tbuckley/cabot-search huggingface dataset:
MBRS-30. TORC1/2 INHIBITION SENSITIZES MYC-DRIVEN MEDULLOBLASTOMA CELLS TO CARBOPLATIN CHEMOTHERAPY
Authors: Rachael Maynard, Allison Hanaford, Bradley Poore, Jeffrey Rubens, Tenley Archer, Pablo Tamayo, Scott Pomeroy, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. We performed an in silico analysis of human stem cell model of medulloblastoma, which predicted mTOR inhibitors as a potential therapeutic agent. We hypothesized that the dual TORC1/1 inhibitor TAK228 would have activity against MYC-driven medulloblastoma. We tested this hypothesis using the MYC-amplified medulloblastoma cell lines D425 and D283. We determined that TAK228 was effective in inhibiting both mTORC1/2 in D425 at concentrations of 20nM as measured by western blots showing decreased p-S6 (90% decrease) and p-AKT473 (70% decrease) expression. We found that treatment with TAK228 decreases cell growth at concentrations of 20nM (D425 p<0.005 vs vehicle, D283 p<0.0005 vs vehicle) and induces apoptosis as measured by cleaved caspase 3 staining and increased expression of cleaved PARP (D425 p<0.05 vs vehicle, D283 p<0.0005 vs vehicle). Because mTOR inhibition can suppress glutathione production, and glutathione is required to detoxify platinum containing chemotherapy, we hypothesized that TAK228 would cooperate with the platinum containing chemotherapy, carboplatin. TAK228 in combination with carboplatin inhibits growth (D425 p<0.05 vs vehicle, D283 p<0.05 vs vehicle) and induces apoptosis as measured by cleaved PARP expression (7-fold increase in combination versus vehicle). In vivo testing is currently underway to determine the survival benefit of TAK228 in combination with carboplatin. TAK228 is effective at inhibiting growth and inducing apoptosis in high-MYC medulloblastoma cell lines and shows combinatorial efficacy with carboplatin.
Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation
Authors: Marito Araki, Yinjie Yang, Misa Imai, Yoshihisa Mizukami, Yoshihiko Kihara, Yoshitaka Sunami, Nami Masubuchi, Yoko Edahiro, Yumi Hironaka, Satoshi Osaga, Akimichi Ohsaka, Norio Komatsu
Journal: Leukemia (2018)
The OEA effect on food intake is independent from the presence of PPARα in the intestine and the nodose ganglion, while the impact of OEA on energy expenditure requires the presence of PPARα in mice
Authors: Aurélie Caillon, Kalina Duszka, Walter Wahli, Françoise Rohner-Jeanrenaud, Jordi Altirriba
Journal: Metabolism (2018)
MBCL-40. UNFAVORABLE CLINICAL COURSE OF A WNT-ACTIVATED MEDULLOBLASTOMA
Authors: Christine Haberler, Andreas Peyrl, Thomas Czech, Marcel Kool, Irene Slavc
Journal: Neuro-Oncology (2018)

Prognostic risk factors in medulloblastomas currently comprise extent of resection, M-staging at diagnosis, histopathological subtype and genetic aberrations (MYC/N status, CTNNB1 mutation). The majority of medulloblastomas with WNT activation (WNT-MB) are characterized by CTNNB1 mutation and associated with a particular good prognosis in children up to 16 years of age. Tumor recurrence and death of disease are exceptional in children having WNT-MB, therefore they are considered as low risk tumors and treated with a decreased chemotherapy protocol in the European PNET5 therapy trial. We report a female patient from Georgia who presented at the age of 9 years with a cerebellar midline tumor. The tumor was completely resected and diagnosed as medulloblastoma. She was treated with RTX and CTX. 5 years after diagnosis a local recurrence occurred and a reoperation was performed. Histopathology revealed a classic medulloblastoma, a CTNNB1 mutation was detected by Sanger sequencing and WNT subgroup confirmed by methylation array. Re-evaluation of the primary tumor confirmed the diagnosis of a classic medulloblastoma, however no CTNNB1 mutation could be detected. Despite gross total resection of the recurrence followed by antiangiogenic metronomic treatment the tumor progressed after one year, and the patient succumbed to her disease. Postmortem analysis revealed a highly anaplastic medulloblastoma with focal myogenic differentiation (medullomyoblastoma) and CTNNB1 mutation. In conclusion, the absence of a detectable CTNNB1 mutation in the primary tumor could indicate its presence only in a small subclone and shows that a WNT-MB with a classic subtype may occasionally evolve into a highly anaplastic MB.
Abstract 20271: A Comprehensive Evaluation of Hospital-Level Appropriateness, Episode Costs and Outcomes for Assessing Value in Percutaneous Coronary Intervention: A Statewide Analysis
Authors: Daniel Alyesh, Milan Seth, David Miller, Jim Dupree, John Syrjamaki, Simon Dixon, Hitinder Gurm, Brahmajee Nallamothu
Journal: Circulation (2016)

