tbuckley/cabot-search huggingface dataset:
ATRT-20. INTRA- AND EXTRA-CRANIAL MALIGNANT RHABDOID TUMOURS SHARE COMMON LOCATION-INDEPENDENT CLINICAL AND MOLECULAR DISEASE CHARACTERISTICS
Authors: Yura Grabovska, Martina Finetti, Matthew P Selby, Edward C Schwalbe, Amanda Smith, Stephen Crosier, Jessica C Pickles, Amy R Fairchild, Aimee Avery, Patricia O’Hare, Barry Pizer, Bernadette Brennan, Darren Hargrave, John Anderson, Thomas S Jacques, Simon Bailey, Steven C Clifford, Daniel Williamson
Journal: Neuro-Oncology (2018)

Atypical Teratoid/Rhabdoid Tumours (ATRT) are the CNS located members of a larger family of Malignant Rhabdoid Tumours (MRT); aggressive early childhood tumours characterised by biallelic inactivation of SMARCB1. ATRT and extra-cranial rhabdoid tumours (ECRT) are often treated as distinct entities therapeutically and in clinical/biological studies. We investigated to what extent this division is justified by the underlying molecular biology. RNA-Seq and methylation profiling of primary MRT was performed on 56 clinico-pathologically annotated tumour profiles from UK cancer centres and combined with published MRT data (n=394) in a meta-analysis. To characterise the common biological features of MRT regardless of location, differential expression, methylation, gene/pathway analyses were compared to other paediatric embryonal tumour expression (n=1073) and methylation (n=520) profiles (i.e. Medulloblastoma, Ewings Sarcoma, Rhabdomyosarcoma, Wilms tumour and Neuroblastoma). Clustering all MRT together recapitulates the subgroups observed in ATRT alone; broadly overlapping with recently published 3 ATRT subgroup models. We further describe a putative expanded subgrouping model encompassing all MRT. While expression, methylation, genetic and clinico-pathological differences by anatomical site are observed these are not innate but rather differences between ATRT and ECRT may be explained by differences in the molecular subgroup membership. We propose that anatomical site does not exclusively predetermine subgroup identity and that the overarching SMARCB1-dependent genetic, epigenetic and transcriptomic commonality is the “main event” in MRT tumorigenesis. Our findings demonstrate a need for common therapeutic approaches and targeting strategies across all MRTs, irrespective of location; these findings have important implications for clinical trial planning and future research studies.
QOL-30. LONG-TERM COGNITIVE FUNCTIONING AND TREATMENT-RELATED RISK FACTORS IN CHILDHOOD POSTERIOR FOSSA TUMOR SURVIVORS
Authors: Charlotte Sleurs, Ellen Turelinckx, Lissa Maes, Sabine Deprez, Anne Uyttebroeck, Sandra Jacobs, Jurgen Lemiere
Journal: Neuro-Oncology (2018)

Each constituent of posterior fossa tumor treatment can affect brain development tremendously. We investigated cognition in survivors of childhood posterior fossa tumor. Neurocognitive assessments and T1-weighted MRI-images were acquired in 21 survivors (mean age at diagnosis 8.3 years; >2 years post-treatment, pilocytic astrocytoma (n=8), ependymoma (n=1) or medulloblastoma (n=12)); and 21 age- and gender-matched controls. A comprehensive neurocognitive test battery and questionnaires (WAIS-IV, RVDLT, AVLT, ANT, PPVT, COWAT, CFQ, BRIEF, STAI, BDI, PedsQL) were assessed. Based on anatomical scans, cerebellar tissue proportions were analyzed (as indication of atrophy). Scores were compared between patients and healthy controls. Interdependence of treatment-related risk factors (craniospinal radiation dose (0, 23.4, 35-36 and 40 Gy), posterior fossa boost, intraventricular MTX, (sub)total resection, postsurgical mutism, age at diagnosis and time since treatment) and cerebellar tissue was assessed, to predict cognitive scores by independent factors. First, IQ subscales, as well as visual memory and object naming were significantly lower in patients. Second, radiation dose, postsurgical mutism and time since treatment were found to be independent, and used for further analyses. Radiation dose was associated IQ and attentional reaction times, whereas the presence of postsurgical mutism was related to worse perceptual reasoning and emotional regulation. After corrections, only the link between RT and attentional reaction times remained significant. Finally, radiation dose and IV-MTX were associated with reduced current cerebellar tissue. Craniospinal irradiation showed the strongest effect on attentional reaction times. The association between decreased cerebellar tissue and RT doses suggests radiation-induced atrophy, which might have additional impact.
The management of locally advanced and metastatic colorectal cancer: A retrospective study of 77 cases
Authors: F. Boudinar, G. Bettache, K. Wahiba, B. Larbaoui
Journal: Annals of Oncology (2018)

