tbuckley/cabot-search huggingface dataset:
TBIO-17. IMPLEMENTATION OF METHYLATION PROFILING FOR CNS TUMOR DIAGNOSIS IN THE PRINCESS MÁXIMA CENTER FOR PEDIATRIC ONCOLOGY, THE NETHERLANDS
Authors: Pieter Wesseling, Loudy Priesterbach-Ackley, Sabine Plasschaert, Eelco Hoving, Benno Küsters, Mirthe Schoots, Eleonora Aronica, Bas Tops, Wendy de Leng
Journal: Neuro-Oncology (2018)

Since the fall of 2016, in the Netherlands diagnosis and treatment of children with CNS tumors is increasingly concentrated in the Princess Máxima Center (PMC), i.e. the newly established, national center for pediatric oncology. Because of its potential as a support tool for CNS tumor diagnosis, Infinium MethylationEPIC BeadChip analysis was readily implemented and ‘routinely’ performed on pediatric CNS tumor samples in the PMC. AIM: To identify the challenges and opportunities of methylation profiling as a support tool for the diagnosis of pediatric CNS tumors. PATIENTS AND We have now analyzed >150 pediatric (formalin-fixed/paraffin-embedded) CNS tumor samples using methylation profiling and matched the profiles with the ‘Heidelberg database’ (https://www.molecularneuropathology.org/mnp). In > 90% of analyzed cases, the suggested methylation class corresponded very well with the pathological (histological +/- molecular) diagnosis. In some other cases, the suggested methylation class was not very helpful because the reliability score of the test was (too) low, or because the suggested class not adequately reflected the actual presence of a tumor (e.g. ‘reactive/inflammatory changes’) or was not (yet) as precise as desired (e.g. ‘diffuse glioma/glioblastoma, IDH-wildtype, midline type (but not H3-mutant)’). However, in many other cases the tool was very helpful for reaching a more precise diagnosis (esp. so for medulloblastomas, ependymomas) or directed towards the right diagnosis. Methylation profiling is a very powerful tool to confirm, fine-tune and/or direct pediatric CNS tumor diagnostics. However, it is crucial to interpret this new level of information in the clinical, radiological and pathological context.
Rituximab monotherapy in splenic marginal zone lymphoma: prolonged responses and potential benefit from maintenance
Authors: Christina Kalpadakis, Gerassimos A. Pangalis, Sotirios Sachanas, Pantelis Tsirkinidis, Flora N. Kontopidou, Maria Moschogiannis, Xanthi Yiakoumis, Efstathios Koulieris, Maria N. Dimopoulou, Stella I. Kokkoris, Marie-Christine Kyrtsonis, Marina P. Siakantaris, Gerassimos Tsourouflis, Penelope Korkolopoulou, Dimitra Rontogianni, Panagiotis Tsaftaridis, Eleni Plata, Helen A. Papadaki, Panagiotis Panagiotidis, Maria K. Angelopoulou, Theodoros P. Vassilakopoulos
Journal: Blood (2018)
Effectiveness and cost-effectiveness of cognitive behavioural therapy and short-term psychoanalytic psychotherapy compared with brief psychological intervention in maintaining reduced depressive symptoms 12 months after end of treatment in adolescents with unipolar major depression (IMPACT): A pragmatic superiority randomised controlled trial.
Authors: I. Goodyer, Shirley Reynolds, Barbara Michelle Barrett, Sarah Byford, Bernadka Dubicka, Jonathan Hill, Fiona Holland, Raphael Kelvin, Nick Midgley, Chris Roberts, Robert Senior, Mary Target, Barry Widmer, Paul Wilkinson, Peter Fonagy
Journal: The Lancet Psychiatry (2016)
Nuclear factor E2-related factor 2 deficiency impairs atherosclerotic lesion development but promotes features of plaque instability in hypercholesterolaemic mice
Authors: Anna-Kaisa Ruotsalainen, Jari P Lappalainen, Emmi Heiskanen, Mari Merentie, Virve Sihvola, Juha Näpänkangas, Line Lottonen-Raikaslehto, Emilia Kansanen, Simone Adinolfi, Kai Kaarniranta, Seppo Ylä-Herttuala, Matti Jauhiainen, Eija Pirinen, Anna-Liisa Levonen
Journal: Cardiovascular Research (2018)