Introduction: Appropriate patient selection, good outcomes, and low episode costs are important dimensions of high value care in percutaneous coronary intervention (PCI). Understanding the interrel...
Counter-terrorism laws are used against doctors, report says
Authors: Janice Hopkins Tanne
Journal: BMJ (2018)

Governments are using counter-terrorism laws to punish doctors and other healthcare professionals who treat alleged terrorists or enemies, says a report. It highlights practices to safeguard the provision of healthcare and lists recommendations for states and UN political agencies.

The report was prepared by the University of Essex Human Rights Centre, the Center for Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health, and the Safeguarding Health in Conflict Coalition at the request of Dainius Puras, United Nations special rapporteur …
GERM-04. MANAGEMENT OF CNS GERM CELL TUMORS: EXPERIENCE FROM SUN YAT-SEN UNIVERSITY CANCER CENTER
Authors: Chengcheng Guo, Qun-ying Yang, Jian Wang, Xiao-fei Sun, Shao-xiong Wu, Zhong-ping Chen
Journal: Neuro-Oncology (2018)

Primary CNS germ cell tumors (CNS-GCTs) are a group of heterogeneous tumors, and comparative higher incidence in Asian countries. Here we present our institutional experience for CNS-GCTs treatment. There are 209 CNS-GCTs cases treated at Sun Yat-sen University Cancer Center during last 15 years. The median age of patients was 16 years old (4-69 y-old). The tumors were classified as Germinoma and Nongerminoma germ cell tumors(NG-GCTs), and also secretory sub-type(AFP≥10 ng/dL and/or β-HCG)≥50 IU/L) or non-secretory sub-type(normal level of tumor marker). There were 60 cases received Ventricle-peritoneal shunt (V-P shunt) or endoscopic third ventricle colostomy due to obstructive hydrocephalus. Treatment modality including: comprehensive treatment 84cases (40.2%), ie chemotherapy plus radiation therapy (some cases with chemo-Radio-chemo Sandwich Therapy) with or without surgical intervention; Monotherapy, ie Chemotherapy only:37 (17.7%), Radiotherapy Only:13 (6.2%). Surgery for tumor removal or biopsy:55cases (25.4%), in which 4 cases were failed from initial diagnostic chemotherapy. There were also some patients(about 6%) received Gamma knife radiosurgery. The 5 years overall survival(OS) rate was better for those with comprehensive treatment, compared those with monotherapy cases: 86.5% vs 66.7%. The 5 ys OS rate according tumor markers was also different: Non Secretory Subtype:79.8%,HCG increased Subtype: 92.9%, AFP increased Subtype: 64.8%, and AFP+HCG coincreased Subtype: 75.0%. Conclusion from our institutional experience: Although smaller number of patients need surgical tumor removal, clinical diagnosed CNS-GCT (without histological confirmation) patients may obtain good responses when receiving comprehensive treatments of chemotherapy combined with radiotherapy.
FRI0707-HPR Patients’ experiences of health in early rheumatoid arthritis – a qualitative study
Authors: E. Landgren, A. Bremander, E. Lindqvist, K. Van der Elst, I. Larsson
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> The World Health Organization defines health as "<i>a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity</i>". Health changes dramatically when a person becomes ill in a chronic disease as rheumatoid arthritis (RA). RA is a disease with great impact on all aspects of life. Living with RA affects patients' health including physical, emotional, psychological and social aspects. The purpose of a person-centered care is to see patients as experts; sharing decisions with them and helping them manage their health. Therefore it is important to understand how patients in early disease stage of RA experience the concept of health. <h3>Objectives:</h3> The purpose of this study was to describe patients' experiences of health in early RA. <h3>Methods:</h3> The study had a descriptive design with a qualitative content analysis approach. Individual interviews were conducted with 24 patients with early RA. In this study the patients had disease duration less than 12 months. A manifest qualitative content analysis was used to analyze the question: "What does health mean to you?" <h3>Results:</h3> In the early stage of RA, patients experienced health as the most important goal in their life. They described health as well-being, independence, life satisfaction and vitality. Health as well-being meant to feel good, be painless and have a good sleep to feel rested. Health as independence meant to have both physical and financial prerequisites to perform everyday activities, to exercise and being able to travel. Health as life satisfaction meant to feel joy in life, enjoy the family and to believe in the future. Health as vitality meant to have the energy, power and strength to cope with everyday life. The patients expressed that their health had been adversely affected by the RA disease and they had a strong desire for full health including well-being, independence, life satisfaction and vitality. <h3>Conclusions:</h3> Patients in an early stage of RA describe a strong desire to regain health in terms of well-being, independence, life satisfaction and vitality. The concept of health at early RA is similar to health at established RA in terms of well-being, independence and life satisfaction. Unique findings for patients with early RA are the description of health as vitality, and the emphasis of having energy, power and strength to cope with everyday life. Health professionals should have these different ways of experiencing health in mind when providing person-centred care to patients with early RA. Depending on the patients' perception of health, different support strategies are needed. <h3>Disclosure of Interest:</h3> None declared
GERM-20. NEUROENDOSCOPIC BIOPSY OF INTRACRANIAL GERM CELL TUMORS: ACCURACY AND COMPLICATIONS
Authors: Tomonari Suzuki, Junichi Adachi, Kazuhiko Mishima, Takamitsu Fujimaki, Takaaki Yanagisawa, Ryo Nishikawa
Journal: Neuro-Oncology (2018)