Introduction: Colorectal cancer is the third most common cause of cancer after lung and breast cancer, with an estimated 1,2 million new cases diagnosed world wide per year and it is the third most common death – related cancer. Liver and lung are the most frequent locations of metastasis. Methods: Retrospectively, we included 77 patients with locally advanced and metastatic colorectal adenocarcinoma, treated in our medical oncology department between 2014 and 2017. Results: We have collected 77 patients with 39 women and 38 men, the mean age is 54 years, range (26-77), 66 patients (85,71%) had WHO performance status of 0 or 1 at the of diagnosis. 17% had IMC < 18,5, risk factors: MICI in 2 cases, TOBACCO in 15 cases. We noted abdominal pain in (67,53%, n = 52), proctorrhagia (54,54%, n 42), Adenocarcinoma account for 100% of cases. Rectal location in 41,15% and colon location in 55,84%. 14,28% (n = 11) were stage III, 66 patients (85, 71%) were stage IV. Metastases sites: liver (35,06%, n = 27), lung (11,68%, n = 9), nodes (9,09%, n = 7), other sites (4%, n = 3). RAS test performed in 48%, RAS WILD TYPE in 26%, RAS MUTANT in 21%. Surgery in primary tumor 30%. 85,71% received chemotherapy 1st line, FOLFIRI 40,25%, FOLFOX 35,06%, XELOX 3,89%, CETUXIMAB 35,06%, PANITUMUMAB 5,19%, BEVACIZUMAB 37,66%. Most common gastrointestinal toxicity (nausea, vomiting, diarrhea). Hematologic toxicity was more frequent in patients receiving FOLFOX regimen. Cutaneous rash noted in patients receiving cetuximab and panitumumab. Evaluation after 1st line progression 22,07%, CR 6,49%, PR 15,58%, ST 11,68%. Chemotherapy 2nd line 29,87%. Chemotherapy 3rd line 11,68%, REGORAFENIB in 5,19%. Conclusion: The multidisciplinary approach at all stages of the process requires the involvement of various specialties in order to give the patient an optimal quality of care.
EPEN-09. RNA-SEQ ANALYSIS OF RECURRENT PAEDIATRIC EPENDYMOMAS REVEALS IMMUNOLOGICAL CHANGES SPECIFIC TO MOLECULAR SUBGROUPS
Authors: Timothy A Ritzmann, Hazel A Rogers, Andrew M Donson, Alex Virasami, Thomas S Jacques, Simon ML Paine, Nicholas Foreman, Richard G Grundy
Journal: Neuro-Oncology (2018)

