tbuckley/cabot-search huggingface dataset:
GERM-22. DECISION-MAKING MANAGEMENT GUIDELINE FOR CHILDREN AND YOUNG PEOPLE UP TO 19 YEARS (CYP) PRESENTING WITH IDIOPATHIC PITUITARY STALK THICKENING (iTPS) AND/OR IDIOPATHIC CENTRAL DIABETES INSIPIDUS (iCDI)
Authors: Manuela Cerbone, Johannes Visser, Chloe Bulwer, Ashraf Ederies, Kirtana Vallabhaneni, Stephen Ball, Ian Kamaly, Ashley Grossman, Helena Gleeson, Marta Korbonits, Vasanta Nanduri, Vaya Tziaferi, Tom Jacques, Helen A Spoudeas
Journal: Neuro-Oncology (2018)

AIM: To develop a high-quality national guideline for the assessment and management of CYP presenting with iTPS and/or iCDI before their 19th birthday, as a joint endeavour by the Britsh paediatric endocrine and oncology societies (BSPED/CCLG) and meeting approved commissioning standards (RCPCH/NIHCE). The interdisciplinary guideline development group (GDG) identified 64 clinical questions. These were reviewed by stakeholders and used to direct a systematic literature search (January 1990 - March 2017). 568 articles were appraised using the GRADE system. Where there was sufficient evidence, the GDG made a guideline recommendation. Where high quality evidence was lacking, the GDG drafted recommendations based on their expert opinion and reviewed these using two rounds of Delphi consensus with international experts. In 11 case series (741 paediatric patients) the commonest individual causes of TPS/CDI were Langerhans cell hystiocytosis (16%), germ cell tumours (13%) and craniopharingiomas (12%). A range of congenital defects accounted for 19% of cases. Infectious diseases (2%), trauma (1%) and inflammatory/autoimmune conditions (1%) were rare. Twenty-nine percent remained idiopathic and some causes of TPS in adults (metastatic tumours and neurosarcoidosis) were not reported in children. The definition of TPS was not consistent across studies. A guideline and decision-making flowchart were developed. The likely aetiology of TPS/CDI in children differs from that in adults and justifies the development of age-appropriate management guidelines. This will form the basis of future audits of practice and outcomes and is intended to improve the care and service provision to CYP with apparent idiopathic TPS/CDI.
DIPG-32. CLINICALLY RELEVANT AND MINIMALLY INVASIVE TUMOR SURVEILLANCE IN PEDIATRIC GLIOMAS USING LIQUID BIOME
Authors: Eshini Panditharatna, Lindsay Kilburn, Mariam Aboian, Madhuri Kambhampati, Heather Gordish-Dressman, Suresh Magge, Nalin Gupta, John Myseros, Eugene Hwang, John Crawford, Kathy Warren, Adam Resnick, Roger J Packer, Michael Prados, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2018)

Pediatric diffuse midline glioma (MLG) constitutes the deadliest childhood CNS cancers. Due to the sensitive anatomical location, lack of surgical access to the tumor has hindered molecularly informed clinical interventions; thus, there is a dire need for the development of a sensitive and accurate approach for mapping tumor DNA fingerprints and monitoring tumor response to therapy. Liquid biopsy is emerging as a minimally invasive method for detecting circulating tumor DNA (ctDNA) in patients’ biofluid. To use liquid biopsy for mapping genomic mutations in pediatric brain tumors, we designed, optimized, and validated probes, and then showed their sensitivity and specificity for clinical assessment of children diagnosed with MLGs. Specifically, we demonstrated the feasibility of generating multiplex assays for detection of multiple driver mutations in patients’ biofluid. Tumor ctDNA was detected in cyst fluid (n=1), cerebrospinal fluid (CSF, n=30) and plasma (n=77), representing 48 subjects admitted or enrolled in a clinical trial. We show that while both CSF and plasma contain ctDNA, CSF tended to be a more enriched medium for tumor-associated ctDNA. Furthermore, we have detected H3K27M in ctDNA of plasma samples in xenograft models of DIPG. Finally, we show that ctDNA analysis closely agree with tumor response, often providing similar trends compared to MR imaging. Our data are the first to indicate the clinical utility of ctDNA for monitoring tumor response, and provide a molecularly-based rapid and sensitive approach for detection and longitudinal survey of childhood CNS tumors.
DIPG-39. UNCOUPLING CAR T CELL RECOGNITION FROM TUMOR KILLING FOR DIPG THERAPY
Authors: Karen D Wright, Alberto Nobili, Steven C Neier, Pratiti Bandopadhayay, Colby P Ledoux, Susanna Baumeister, Hye-Jung Kim, Carl D Novina, Mark W Kieran
Journal: Neuro-Oncology (2018)