Oxidative stress and inflammation play an important role in the progression of atherosclerosis. Transcription factor NF-E2-related factor 2 (Nrf2) has antioxidant and anti-inflammatory effects in the vessel wall, but paradoxically, global loss of Nrf2 in apoE deficient mice alleviates atherosclerosis. In this study, we investigated the effect of global Nrf2 deficiency on early and advanced atherogenesis in alternative models of atherosclerosis, LDL receptor deficient mice (LDLR-/-), and LDLR-/- mice expressing apoB-100 only (LDLR-/- ApoB100/100) having a humanized lipoprotein profile.LDLR-/- mice were fed a high-fat diet (HFD) for 6 or 12 weeks and LDLR-/-ApoB100/100 mice a regular chow diet for 6 or 12 months. Nrf2 deficiency significantly reduced early and more advanced atherosclerosis assessed by lesion size and coverage in the aorta in both models. Nrf2 deficiency in LDLR-/- mice reduced total plasma cholesterol after 6 weeks of HFD and triglycerides in LDLR-/-ApoB100/100 mice on a chow diet. Nrf2 deficiency aggravated aortic plaque maturation in aged LDLR-/-ApoB100/100 mice as it increased plaque calcification. Moreover, ∼36% of Nrf2-/-LDLR-/-ApoB100/100 females developed spontaneous myocardial infarction (MI) or sudden death at 5 to 12 months of age. Interestingly, Nrf2 deficiency increased plaque instability index, enhanced plaque inflammation and calcification, and reduced fibrous cap thickness in brachiocephalic arteries of LDLR-/-ApoB100/100 female mice at age of 12 months.Absence of Nrf2 reduced atherosclerotic lesion size in both atherosclerosis models, likely via systemic effects on lipid metabolism. However, Nrf2 deficiency in aged LDLR-/-ApoB100/100 mice led to an enhanced atherosclerotic plaque instability likely via increased plaque inflammation and oxidative stress, which possibly predisposed to MI and sudden death.
MBRS-20. KETOLYTIC AND GLYCOLYTIC ENZYMATIC EXPRESSION IN PAEDIATRIC MEDULLOBLASTOMAS: IMPLICATION FOR KETOGENIC DIET THERAPY
Authors: Lisa C D Storer, Zacharias de Beer, George Lockwood, Simon Paine, Richard G Grundy
Journal: Neuro-Oncology (2018)

Medulloblastomas are the most common malignant brain tumour of childhood. Long term survival is approximately 75%, however, therapy often results in disabling outcomes and reduced quality of survival. One potential strategy to improve outcome, whilst reducing side effects, is exploiting the metabolic differences between normal and tumour cells. Under normal physiological conditions, brain cells metabolise glucose for energy. If “starved” of glucose, ketone bodies are metabolised. Mitochondrial defects in brain tumour cells obviate this metabolic flexibility resulting in glycolytic dependence. Thus, a high fat, low carbohydrate ketogenic diet (KD) may control tumour growth. We evaluated the expression of succinyl-CoA:3-oxoacid CoA transferase 1 (OXCT1) and D-β-hydroxybutyrate dehydrogenase 1 (BDH1), both involved in ketone body utilization and pyruvate kinase M2 (PKM2), essential for aerobic glycolysis, in 84 paediatric medulloblastomas by immunohistochemistry. Expression was assessed as low (<20%) or high (>20%). 70.2% showed low expression of OXCT1 and 82.5% of BDH1. Low expression of either results in an inability to metabolise ketones. 34.9% showed high expression of PKM2, increasing the Warburg effect and when combined with low expression of BDH1 (27.5%) or OXCT1 (22.0%), the optimal immunohistochemistry profile, to arrest ketone metabolism. No statistical difference was seen with gender or age. Expression of OXCT1 was significantly lower in children with a Group 4 medulloblastoma (p=0.032) when compared to other molecular subgroups (WNT, SHH and Group 3). Therefore the KD may offer a potential addition to current medulloblastoma therapies including in the prevention of disseminated recurrence characteristic of Group 4 tumours.
Different menopausal hormone regimens and risk of breast cancer
Authors: N. Brusselaers, R.M. Tamimi, P. Konings, B. Rosner, H.-O. Adami, J. Lagergren
Journal: Annals of Oncology (2018)