Intracranial germ cell tumors (GCTs) are a heterogeneous group of lesions. It is important to obtain the accurate histological diagnosis since the treatment outcomes can depend on histology. Neuroendoscopic biopsy is a minimally invasive procedure and employed widely. But it is not yet clear whether neuroendoscopy can make so accurate diagnosis as craniotomy without increasing the risk of dissemination. We compared the diagnostic rate and recurrence rate of these two procedures. Forty patients with intracranial GCTs treated in our institute from 2007 to 2017 were included in this study. More than 6 pieces of tumor tissues were obtained with neuroendoscopy. As highly elevated tumor marker signifies highly malignant tumor, we started treatment without a histological diagnosis. For all patients except those with extremely highly elevated tumor markers, the histological diagnoses were made by neuroendoscopy or craniotomy. Of number cases with germinoma, 3 cases (neuroendoscopy 2, craniotomy 1) relapsed. All three cases were treated with additional chemotherapy and/or radiotherapy to survive. Of number cases with intermediate risk group tumors, 1 case who underwent craniotomy developed recurrence. High-risk tumors were diagnosed by tumor markers in 2 patients, 5 by endoscopy and one by craniotomy. One patient thought to be intermediate risk group by tumor marker, obtained the histological diagnosis of yolk sac tumor. The recurrence rate for neuroendoscopy and craniotomy was 8% and 15% respectively. Neuroendoscopy is useful for histological diagnosis as well as craniotomy and would not increase recurrence rate.
ATRT-26. AN ANALYSIS OF PUTATIVE CELLS OF ORIGIN FOR MALIGNANT RHABDOID TUMOURS (MRT): A FRONTIER FOR DEVELOPMENT OF MRT CANCER MODELLING AND IDENTIFICATION OF POTENTIAL THERAPEUTIC TARGETS
Authors: Ras Ramli, Martina Finetti, Matthew Selby, Yura Grabovska, Stepehn Crosier, Simon Bailey, Steven Clifford, Daniel Williamson
Journal: Neuro-Oncology (2018)

