tbuckley/cabot-search huggingface dataset:
DIPG-29. PRECLINICAL EFFICACY OF COMBINED ACVR1 AND PI3K/mTOR INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Diana Carvalho, Nagore Gene Olaciregui, Ruth Ruddle, Adam Donovan, Akos Pal, Florence Raynaud, Peter J Richardson, Angel Montero Carcaboso, Chris Jones
Journal: Neuro-Oncology (2018)

Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of DIPG patients. Treatment of ACVR1-mutant DIPG patient-derived models with multiple ALK2 inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though as monotherapies they are not sufficient to achieve complete anti-tumour response. As alterations in the PI3-kinase pathway (PIK3CA,PIK3R1,PTEN) co-segregate with ACVR1 mutations in patient samples, we sought to explore the utility of combinatorial targeting of ALK2 and PI3K/mTOR. Two orally bioavailable ALK2 inhibitors with good CNS penetration (LDN-193189,LDN-214117) showed synergy with the mTOR inhibitors AZD8055 and everolimus in a series of patient-derived DIPG cells in vitro, though these molecules remain lead compounds and not clinically-approved drugs. In an Artifical Intelligence-augmented search for approved compounds which could be used to treat DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ALK2 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits the ABCG2 and P-gp transporters, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, results in micromolar levels of vandetanib in the mouse brain, and is shown to effectively inhibit pharmacodynamic biomarkers. This may represent a rapidly translatable approach in children with ACVR1 mutant DIPG.
RADI-14. SPORADIC MENINGIOMAS OF THE PEDIATRIC POPULATION: A REVIEW OF NEURORADIOLOGICAL, NEUROPATHOLOGICAL, AND NEURO-ONCOLOGICAL ATTRIBUTES
Authors: Paraag Bhatt, Kathleen Dorris, Jean Mulcahy Levy, Kami Wolfe Schneider, Alexandra Suttman, Andrew Donson, Nicholas Foreman, Bette K Kleinschmidt-DeMasters, Nicholas Spence, Ilana Neuberger, David Mirsky
Journal: Neuro-Oncology (2018)

Sporadic meningiomas within the pediatric population manifest neuroimaging features that are poorly defined in the literature. We sought to establish a set of imaging features which may help lead to early diagnosis, as well as determine whether the imaging attributes, neuropathology, and clinical outcomes of sporadic meningiomas differ from those that occur in the context of neurofibromatosis type 2 (NF2). A single center retrospective study was performed. Inclusion criteria consisted of diagnosis at ≤21 years of age, histological confirmation of meningioma (sporadic cases), and available pre-operative imaging. Patients were stratified by NF2 genetic status. Medical records served as the source for followup of clinic data and CT and MRI imaging features were re-reviewed. Twenty total meningiomas were reviewed for neuroimaging characteristics, representing multiple meningiomas in 5 patients (all NF2), and solitary meningiomas in 8 patients (all sporadic). The median age at presentation was 12 years (range, 10 months-19 years). Sporadic cases presented with more atypical imaging features including larger size, mixed cystic and solid appearance, presence of calcification, and more peri-lesional edema than did those with confirmed NF2. Sporadic pediatric meningioma imaging characteristics differ from those occurring in the context of NF2. Recognition of these features may help lead to early diagnosis and guide surgical planning and management.
DIPG-54. TREATMENT OF A PEDIATRIC PATIENT WITH AN H3.3 K27M MUTANT DIPG WITH ONC201, A SELECTIVE DRD2 ANTAGONIST
Authors: Fernando Suarez, James M Stafford, Rohinton Tarapore, Wolfgang Oster, Joshua E Allen, Andrew S Chi, Sharon Gardner
Journal: Neuro-Oncology (2018)