Ependymoma is the second most common malignant childhood brain tumour. Immunity has been implicated in recurrence but its role needs further definition to inform therapy. We profiled two independent ependymoma cohorts using RNA sequencing and DNA methylation profiling; one from fresh frozen (FF), and the other from paraffin embedded (FFPE), material. FF and FFPE cohorts contained 27 and 25 matched primary and recurrent pairs respectively. Following differential expression (DEA) and gene set enrichment analyses (GSEA), we used validated algorithms to calculate parameters associated with anti-tumour immune responses, including: immunophenoscore (IPS), cytolytic activity (CYT), and expression of immune checkpoint genes. Clustering using RNA-seq data, from primary and recurrent tumours, formed location based groups. Posterior fossa (PF) clusters formed two groups, PF1 and PF2, with expression patterns similar to EPN_PFA and EPN_PFB tumours, however, both contained predominantly EPN_PFA DNA methylation designations. GSEA comparing primary to first relapse was similar in both cohorts. PF1 demonstrated treatment independent downregulation of inflammatory responses, cytokine activity and chemotaxis. Radiotherapy treated PF1 relapses were associated with upregulation of immune related ontologies. PF2 and ST relapses showed upregulation of B- and T-cell ontologies. IPS did not change at recurrence, and was below levels associated with response to checkpoint inhibition. CYT and expression of checkpoint inhibition molecules were low. Whilst these independent datasets demonstrated shared immunological changes at recurrence; immune based algorithms indicated that activity may be inadequate to respond to immune checkpoint therapy. Other immunotherapeutic approaches may be effective, but better understanding of ependymoma’s immunological basis is essential.
Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome
Authors: Jonathan M. Davis, Jeffrey Shenberger, Norma Terrin, Janis L. Breeze, Mark Hudak, Elisha M. Wachman, Peter Marro, Erica L. Oliveira, Karen Harvey-Wilkes, Adam Czynski, Barbara Engelhardt, Karen D’Apolito, Debra Bogen, Barry Lester
Journal: JAMA Pediatrics (2018)

Although opioids are used to treat neonatal abstinence syndrome (NAS), the best pharmacologic treatment has not been established.To compare the safety and efficacy of methadone and morphine in NAS.In this randomized, double-blind, intention-to-treat trial, term infants from 8 US newborn units whose mothers received buprenorphine, methadone, or opioids for pain control during pregnancy were eligible. A total of 117 infants were randomized to receive methadone or morphine from February 9, 2014, to March 6, 2017. Mothers who declined randomization could consent to data collection and standard institutional treatment.Infants were assessed with the Finnegan Neonatal Abstinence Scoring System every 4 hours and treated with methadone or placebo every 4 hours or morphine every 4 hours. Infants with persistently elevated Finnegan scores received dose increases. Infants who exceeded a predetermined opioid dose received phenobarbital. Dose reductions occurred every 12 to 48 hours when signs of NAS were controlled with therapy, stopping at 20% of the original dose.The primary end point was length of hospital stay (LOS). The secondary end points were LOS attributable to NAS and length of drug treatment (LOT).A total of 183 mothers consented to have their infants in the study; 117 infants required treatment. Because 1 parent withdrew consent, data were analyzed on 116 infants (mean [SD] gestational age, 39.1 [1.1] weeks; mean [SD] birth weight, 3157 [486] g; 58 [50%] male). Demographic variables and risk factors were similar except for more prenatal cigarette exposure in infants who received methadone. Adjusting for study site and maternal opioid type, methadone was associated with decreased mean number of days for LOS by 14% (relative number of days, 0.86; 95% CI, 0.74-1.00; P = .046), corresponding to a difference of 2.9 days; 14% reduction in LOS attributable to NAS (relative number of days, 0.86; 95% CI, 0.77-0.96; P = .01), corresponding to a difference of 2.7 days; and 16% reduction in LOT (relative number of days, 0.84; 95% CI, 0.73-0.97; P = .02), corresponding to a difference of 2.3 days. Methadone was also associated with reduced median LOS (16 vs 20 days, P = .005), LOS attributable to NAS (16 vs 19 days, P = .005), and LOT (11.5 vs 15 days, P = .009). Study infants had better short-term outcomes than 170 nonrandomized infants treated with morphine per standard institutional protocols.With use of weight- and sign-based treatment for NAS, short-term outcomes were better in infants receiving methadone compared with morphine. Assessment of longer-term outcomes is ongoing.ClinicalTrials.gov Identifier: NCT01958476.
MBCL-24. INCIDENCE AND RISK FACTORS OF POSTERIOR FOSSA SYNDROME IN CHILDREN WITH POSTERIOR FOSSA TUMORS
Authors: Mariko Sato, Demi Eble, Tomoaki Sasaki, Bridget Zimmerman, Arnold Menezes, Jeremy Greenlee, Saul Wilson, Brian Dlouhy, Satsuki Matsumoto, Aaron Boes, Sue O’Dorisio
Journal: Neuro-Oncology (2018)