Malignant Rhabdoid Tumours (MRT) are rare, highly aggressive childhood malignancies characterised by biallelic inactivation of gene SMARCB1. MRT may occur anywhere, most frequently in the brain (Atypical Teratoid/Rhabdoid Tumor, ATRT), kidneys and soft tissues. The aetiology of MRT regarding cell of origin and how this relates to tumour location and molecular subtype is largely unknown. Although biallelic loss of SMARCB1 is minimally sufficient to initiate tumourigenesis, we postulate that this is exquisitely dependent upon mutation in a particular type of cell of origin most likely an early pluripotent cell. We performed a meta-analysis cross-referencing expression profiles from primary MRT (n= 119), and functional models in which SMARCB1 was re-expressed (n=5 lines) with expression profiles from multiple candidate stem cell types including epithelial, embryonic, neural, mesenchymal and neural crest (n= 446) suggesting three putative candidate cell populations within the family of neural crest (NC), neural progenitor and mesenchymal stem cells. The extent of transcriptional overlap clearly reflects differences in tumor location and molecular subgroup. We developed a lentiviral CRISPR-CAS9 system to efficiently model SMARCB1 mutation in primary candidate cells of origin ex vivo. Unlike most cells tested, early neural crest cells (O9-1) tolerated SMARCB1 mutation and conferred proliferative advantage resembling human MRT molecularly and immunophenotypically. Our findings suggest NC as a potential cell of origin for MRT. We describe a system for ranking putative cells of origin and a practical means for testing SMARCB1 mutation ex vivo. Furthermore, we show evidence that subtypes within MRT have different cells of origin.
MBCL-28. PREDISPOSITION OF WNT-ACTIVATED MEDULLOBLASTOMA FOR PRIMARY INTRATUMORAL HEMORRHAGE
Authors: Dominik Reisinger, Johannes Gojo, Andreas Peyrl, Amedeo Azizi, Lisa Mayr, Marcel Kool, Thomas Czech, Gregor Kasprian, Irene Slavc
Journal: Neuro-Oncology (2018)

Primary intratumoral hemorrhage as a presenting sign is rare in children with medulloblastomas but may result in severe complications. Purpose of this study was to investigate clinical as well as radiological presentation of intratumoral hemorrhage in medulloblastoma patients in the context of molecular subgroups. We included 97 consecutive medulloblastoma patients treated at the Medical University of Vienna between 1993 and 2017. Medulloblastoma subgroups were assigned in 77 cases, by either 450K methylation array (n=58) or immunohistochemistry and CTNNB1 sequencing in 19 additional cases. For 57 patients imaging at diagnosis was available and reviewed by an experienced neuroradiologist. Cases were reviewed in terms of subgroup analysis and clinical and radiological presentation as well as outcome. Overall, four patients in our study cohort presented with an acute event due to a local space occupying hemorrhage. While no patient died as a direct consequence of hemorrhage, all suffered from severe sequelae. Interestingly, all four cases belonged to the wingless (WNT) subgroup (n=12). Moreover, two additional patients of the WNT subgroup displayed radiological evidence of hemorrhagic foci at primary imaging whereas it was absent in the other subgroups. Our results suggest that half of WNT medulloblastomas display varying degrees of intratumoral hemorrhage at the time of diagnosis. Moreover, this appears to be a unique propensity of the WNT subgroup and heralds severe neurological long-term sequelae in this favorable subgroup. Consequently, presence of hemorrhage in tumors arising from the cerebellar peduncle or cerebellopontine angle could aid in radiological diagnosis of WNT medulloblastomas.
HDL-apoA-I induces the expression of angiopoietin like 4 (ANGPTL4) in endothelial cells via a PI3K/AKT/FOXO1 signaling pathway
Authors: Dimitris Theofilatos, Panagiotis Fotakis, Efi Valanti, Despina Sanoudou, Vassilis Zannis, Dimitris Kardassis
Journal: Metabolism (2018)
NSRG-05. SAFETY OF ULTRASOUND-INDUCED BLOOD-BRAIN BARRIER OPENING IN PEDIATRIC PATIENTS WITH REFRACTORY SUS-TENTORIAL MALIGNANT BRAIN TUMORS BEFORE CHEMOTHERAPY ADMINISTRATION – THE SONOKID CLINICAL TRIAL
Authors: K Beccaria, M Canney, G Bouchoux, S Zohar, N Boddaert, F Bourdeaut, F Doz, C Dufour, J Grill, A Carpentier, S Puget
Journal: Neuro-Oncology (2018)