Although radiotherapy is the mainstay of treatment for children with diffuse intrinsic pontine gliomas (DIPG), fewer than 10% of patients survive past two years from diagnosis despite 30 years of clinical trials. ONC201 is an oral, selective DRD2 antagonist that induces p53-independent apoptosis and has been reported to produce a durable response in an adult with a H3 K27M mutant recurrent glioblastoma. In April 2017, a 33 month old female presented with headaches, right 6th nerve palsy and MRI findings consistent with a DIPG. A biopsy revealed an H3.3 K27M mutant glioblastoma. A patient-derived DIPG tumorsphere cell line was created from the biopsy sample and in vitro studies revealed a potent reduction in cell viability following 5 days of treatment with ONC201, with an IC50 of approximately 600nM. She received involved field irradiation (54Gy). Starting one month following irradiation, single agent, oral ONC201 125mg (11mg/kg) was given weekly on a compassionate use protocol. An MRI, 4 months later revealed stable disease. Clinically, her 6th nerve palsy and left hemiparesis have improved. She is otherwise asymptomatic. Pharmacokinetic studies are being analyzed. She has had no side effects detected. Based on our in vitro and clinical findings as well as other experience in vitro and in adults, ONC201 is currently being investigated with a phase 1 trial in pediatric patients with H3 K27M mutant gliomas.
MBRS-19. BIOCHEMICAL AND ONCOGENIC CHARACTERIZATION OF HOTSPOT KBTBD4 MUTATIONS IN MEDULLOBLASTOMA
Authors: Hilmarie Muniz-Talavera, Jennifer Hadley, Paul A Northcott
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant childhood brain tumor. Our recent analysis of the MB genomic landscape in a cohort of 500 patients discovered subgroup-specific hotspot mutations targeting KBTBD4, a poorly characterized member of the BTB-BACK-Kelch domain family of proteins. Based on homology with other family members, KBTBD4 is predicted to function as a substrate adaptor for E3 ubiquitin ligases, facilitating substrate recruitment via its C-terminal Kelch domain. KBTBD4 mutations occurred exclusively in Group 3 and Group 4 patients as in-frame insertions clustered in the Kelch domain, suggesting these variants may disrupt physiological KBTBD4-substrate interactions. Herein, we used a combination of advanced proteomic and gene targeting strategies to determine the normal physiological function of KBTBD4 and elucidate its role in MB pathogenesis. IP-MS/MS results identified proteins associated with the ubiquitin-proteasome system (UPS), including E3 ubiquitin ligases (CUL3, CHIP, UBR4), ubiquitin-associated proteins (CACUL1, RPS27A), as well as chaperone-associated proteins (HSP90, TCP1, BAG2, NUDC3). Candidate interacting partners were subsequently confirmed through co-IP/Western-blot experiments, substantiating preliminary hypotheses related to KBTBD4 function. To investigate the role of mutant KBTBD4 in MB progression, we aim to target KBTBD4 in MB PDX models harboring prototypic insertions. Parallel studies encompassing a complete phenotypic characterization of Kbtbd4 knock-out and knock-in mice carrying MB-specific mutations will further validate KBTBD4 as a bona fide MB driver gene, and mechanistically disentangle how KBTBD4 Kelch domain mutations promote tumorigenesis. These studies will provide new insights into MB biology with the potential to disclose novel therapeutic vulnerabilities for treating mutant KBTBD4-driven MB.
The role of endothelial filtration for locoregional targeting of hepatic tumours with endothelium-specific antibodies and nanoparticles
Authors: N. Winkler, F. Strübing, D. Kyuno, B. Qian, Z. Wang, W. Groß, W. Mier, E. Ryschich
Journal: Annals of Oncology (2018)

Introduction: Tumour targeting using the microvascular system represents a highly promising approach for therapy of hepatic tumours. The aim of this study was to assess the role of endothelial filtration for locoregional targeting of hepatic tumours using endothelium-specific antibodies (Abs) and nanoparticles (NP). Methods: Fast-binding endothelium-specific Abs were selected based on histological analysis of their binding capacity. The capture efficacy and specific local enrichment of near-infrared and fluorescence-labelled Abs as well as Ab-coated NP (magnetic NP and doxorubicin-encapsulating liposomes) by hepatic endothelium under different hydrodynamic conditions was analysed using isolated liver perfusion models. The targeting potential of the fluorescence- or 125I-labelled carriers was studied in vivo in different hepatic tumour models using biodistribution analysis, scintigraphic imaging, and fluorescence microscopy. Results: Several selected mouse and human Ab clones showed a very fast binding capacity to normal and/or tumour-associated endothelium. Upon injection into the tumour-feeding artery, the Ab was immediately captured in the microvasculature during the first passage. At doses not exceeding the saturation level of endothelial epitopes, the filtration efficacy was almost 90%. Our results showed that the efficacy of endothelial filtration is controlled by factors such as Ab affinity, number of binding sites on the endothelium, and microvascular flow rate. The method of endothelial Ab filtration demonstrated a very high intratumoural enrichment of targeting substance in vivo after locoregional intraarterial injection of 125I-labelled Abs in hepatic tumour models. In contrast to Abs, coated NP showed a strongly reduced potential for endothelial filtration under flow conditions. However, use of liposomes coated with one specific Ab clone achieved effective local liposome enrichment even under moderate flow reduction. Conclusion: Here, we provide an initial demonstration of the phenomenon of endothelial filtration for specific tumour targeting and analyse hydrodynamic and molecular mechanisms that control this process in the microcirculation. This unique phenomenon can broadly prevent systemic circulation of the drug applied by intravascular injection and may have specific relevance for targeting of hepatic tumours using both Abs and NP.
QOL-37. LATE ONSET OR ATYPICAL ADRENAL INSUFFICIENCY DUE TO ACTH DEFICIENCY IN SURVIVORS OF NON-PITUITARY BRAIN TUMORS
Authors: Malinda Wu, Claire Mazewski, Dolly Aguilera, Natia Esiashvili, Briana Patterson
Journal: Neuro-Oncology (2018)