The pathophysiology of posterior fossa syndrome (PFS) are not completely unraveled and its unpredictable outcome makes the clinical management of PFS challenging. To examine the incidence, clinical outcome and prognostic risk factors for PFS. The retrospective chart review from 1976 to March 2017 was conducted and medical records of 87 children with posterior fossa tumors were analyzed to look for outcomes, clinical variables such as tumor type, presentation and surgical methods. Pre- and post-operative MRI features of 64 patients were evaluated whether a damage was present or not in an anatomical structure for PFS prediction using a chi-square test. Of the 87 charts reviewed 48 (55%) had medulloblastoma, 26 (30%) had low grade glioma, 10 (11%) had ependymoma, and 3 (3%) had ATRT. Fifteen (17%) patients developed PFS, 10 (67%) had medulloblastoma, 2 (13%) had low grade glioma, 2 (13%) had ATRT, and 1 (7%) had ependymoma. Ten out of 15 patients (67%) with PFS had severe PFS symptoms. Among observed clinical variables, the intraoperative incision in the vermis was highly associated with the incidence of PFS (p=0.009). In the post-operative MRI, the damage of bilateral dentate nuclei and superior cerebellar peduncles were detected significantly in PFS (P=0.008 and p=0.018, respectively). Symptoms of PFS vary thus retrospective chart review may underestimate the actual incidence. Post-operative MRI findings may be predictive of PFS and may lead to prevention or to early interventions.
Pancreatic cancer in Morocco: A retrospective review
Authors: A. Haimer, F. Habib, A. Soulaymani, A. Mokhtari, H. Hami
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer is an uncommon and aggressive cancer in Northern Africa. It is the 14th most commonly diagnosed cancer in men and women and the 11th leading cause of cancer-related death, with about 4 034 new cases of pancreatic cancer and 3 915 cancer deaths estimated to have occurred in 2012 (GLOBOCAN 2012). The aim of this study is to determine the epidemiological profile of pancreatic cancer in Morocco. Methods: This is a descriptive retrospective study of pancreatic cancer cases, diagnosed and treated at Al Azhar Oncology Center in Rabat between 2005 and 2015. Results: There were 120 new cases of pancreatic cancer diagnosed at Al Azhar Oncology Center (71 men and 49 women), accounting for 1.5% of all new cancer cases reported during the study period. The average age at diagnosis of pancreatic cancer was 59.6±15 years (range 0-94 years). The risk of developing pancreatic cancer increases with age. More than three-quarters of people diagnosed with pancreatic cancer (82.5%) were aged 50 years or older at the time of diagnosis, with 77.5% of new cancer cases occurring among those aged 50-79 years. Among all detected cases, 1.7% were diagnosed with metastatic disease and 13.3% died from the disease during the study period, accounting for 2.4% of all cancer deaths. Conclusion: Pancreatic cancer remains a significant public health issue. Early diagnosis is difficult because the disease is asymptomatic in its early stages "silent disease".
TBIO-24. INTEGRATION OF GENETIC COUNSELING INTO MULTIDISCIPLINARY BRAIN TUMOR CLINIC IMPROVES IDENTIFICATION AND COUNSELING FOR CANCER PREDISPOSITION SYNDROMES
Authors: Shannon M Stasi, Bonnie Lynn Cole, Christina M Lockwood, Sarah ES Leary
Journal: Neuro-Oncology (2018)

