.
PDCT-17. SURVIVAL OUTCOMES IN PEDIATRIC RECURRENT HIGH-GRADE GLIOMA: RESULTS OF A 20-YEAR SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Cassie Kline-Nunnally, Erin Felton, Elaine Allen, Peggy Tahir, Sabine Mueller
Journal: Neuro-Oncology (2017)

Recurrent pediatric high-grade glioma (HGG) is a leading cause of cancer-related death in children. Limited survival data on children with recurrent HGG can impede design of clinical trials for this group and lead to incorrect anticipatory guidance for patients and families. We report results of a systematic review and meta-analysis investigating survival outcome in pediatric patients with recurrent HGG over the last 20 years. MEDLINE/PubMed, EMBASE, Web of Science and Cochrane Review databases were searched for relevant studies reporting on survival outcomes for pediatric patients with recurrent HGG treated between 1996-2016. Progression-free survival (PFS) and overall survival (OS) were calculated cumulatively over all studies, by therapy subgroup, and by decade of treatment. Random effects models were used for survival and subgroup comparisons to control for heterogeneity as measured by the I2 statistic. A total of 17 studies were included across 4 treatment strategies. Eleven studies investigated traditional chemotherapy, 1 investigated targeted therapy, 3 investigated immunotherapy, and 2 investigated radiotherapy. A total of 129 patients were included with a median age of 10.0 years. Cumulative PFS was 3.5 months (95% CI 2.1, 5.0). Cumulative OS was 5.6 months (95% CI 3.9, 7.3). OS was 4.0 months (95% CI 1.9, 6.1) using traditional chemotherapy, 9.3 months using targeted therapies (95% CI 5.4, 13), 6.9 months in studies using immunotherapy (95% CI 2.1, 12), and 14 months for reirradiation (95% CI 2.8, 25). OS in studies between 1996 and 2006 was 4.2 months (95% CI 2.1, 6.2) compared to 8.5 months (95% CI 5.6, 12) in studies completed after 2006. Pediatric patients with recurrent HGG suffer from poor PFS and OS, regardless of therapy. There may be a trend towards improved OS with the use of targeted therapy, immunotherapy, and reirradiation and in the last decade.
SCDT-32. THERAPEUTIC USE OF VEGF IN BLOOD-BRAIN BARRIER MODULATION
Authors: Matthew McCord, Amelie Vezina, Virginia Rodriguez, Cody Peer, Oliver Hall, William Figg, Mark Gilbert, Sadhana Jackson
Journal: Neuro-Oncology (2017)

The poor permeability of the blood-brain barrier (BBB) poses a challenge for several effective chemotherapeutic agents against aggressive CNS tumors, such as glioblastoma. Previous studies demonstrated that physiologic vascular endothelial factor (VEGF) can increase CNS permeability in traumatic brain injury/stroke and exogenously administered VEGF induced vascular leakage in non-diseased CNS. In our study, we hypothesized that exogenous VEGF therapy could modulate BBB permeability to increase CNS drug delivery. Mouse brain endothelial cells (bEnd.3) were treated with rVEGF165 and then paracellular electrical impedance, electron microscopy/immunofluorescence and western blotting were performed to evaluate the effects on junctional and fenestration-associated proteins (Claudin-5, ZO-1, VE-cadherin, PV-1, actin). C57BL/6 mice were given either intravenous VEGF or PBS pretreatment 8hrs prior to oral temozolomide. Temozolomide levels were measured in blood and whole brain by LC/MS/MS. Cell treatments demonstrated a significant drop in cell impedance approximately 8hrs after rVEGF165 (200ng/mL) compared to control. Subsequent treatment with VEGF inhibitor, bevacizumab (500ng/mL), reversed the VEGF effect within 2hrs. Immunofluorescence for ZO-1 and VE-cadherin demonstrated junctional disassembly and decreased expression between 4 and 8hrs post VEGF treatment. Additionally, Claudin-5 protein expression decreased 8hrs after VEGF treatment, while it increased expression of PV-1 two-fold; inducing actin rearrangement seen via immunofluorescence. In non-tumor bearing mice pretreated with VEGF, cell-cell junction electron density was significantly decreased but VEGF failed to enhance temozolomide CNS concentrations 8hrs after administration. Our in-vitro results are consistent with the known properties of VEGF to influence vasculature permeability. Yet, our animal studies demonstrated that while VEGF affects the BBB on the cellular level, in non-tumor bearing animals VEGF fails to increase chemotherapy penetration. Thus, further animal studies using tumor models and varied VEGF dosing schedules with and without bevacizumab is needed to evaluate the plausible use of VEGF to aid chemotherapy distribution in glioblastoma.