Treatment with cranial irradiation increases the risk for ACTH deficiency (ACTH-D). Screening for ACTH-D is controversial due to lack of an ideal modality. The Children’s Oncology Group Long-Term Follow-up Guidelines (version 4.0) recommends that patients exposed to ≥30 Gy of cranial irradiation have annual endocrine evaluation. The duration of follow-up is not specified. We describe three patients with late onset or atypical presentation of symptomatic ACTH-D after treatment of brain tumors. Prior to ACTH-D diagnosis, these patients had no daily exogenous glucocorticoids for more than four years (Y). Patient 1 had standard-risk medulloblastoma, received 23.4 Gy to the craniospinal axis and 54.8 Gy posterior fossa boost. She had spells of dehydration, syncope, hypoglycemia and hypotension 4Y after radiation. Testing confirmed ACTH-D. Symptoms resolved with treatment. Patient 2 had high-risk medulloblastoma, received 48 Gy to the hypothalamic-pituitary axis (HPA). He had annual assessment of adrenal function; 7Y after irradiation, testing demonstrated ACTH-D. Weight and appetite improved with treatment. Patient 3 had right temporal xanthoastrocytoma treated with 54 Gy photon radiation during which he received maximum dose 32 Gy to HPA. He developed left frontal glioblastoma multiforme 5Y later treated with 59.4 Gy proton radiation. 7.5Y after second radiation, he developed anorexia and fatigue. Testing demonstrated ACTH-D. ACTH-D is a potentially life-threatening complication of cranial irradiation which may occur many years after cancer treatment has ended. It is important to continue serial evaluations and remain vigilant for ACTH-D.
TBIO-07. ASSESSING THE UTILITY OF DNA METHYLATION PROFILING IN BRAIN TUMOR DIAGNOSTICS—THE PROSPECTIVE MNP2.0 STUDY
Authors: Dominik Sturm, Felix Sahm, Felipe Andreiuolo, David Capper, Agata Rode, Kerstin Grund, Stefan Rutkowski, Brigitte Bison, Marco Gessi, Andreas von Deimling, Monika Warmuth-Metz, Torsten Pietsch, Stefan M Pfister, David T W Jones
Journal: Neuro-Oncology (2018)

Children can be affected by a large variety of CNS tumor entities with very divergent outcomes, some of which are exceedingly rare. DNA methylation analysis is a powerful tool to distinguish biologically distinct CNS tumor classes within and across histological entities. The Molecular Neuropathology 2.0 study aims to integrate genome wide (epi-)genetic diagnostics with reference neuropathological assessment for all newly-diagnosed pediatric CNS tumors in Germany. In the first 2 ½ years, 675 patients with sufficient tissue were enrolled from 55 centers. For >95% of patients, a diagnosis according to the WHO classification was assigned by reference neuropathology. Using 10 FFPE sections as input, a DNA methylation-based molecular diagnosis was established in 95% of cases, of which 84% were assigned to a distinct CNS tumor methylation class. The remaining 16% did not match any of 82 currently established classes, with evidence for novel rare entities. Targeted gene panel sequencing of >130 genes performed for 88% of patients with matched blood samples indicated diagnostically, prognostically, or therapeutically relevant somatic alterations in 47%. Germline DNA sequencing data indicated potential predisposition syndromes in ~10% of patients. Discrepant results by neuropathological and molecular classification (~20%) were discussed in a weekly multi-disciplinary tumor board including reference neuroradiological evaluation. Clinical follow-up data for all patients is being collected by the HIT study centers. This ongoing study adds a valuable layer of information to clinical neuropathological diagnostics in Germany and will provide insight into CNS tumors with divergent neuropathological and molecular classification with potential implications for future patient management.
NSRG-23. 5-AMINOLEVULINIC ACID GUIDED RESECTION OF PAEDIATRIC CENTRAL NERVOUS SYSTEM TUMOURS: THE LARGEST SINGLE CENTRE SERIES IN THE UK
Authors: Charlotte Burford, Nida Kalyal, Anand Pandit, Jose Pedro Lavrador, Cristina Bleil, Ahilan Kailaya-Vasan, Bassel Zebian
Journal: Neuro-Oncology (2018)