There are considerable knowledge gaps concerning different estrogen and progestin formulations, regimens, and modes of administration of menopausal hormone therapy (HT) and the risk of breast cancer. Our objective was to assess the different treatment options for menopausal HT and the risk of breast cancer.This Swedish prospective nationwide cohort study included all women who received ≥1 HT prescription during the study period 2005-2012 (290 186 ever-users), group-level matched (1 : 3) to 870 165 never-users; respectively, 6376 (2.2%) and 18 754 (2.2%) developed breast cancer. HT, ascertained from the Swedish Prescribed Drug Register, was subdivided by estrogen and progestogen formulation types, regimens (continuous versus sequential) and modes of administration (oral versus transdermal). The risk of invasive breast cancer was presented as adjusted odds ratios (OR) and 95% confidence intervals.Current use of estrogen-only therapy was associated with a slight excess breast cancer risk [odds ratio (OR) = 1.08 (1.02-1.14)]. The risk for current estrogen plus progestogen therapy was higher [OR = 1.77 (1.69-1.85)] and increased with higher age at initiation [OR = 3.59 (3.30-3.91) in women 70+ years]. In contrast, past use was associated with reduced breast cancer risk. Current continuous estrogen/progestin use was associated with higher risk [OR = 2.18 (1.99-2.40) for progesterone-derived; OR = 2.66 (2.49-2.84) for testosterone-derived] than sequential use [OR = 1.37 (0.97-1.92) for progesterone-derived; OR = 1.12 (0.96-1.30) for testosterone-derived]. The OR for current use was 1.12 (1.04-1.20) for estradiol, 0.76 (0.69-0.84) for estriol, 4.47 (2.67-7.48) for conjugated estrogens, and 1.68 (1.51-1.87) for tibolone. Oral and cutaneous HT showed similar associations.Different HT regimens have profoundly different effects on breast cancer risk. Because of registry limitations some confounders could not be assessed. This knowledge may guide clinical decision-making when HT is considered.
Defining the New Normal in Cardiovascular Risk Factors
Authors: Philip Greenland, Donald M. Lloyd-Jones
Journal: JAMA Cardiology (2018)

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QOL-26. PLAYFUL SENSORIMOTOR TRAINING TO REDUCE THE SYMPTOMS OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY IN PEDIATRIC BRAIN TUMOR PATIENTS- A RANDOMIZED CONTROLLED TRIAL (RESET)
Authors: Fiona Streckmann, Vanessa Rustler, Uta Tacke, Patricia Hafner, Oliver Faude, Katrin Scheinemann
Journal: Neuro-Oncology (2018)

Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and clinically relevant side-effect of cancer treatment. There are no effective treatment options to reduce the symptoms of CIPN. Promising results have so far been achieved with specific exercise interventions. We would therefore like to conduct a prospective, multicenter, randomized two-armed trial. Patients (n=20) will be recruited. Prior to randomization, all primarily eligible patients that have received a platin derivate or vinca-alkaloid, will be screened for symptoms of CIPN. Eligible patients with a neurologically confirmed CIPN will then be randomized either into an intervention group or a control group. Patients in the intervention group will perform a standardized, age-adjusted, specific playful sensorimotor training program twice a week for 12 weeks in addition to usual care, while the control group receives treatment as usual. Data will be assessed at 3 time points: at baseline, after 12 weeks and after 12 weeks of follow-up. Primary endpoint is the Ped-mTNS score in order to subjectively as well as objectively assess the severity of CIPN symptoms. Additional parameters will be assessed via nerve conduction studies, CIPN related pain, dorsiflexion and knee extension as well as postural control. Furthermore, we will be evaluating patients’ level of physical activity, walk to run transition time, lower limb power as well as their integration in physical education in school and sport club activities. We hypothesize that patients in the intervention group will be able to reduce relevant symptoms of CIPN, improving related physical functions and enhancing children’s social reintegration.
Abstract 15267: Cardiac-Specific Insulin-Like Growth Factor-1 Receptor (IGF-1R) Expression Targets Maladaptive Hexosamine Biosynthesis and O-Linked GlcNAc Modification of Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA2a) in Diabetic Myocardium
Authors: Miles J De Blasio, Darnel Prakoso, Chengxue Qin, Sarah Rosli, Helen Kiriazis, Xiao-Jun Du, John C Chatham, Julie R McMullen, Rebecca H Ritchie
Journal: Circulation (2016)