To determine the safety of repeated disruption of the blood-brain barrier (BBB) by low intensity pulsed ultrasound (LIPU) with the Sonocloud® device in children with recurrent malignant supra-tentorial brain tumors prior to intra-venous carboplatin chemotherapy. The safety of this procedure is currently being validated in adult patients with recurrent glioblastoma (Carpentier et al. 2016). MATERIAL AND This single-center phase I/IIa clinical trial will include 12 to 24 patients aged 5 to 18 years, with recurrent malignant supra-tentorial brain tumors. The Sonocloud® device will be implanted into the skull under general anesthesia, during a standard procedure (biopsy or resection). Thanks to a transdermic connexion, sonications will be performed monthly in combination with injection of an ultrasound contrast agent (Sonovue®). US parameters will be based on the adult patients study. BBB disruption will be evaluated using multimodal magnetic resonance imaging (MRI). Carboplatin will be injected during the hour following the sonication. Patients will receive a maximum of 6 monthly sonications and will be followed at least for 6 months after the last sonication. EXPECTED The principal criteria will be the absence of grade ≥ 3 neurological toxicity (NCI-CTCAE 4.0 Version, clinical and radiological assessment) linked to the US-induced opening of the BBB after first treatment. Secondary evaluation criterias will include tolerance of repeated sonications, overall survival and progression-free survival, and feasibility of the technique. SONOKID is the first clinical trial assessing the feasibility and tolerance of US-induced opening of the BBB in children. SPONSOR Canceropole Ile de France.
MBCL-01. VINCRISTINE NEUROTOXICITY UNMASKING CHARCOT-MARIE-TOOTH DISEASE
Authors: Trisha Kissoon, Sridharan Gururangan
Journal: Neuro-Oncology (2018)

Vincristine-induced neuropathy has been well described in the literature. However, few cases of underlying hereditary neuropathy revealed after vincristine therapy in pediatrics have been reported. We present a case of a 6 year old female with medulloblastoma. Patient presented with two weeks of headaches, gait instability, and vomiting. Pathology from tumor resection was consistent with SHH medulloblastoma. She started treatment per the SJMB12 study and received CSI+ focal boost for average risk disease followed by chemotherapy with vincristine, cisplatin, and cyclophosphamide. Ten days after Cycle 2, she developed lower extremity weakness that ascended to her upper extremities. Magnetic resonance imaging of the brain and spine noted thickening and enhancement of lower cranial nerves and the anterior and posterior spinal nerve roots. A presumptive diagnosis of Guillain-Barre syndrome was made and she received IVIG 1 mg/kg daily for three consecutive days. Vincristine was removed from her treatment regime given its known association with peripheral neuropathy. Further evaluation of patient noted presence of deep tendon reflexes and persistent foot drop, leading to consideration of hereditary neuropathy. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Decision was made to exclude Cisplatin from her regime due to reported exacerbations of underlying peripheral neuropathy. At the time of this report, our patient is without disease three months post-treatment. She has returned to school and shown significant improvements with physical therapy. This case highlights the importance of early recognition of acute vincristine neurotoxicity as it may raise a suspicion of an underlying hereditary neuropathy.
ATRT-33. TARGETING THE LETHAL PEDIATRIC TUMORS ATRT AND DIPG WITH THE DNA MINOR-GROOVE BINDING AGENT QUINACRINE
Authors: Harpreet Kaur, Huizi Guo, Smit Shah, Sepehr Akhtarkhavari, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

Atypical teratoid/rhabdoid tumors (AT/RT) and diffuse intrinsic pontine glioma (DIPG) are incurable pediatric brain tumors. Developing new targets and novel therapeutics are urgently needed. We have shown that AT/RT and DIPG tumors and cell lines express increased amounts of the epigenetic modifier high mobility group AT-hook 2 (HMGA2). HMGA2 is a DNA-binding oncoprotein that regulates transcription during normal embryogenesis and in cancer stem cells. Targeting HMGA2 using short hairpins significantly decreased AT/RT growth and increased survival of xenografted mice. We hypothesized that pharmacological inhibition of HMGA proteins using DNA minor-groove binding drugs like quinacrine will decrease AT/RT and DIPG growth due to displacement of HMGA proteins from the DNA. We used quinacrine in three AT/RT (BT37, CHLA-06, CHLA-04) and DIPG (JHHDIPG1, SUDIPGXIII, JHHDIPG16A) lines. Quinacrine has been used in millions of humans to treat malaria and parasitic infections and has a well-known safety profile. Quinacrine penetrates the brain, and we can achieve micromolar levels in brain after oral administration. In both tumor cell lines, quinacrine causes a dose-dependent reduction in growth (MTS) and proliferation (BrdU) compared to vehicle-treated cells (P<0.05). Treatment of both tumor lines with quinacrine significantly increased apoptosis (cleaved caspase-3 and cleaved PARP) compared to control cells (P<0.05). Quinacrine had no effect on growth of normal hindbrain cells. Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for these devastating tumors. Future studies are aimed at validating the in vivo efficacy and mechanism of quinacrine in AT/RT and DIPG.