5-aminolevulinic acid (5-ALA, Gliolan) is widely used in adults for facilitating the resection of high-grade gliomas. However, its safety and efficacy in the paediatric population remains to be established. We present the UK’s first case series of 10 patients, undergoing 11 operations with 5-ALA. 10 consecutive patients (aged 1.6-15 years) underwent pre-operative administration of 20mg/kg of 5-ALA. The tumours were visualised intra-operatively under violet-blue light and the presence and usefulness of fluorescence was assessed. Strong fluorescence was observed in two WHO grade III ependymomas and a GBM (IV). Moderate fluorescence was seen in one pilocytic astrocytoma (I) and a pilomxyoid astrocytoma (II). Weak fluorescence was observed in a diffuse astrocytoma (II). The tumours types which showed no fluorescence included: a pilocytic astrocytoma, a glioneuronal tumour (II) and an anaplastic medulloblastoma (IV). No significant adverse drug reactions were recorded in any of the patients. Our case series adds to the evidence base supporting the safety of 5-ALA in the paediatric population. However, the diverse range of responses to 5-ALA in these tumours highlights the need for further trials into its usefulness in specific tumour types.
Comparison of different risk classification systems in patients with high risk gastrointestinal stromal tumors
Authors: Y. Yin, Z. Cai, B. Zhang, C. Shen
Journal: Annals of Oncology (2018)

Introduction: To assess and compare the accuracy of different risk classification systems for predicting recurrence risk in patients with high risk GIST (Modified NIH classification) after R0 resection. Methods: The clinicopathological and follow-up data of patients with high-risk GIST without adjuvant IM therapy in our hospital from January 2009 to April 2015 were retrospectively analyzed. Receiver Operating Characteristic (ROC) curves were used to analyze the accuracy of different risk classification systems for predicting recurrence risk in patients with high risk GIST after R0 resection. Results: The research identified 82 patients with a median follow-up of 37 months. During the follow-up period, 36 patients had recurrent or metastatic disease. Univariate analysis showed that tumor site (P = 0.026), size (P = 0.002) and mitotic count (P < 0.001) were associated with recurrence or metastasis disease after surgical resection. Logistic regression analysis showed Logit (P1) = -0.081 * a + 0.031 * b + 0.155 * c-2.113 for predicting the recurrent or metastatic disease in patients with high-risk GIST without adjuvant IM therapy. In this study, the prognostic contour maps, AFIP criteria and Logit models have high accuracy in predicting the risk of postoperative recurrent disease (AUC = 0.882,0.813,0.928, respectively), the prognostic contour maps and Logit models were superior to the AFIP criteria. Conclusion: The prognostic contour maps, AFIP criteria and Logit model provide high accuracy predictions of the risk of postoperative recurrence in patients with high risk GIST, which help guide clinical management of GIST.
IMMU-24. IMMUNOTHERAPEUTIC NANOTECHNOLOGY TARGETING IDO1 FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Alicia Lenzen, Lisa Cole, Kristen L Lauing, Lijie Zhai, Erik Ladomersky, Rishi R Lulla, Rintaro Hashizume, Alexander Stegh, Derek A Wainwright
Journal: Neuro-Oncology (2018)

Research on adult high-grade gliomas has shown a targetable pathway through the inflammation-induced expression of indoleamine 2,3 dioxygenase (IDO1) and its recognized ability to suppress the anti-tumor immune response. Our project delineates the role of indoleamine 2,3 dioxygenase 1 (IDO1) in pediatric diffuse intrinsic pontine glioma (DIPG) and develops small inhibitory (si)RNA oligonucleotides and spherical nucleic acids (SNAs) aimed at therapeutically inhibiting the gene expression of immunosuppressive IDO1. SNAs composed of nanoparticles have been shown to transverse cellular membranes, exhibit stability in physiological environments, escape from degradation, and create precise targeting in brain tumors, and therefore make it a fundamental step for the investigation and targeting of IDO1. Our specific aims are to: (1) confirm the gene expression IDO1 in different human DIPG cell lines; (2) generate and characterize siRNA oligonucleotides targeting human IDO1 in vitro; and (3) generate and characterize gold nanoparticles for targeted inhibition of IDO1. Unique patient-derived DIPG cell lines were grown in culture, stimulated with proinflammatory cytokine IFNγ, and treated with increasing concentrations of IDO1 targeted siRNAs and SNAs. Cells were analyzed for mRNA, protein, enzymatic levels, cell viability and apoptosis. IDO1 is expressed in multiple human pediatric DIPG cell lines. Custom siRNA targeting IDO1 among exons 9-10 results in a significant decrease in overall IDO1 expression in multiple DIPG cell lines. SNA generation for targeting IDO1 is ongoing, with preliminary results demonstrating a robust ability to inhibit IDO1 expression in multiple cells lines while maintaining stability and precise targeting.
The new 8th edition of TNM staging and its implications for skin cancer: a review by the British Association of Dermatologists and the Royal College of Pathologists, U.K.
Authors: S.G. Keohane, C.M. Proby, C. Newlands, R.J. Motley, I. Nasr, M.F. Mohd Mustapa, D.N. Slater
Journal: British Journal of Dermatology (2018)