Diabetes-induced cardiac complications include left ventricular (LV) fibrosis and dysfunction. Progression of “diabetic cardiomyopathy” has been linked to altered activation of the hexosamine biosy...
NIMG-42. INCIDENCE OF CAVERNOMATOUS LESIONS ON BRAIN MR OF PEDIATRIC PATIENTS TREATED WITH INTRAVENTRICULAR RADIOIMMUNOTHERAPY
Authors: Gurcharanjeet Kaur, Suzzane Wolden, Maria Donzelli, Sofia Haque, Kim Kramer
Journal: Neuro-Oncology (2018)

Cerebral cavernomas are encountered in pediatric patients with central nervous system (CNS) tumors and may cause neurological compromise. The incidence of cavernomatous lesions on brain MR of pediatric patients treated with intraventricular radioimmunotherapy is unknown. 217 patients were treated on institutional clinical trials with 2- 5 serial intraventricular injections 124I- or 131I- (2- 100 mCi) labeled monoclonal antibodies (cRIT) targeting tumor associated antigens. Pre-treatment brain MR at baseline and periodically for follow up over several years were obtained. Brain MR with Gradient echo T2*-weighted imaging and susceptibility-weighted imaging was used to identify cavernomatous lesions. Of 217 patients, 175/ (80.645%) identified as Caucasian, 18 (8.29%) African American, 9 (4.15%) Asian and 15 (6.91%) wished not to identify. Median age at the time of cRIT was 7.6 years (9 months-34.5 years). Median time for MR follow-up examinations was 38.4 months from the time of first cRIT. Cavernomatous lesions were detected in 22/217 (10 %) patients, and in 17/80 patients (21%) who survived > 2 years since cRIT. All in patients with prior external beam radiotherapy 22 (99%) Caucasian, 1 (1%) African American. Diagnoses were, metastatic neuroblastoma (N=12), medulloblastoma (N=8), ependymoma (n=1), pineoblastoma(n=1), and rhabdomyosarcoma (n=1). 12 patients had unifocal cavernomas frontal lobes (N=9), temporal lobe (N=2) or parietal (N=1). Multiple supratentorial and infratentorial lesions were detected in 9 patients; Only 1 patient had lesions involving the brainstem. One patient with cavernomas and concurrent vasculitis had neurologic symptoms; remaining patients were asymptomatic. CONCLUSIONS: Cavernomatous lesions are found in 10% of all patients and 21% of long term survivors treated with cRIT and external beam radiotherapy. The majority of lesions are multifocal and supratentorial. Despite numerous lesions, patients remain without neurologic compromise.
MBRS-48. DECIPHERING AND TARGETING EZH2 OVEREXPRESSION IN MEDULLOBLASTOMA
Authors: Etienne Danis, Angela Pierce, Ilango Balakrishan, Dong Wang, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite treatment with surgery, radiation, and chemotherapy, outcomes are unsatisfactory. MB is a heterogenous disease with four major and distinct molecular subgroups (WNT, SHH, Group 3 and Group 4) characterized by unique genomic and clinical features. Group 3 tumors have the worst outcomes and are frequently characterized by MYC amplification. Among the features of many of the group 3 tumors are the overexpression of EZH2, gains of the chromosome 7 and increased global H3K27me3 chromatin-repressive marks. EZH2, the histone methyltransferase responsible for H3K27me3 and located on 7q36.1 is critical during embryonic development to establish cell identities. In many cancers, both oncogenic and tumor suppressor functions have been observed for EZH2. More studies are required to better understand the role of EZH2 overexpression in medulloblastomas. Using RNAi, chromatin immunoprecipitation and pharmacological approaches, we were able to show that EZH2 inhibition impairs the pluripotency and self-renewal properties of human medulloblastoma cells and reactivates a differentiation program associated with differentiated cerebellar cells. Combinatorial drug screenings have been developed to identify drugs synergizing with EZH2 inhibition in human MB cell lines. Using human cerebellar stem cells and medulloblastoma cell lines, we also evaluated the effects of both EZH2 overexpression and pharmacological inhibition in the context of MYC overexpression in immunocompromised mice. The results of our in vitro and in vivo experiments will be presented.
MBCL-32. SAFETY AND EFFICACY OF CONCURRENT CARBOPLATIN DURING CRANIOSPINAL IRRADIATION FOR HIGH-RISK/ MEDULLOBLASTOMA IN A RESOURCE-LIMITED SETTING
Authors: Tejpal Gupta, Girish Chinnaswamy, Hari Sankaran, Tushar Vora, Maya Prasad, Sridhar Epari, Ayushi Sahay, Aliasgar Moiyadi, Prakash Shetty, Neelam Shirsat, Rahul Krishnatry, GodaJayant Sastri, Rakesh Jalali
Journal: Neuro-Oncology (2018)