Next-generation sequencing (NGS) panels, while typically used clinically to identify somatic tumor mutations to guide therapeutics, can identify possible germline mutations. Incidental identification of a cancer predisposition syndrome has psychosocial and management implications for the patient and family beyond routine oncology care. We implemented a pilot integrating a genetic counselor (GC) within a multidisciplinary brain tumor clinic to facilitate follow-up germline testing on at-risk patients based on tumor testing results and to develop a clinical process for paired tumor plus blood testing for suspected hereditary cancer predisposition syndromes. From November 2015 to present, 116 brain tumors underwent clinical targeted molecular tumor profiling. Testing identified 35 (30%) patients with possible germline variants based on results and family history. Of those, 16 patients have had follow-up germline testing coordinated to date; 8 patients tested positive for an inherited cancer predisposition syndrome (RAD51D, TP53 (2), BAP1, MSH2, SUFU (2), ATM). Five patients tested negative on follow-up germline testing. Two patients were previously identified to have Neurofibromatosis 1 and one patient was previously identified to have Neurofibromatosis 2. Paired tumor testing has been coordinated for two patients so far and identified a pathogenic germline TP53 variant in one patient and a likely pathogenic germline SUFU variant in the other. Molecular diagnostics are now standard for pediatric brain tumors, and an embedded GC can improve the coordination of care for children with brain tumors. Timely counseling and diagnosis of a hereditary cancer syndrome has important health care implications for both the patient and the family.
Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart
Authors: Nataliya Dybkova, Shakil Ahmad, Steffen Pabel, Petros Tirilomis, Nico Hartmann, Thomas H Fischer, Philipp Bengel, Theodoros Tirilomis, Senka Ljubojevic, André Renner, Jan Gummert, David Ellenberger, Stefan Wagner, Norbert Frey, Lars S Maier, Katrin Streckfuss-Bömeke, Gerd Hasenfuss, Samuel Sossalla
Journal: Cardiovascular Research (2018)

In heart failure (HF), enhanced persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel NaV1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy.By western blot, we found that NaV1.8 protein expression is significantly up-regulated, while of the predominant cardiac isoform NaV1.5 is inversely reduced in human HF. Furthermore, to investigate the relation of NaV1.8 regulation with the cellular proarrhythmic events, we performed comprehensive electrophysiology recordings and explore the effect of NaV1.8 on INaL, action potential duration (APD), Ca2+ spark frequency, and arrhythmia induction in human failing cardiomyocytes. NaV1.8 inhibition with the specific blockers A-803467 and PF-01247324 decreased INaL, abbreviated APD and reduced cellular-spontaneous Ca2+-release and proarrhythmic events in human failing cardiomyocytes. Consistently, in mouse cardiomyocytes stressed with isoproterenol, pharmacologic inhibition and genetically knockout of NaV1.8 (SCN10A-/-), were associated with reduced INaL and abbreviated APD.We provide first evidence of differential regulation of NaV1.8 and NaV1.5 in the failing human myocardium and their contribution to arrhythmogenesis due to generation of INaL. We propose inhibition of NaV1.8 thus constitutes a promising novel approach for selective anti-arrhythmic therapy in HF.
Anti–Myelin Oligodendrocyte Glycoprotein Antibody–Associated Central Nervous System Demyelination—A Novel Disease Entity?
Authors: Martin S. Weber, Tobias Derfuss, Wolfgang Brück
Journal: JAMA Neurology (2018)

This Viewpoint summarizes the current knowledge of the clinical, radiologic, and immunologic features of adult patients who are positive for anti–myelin oligodendrocyte glycoprotein and compares these individuals with patients with multiple sclerosis and patients with neuromyelitis optica.
ABT-165 plus FOLFIRI vs bevacizumab plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bevacizumab - Trial in progress
Authors: Z. Wainberg, L. Wang, H. Yue, M. Motwani, S. Kasichayanula, M. Blaney, L. Naumovski, J. Strickler
Journal: Annals of Oncology (2018)