The 8th edition of TNM (tumour, node and metastasis) has numerous and important changes compared with the 7th edition. Public Health England and the Royal College of Pathologists, U.K., have adopted the 8th edition of TNM (TNM8) published by the Union for International Cancer Control for skin cancer staging. These changes will have an impact on the management and commissioning of melanoma and nonmelanoma skin cancer (NMSC). The T1-T3 categories for NMSC staging require the clinician to measure the maximum dimension (usually diameter) of every potential invasive cancer. For squamous, basal and adnexal carcinomas, but not Merkel cell carcinoma (MCC), the T1-T3 categories are defined by new 20-mm and 40-mm divisions based on the maximum dimension of the lesion. In addition, new risk factors upstage T1 or T2 to T3. For melanoma, mitotic index no longer influences separation of pathological stage (pT1). There is a new, additional stratification level at 0·8-mm Breslow thickness. Subdivision pT1b, with a negative sentinel lymph node biopsy (SLNB) of pN0, is now stage IA compared with the previous IB. For MCC, SLNB is now included specifically in the pN staging system. The pT1 subdivision requires clinical information as to whether histologically involved nodes were clinically occult or detectable. For both melanoma and MCC the clinician must state whether the lymph nodes are occult or clinically detectable. Eyelid carcinoma continues to have a staging system different from that in general skin and the system is substantially revised in TNM8.
LINC00470 Coordinates the Epigenetic Regulation of ELFN2 to Distract GBM Cell Autophagy
Authors: Changhong Liu, Haijuan Fu, Xiaoping Liu, Qianqian Lei, Yan Zhang, Xiaoling She, Qiang Liu, Qing Liu, Yingnan Sun, Guiyuan Li, Minghua Wu
Journal: Molecular Therapy (2018)

The epigenetics and genomics of glioblastoma (GBM) are complicated. Previous reports indicate that ELFN2 is widely distributed in the cerebral cortex neurons, striatum, and hippocampus cone and in granular cells. However, the function and mechanism of ELFN2, particularly in GBM, have rarely been explored. In this study, we identified ELFN2 as a new hypomethylation gene that acts as an oncogene in GBM. ELFN2 promoted cell autophagy by interacting with AurkA and eIF2α and inhibiting the activation of AurkA. We also demonstrated that aberrantly high ELFN2 expression is obtained due to hypomethylation of its promoter and abnormal miR-101 and LINC00470 expression in GBM. LINC00470 not only enhanced the expression of ELFN2 through adsorption of miR-101 but also affected the methylation level of ELFN2 by decreasing H3K27me3 occupancy. In addition, LINC00470 played a dominant role in the regulation of GBM cell autophagy, even though it upregulated ELFN2 expression. The results indicate that the combination of LINC00470 and ELFN2 has important significance for evaluating the prognosis of astrocytoma patients. The epigenetics and genomics of glioblastoma (GBM) are complicated. Previous reports indicate that ELFN2 is widely distributed in the cerebral cortex neurons, striatum, and hippocampus cone and in granular cells. However, the function and mechanism of ELFN2, particularly in GBM, have rarely been explored. In this study, we identified ELFN2 as a new hypomethylation gene that acts as an oncogene in GBM. ELFN2 promoted cell autophagy by interacting with AurkA and eIF2α and inhibiting the activation of AurkA. We also demonstrated that aberrantly high ELFN2 expression is obtained due to hypomethylation of its promoter and abnormal miR-101 and LINC00470 expression in GBM. LINC00470 not only enhanced the expression of ELFN2 through adsorption of miR-101 but also affected the methylation level of ELFN2 by decreasing H3K27me3 occupancy. In addition, LINC00470 played a dominant role in the regulation of GBM cell autophagy, even though it upregulated ELFN2 expression. The results indicate that the combination of LINC00470 and ELFN2 has important significance for evaluating the prognosis of astrocytoma patients.