To review the safety and efficacy of concurrent carboplatin during craniospinal irradiation (CSI) in patients with high-risk/metastatic medulloblastoma. Following surgery, patients with high-risk/metastatic medulloblastoma were treated with standard-dose CSI (35Gy/21 fractions) plus focal boost to primary site (19.8Gy/11 fractions) with concurrent carboplatin administered intravenously daily (30 mg/m2) during the first 15 fractions of CSI. Prophylactic growth factors during concurrent phase were used as appropriate. All patients received six cycles of adjuvant systemic chemotherapy after completion of concurrent regimen. Worst toxicity during concurrent chemoradiotherapy was analyzed for safety, while progression-free survival (PFS) and overall survival (OS) were analyzed as measures of efficacy. A total of 94 patients (median age of 10 years) were included. Eighty-five (91.5%) patients completed the planned concurrent chemoradiotherapy regimen, with interruption of carboplatin dosing in only 9 (9.5%) patients. Grade 3 and 4 toxicities of concurrent carboplatin during CSI included thrombocytopenia (n=21, 22.3%), neutropenia (n=37, 39.3%), anemia (n=7, 7.4%), and nausea/vomiting (n=3, 3.2%). There were no toxic deaths during concurrent chemoradiotherapy. At a median follow-up of 31.8 months, the 3-year PFS for localized high-risk disease was significantly better at 76.8% (95%CI: 58.4-87.8%) compared to 51.9% (95% CI: 33.8-67.2%) for metastatic disease (p=0.006). Similar estimates for 3-year OS were 83.9% (95%CI: 67.4-92.5%) and 56.2% (95%CI: 38.3-70.7%) for localized high-risk and metastatic medulloblastoma respectively (p=0.048). Concurrent carboplatin during CSI results in acceptable rates of acute toxicity, but significantly improved disease-related outcomes in high-risk/metastatic medulloblastoma compared to historical data reported previously from developing countries.
MBCL-29. FEASIBILITY OF SCREENING AND REASONS FOR SCREENING FAILURES IN THE SIOPE PNET 5 MB TRIAL
Authors: François Doz, Steven Clifford, Torsten Pietsch, Shivaram Avula, Martin Mynarek, Regine Riechers, Martin Benesch, Nicolas U Gerber, Maura Massimino, Magnus Sabel, Sandra Jacobs, Miguel Garcia Ariza, Antony Michalski, Jaroslav Sterba, Virve Pentikäinen, Stefan Rutkowski
Journal: Neuro-Oncology (2018)

Current medulloblastoma treatment must take into account bio-pathological risk-categories. The ongoing European PNET 5 MB trial for standard risk medulloblastoma comprises two sub-studies: a LR (low-risk) arm for WNT-medulloblastoma and a SR (standard-risk) arm for non-anaplastic/LCA, non-WNT-medulloblastoma without MYCN or MYC amplification. Submission of frozen tumor sample is mandated for this biomarker-based patient stratification. Pre-screening also includes pathological and imaging review. We investigated all pre-screened standard-risk medulloblastoma patients (i.e. excluding those diagnosed locally with residual or metastatic disease*) and reasons for non-inclusion in the LR or SR arm. 235 standard-risk medulloblastoma patients from 11 countries were pre-screened. Reasons for non-inclusion (130) were: imaging review demonstrating metastatic disease (12*), or surgical residue above 1.5 cm2 (12), histology review demonstrating anaplastic or LCA-MB (31), unavailability of frozen tumor tissue (24), biological criteria demonstrating high risk factors MYCN or MYC amplification (17), randomization refusal in the SR-arm (13), or other (21). 105 of 235 patients (45%) of screened patients have been included into the PNET 5 MB trial per 31 Aug 2017. Histopathological review, frozen sample collection, biological pre-inclusion-assessments, and radiological review are feasible within 28 days of surgery, allowing inclusion of a comprehensively screened cohort of patients, as planned in the study. An amendment for upfront prospective subgrouping of all medulloblastoma samples, and constitutional genetic testing in SHH-MB and in WNT-MB without somatic CTNNB1 mutation will be implemented in 2018. *No results from Germany included, as reports on local assessments of metastatic disease are not yet available.