Introduction: The dual variable domain immunoglobulin ABT-165 targets human vascular endothelial growth factor (VEGF) and delta-like ligand 4 (DLL4). Combined VEGF and DLL4 blockade increased inhibition of subcutaneous xenograft growth of human colon cancer-derived cell lines vs blockade of either axis alone. In vivo, ABT-165 plus chemotherapy (CT) induced tumor regression with improved efficacy, vs anti-VEGF monoclonal antibody plus CT. In a phase 1 study, a tolerable recommended phase 2 dose was identified for ABT-165 plus FOLFIRI and showed promising efficacy. This phase 2 trial in progress assesses the efficacy/safety of ABT-165 plus FOLFIRI vs bevacizumab (bev) plus FOLFIRI in patients with second-line mCRC. Methods: This is an open-label, multicenter, phase 2 randomized (1:1) trial (NCT03368859) in patients (≥18 years; Eastern Cooperative performance status: 0–1) with histologically/cytologically confirmed mCRC who progressed after fluoropyrimidine/oxaliplatin and bev. ABT-165 (2.5 mg/kg) plus FOLFIRI (irinotecan: 180 mg/m2; leucovorin: 400 mg/m2; fluorouracil bolus: 400 mg/m2, infusion: 2400 mg/m2) or bev (5 mg/kg) plus FOLFIRI are given intravenously on day 1 of each 14-day cycle, until disease progression/intolerable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. Exploratory endpoints include biomarkers predictive for efficacy/safety, correlation of DLL4 levels with PFS, OS, and ORR, pharmacodynamic effects, and the efficacy/safety-exposure relationships in the ABT-165 arm. The hazard ratios of PFS and OS comparing the 2 groups are estimated using the Cox proportional hazard model. Kaplan-Meier methodology is used to estimate the PFS and OS curves, median PFS and OS, and their 90% confidence intervals. Safety is assessed by ABT-165 exposure, adverse events (AEs), serious AEs, all deaths, and changes in laboratory data and vital signs. Archival tissue is collected and evaluated for DLL4 expression and angiogenesis signature. Approximately 100 patients are planned to be enrolled, with recruitment initiated in January 2018.
LGG-45. RESPONSE TO THE FIRST-LINE CHEMOTHERAPY IN PEDIATRIC LOW-GRADE GLIOMAS ACCORDING TO HISTOPATHOLOGY AND BRAF ALTERATIONS
Authors: Tasnime Akbaraly, Volodia Dangouloff-Ros, Arnault Tauziede-Espariat, Ludovic Lacroix, Stéphanie Puget, Pascale Varlet, Léa Guerrini-Rousseau, Jacques Grill, Christelle Dufour
Journal: Neuro-Oncology (2018)

To assess radiological response to first-line chemotherapy in pediatric low-grade gliomas (pLGG) according to histopathology and BRAF alterations. We performed a population-based study of all patients diagnosed with a pLGG between 2006 and 2015 at Gustave Roussy and treated with vincristine-carboplatin, as first-line chemotherapy. Pathology samples were reviewed according to 2016 WHO classification. BRAF alterations were detected using immunohistochemistry, fluorescence in situ hybridization and/or sequencing. Tumor response was assessed by an independent central review. Sixty-one patients were included in our cohort: 46 pilocytic astrocytomas (75.4%) and 15 gangliogliomas (24.6%). BRAF was found with an alteration in 44 samples (72%) and wild-type (WT) in 11 (18%) cases (molecular data incomplete = 6). Eleven pLGGs harbored the BRAF V600E mutation and 33 BRAF rearrangements. At the end of the first-line of chemotherapy, the objective response rate (complete or partial response) of pilocytic astrocytomas and gangliogliomas were 69% and 38%, respectively. The objective response rate of BRAF rearrangement, BRAF V600E and WT pLGGs were 72%, 22% and 60%, respectively. The 3-year event-free survival of patients with BRAF duplication pLGGs was 70% versus 45% for those with BRAF V600E pLGGs. BRAF V600E pLGG constitutes a distinct entity with poor prognosis when treated with standard treatments.