T cells play a central role in our immune system’s responses to infections. Recent promising clinical studies have shown that the immune system can be ‘engineered’ to recognize and kill tumor cells by binding to specific proteins found on the tumor cell surface. The use of ‘chimeric antigen receptor’ (CAR) T cells, now approved for the treatment of certain childhood leukemias, exemplify this strategy. The success of CAR T cells to treat leukemias has expanded efforts to apply this technology to solid tumors. METHODS AND We have developed CAR T cells directed against synthetic (small molecule) antigens including fluorescein, which is not present on any normal cells in the body and serves as the recognition small molecule. Fluorescein is then linked to different antibodies that target overexpressed or mutant proteins on tumors (for example, ACVR1, PDGFR, etc.). These CAR T cells uncouple tumor recognition from tumor killing. Furthermore, this two-step process allows for titration of antibody-small molecule conjugates, which enables increased on-target killing of tumor cells and reduced killing of normal cells expressing a shared protein; however, uncontrolled tumor reactivity remains a major toxicity of CAR T cell therapies. By using this two-step process, antigen can be withdrawn to control CAR T cell-related toxicities such as cytokine storm and vascular leak syndrome. By targeting overexpressed and/or mutated antigens, we anticipate that we will be able to preferentially kill DIPG cells in patients while sparing healthy tissues.
Circulating Tumor DNA Assays in Clinical Cancer Research
Authors: Miguel R Ossandon, Lokesh Agrawal, Eric J Bernhard, Barbara A Conley, Sumana M Dey, Rao L Divi, Ping Guan, Tracy G Lively, Tawnya C McKee, Brian S Sorg, James V Tricoli
Journal: JNCI Journal of the National Cancer Institute (2018)

The importance of circulating free DNA (cfDNA) in cancer clinical research was recognized in 1994 when a mutated RAS gene fragment was detected in a patient's blood sample. Up to 1% of the total circulating DNA in patients with cancer is circulating tumor DNA (ctDNA) that originates from tumor cells. As ctDNA is rapidly cleared from the blood stream and can be obtained by minimally invasive methods, it can be used as a dynamic cancer biomarker for cancer early detection, diagnosis, and treatment monitoring. Despite the potential for clinical use, few ctDNA assays have been cleared or approved by the US Food and Drug Administration. As tools for clinical and translational research, current ctDNA assays face some challenges, and more research is needed to advance use of these assays. On September 29–30, 2016, the Division of Cancer Treatment and Diagnosis at the National Cancer Institute convened a workshop entitled "Circulating Tumor DNA Assays in Clinical Cancer Research" to garner input from industry experts, academia, and government research and regulatory agencies to understand and promote the translation of ctDNA assays to clinical research, with potential to advance to use in clinical practice. This Commentary presents the topics of the workshop covered in the presentations and points made in the discussions that followed: 1) background on ctDNA, 2) potential clinical utility of ctDNA assays, 3) assay technology, 4) assay clinical and analytical validation, and 5) industry perspectives. Additional relevant information that has come to light since the workshop has been included.
PHRM-03. CEREBROSPINAL FLUID PENETRATION OF PEXIDARTINIB (PLX3397), A CSF1R INHIBITOR, IN A NONHUMAN PRIMATE MODEL
Authors: Arman Odabas, Cynthia M Lester McCully, Rafael Cruz, William D Figg, John Glod, Andrey Rymar, Cody Peer, Katherine E Warren
Journal: Neuro-Oncology (2018)

Pexidartinib (PLX3397) is a colony stimulating factor-1 receptor (CSF1R) inhibitor under clinical evaluation including potential CNS tumor treatment. This study aims to estimate CNS penetration of pexidartinib in a nonhuman primate (NHP) CSF Reservoir model. 4 male rhesus macaques, each with an indwelling CSF ventricular reservoir and central venous lines, were used. NHPs received pexidartinib (40 mg/kg, single dose, human equivalent dose of 20 mg/m2) administered orally. Serial paired samples of blood and CSF were collected from 0-8, 24, 48, and 72 hours. Pexidartinib concentrations were assayed by Plexxikon Inc. using HPLC/MS/MS. Pharmacokinetic analysis was performed with Phoenix® WinNonlin® software. Average plasma pharmacokinetic parameters were as follows: Cmax = 16500 (± 6700) ng/mL; Tmax = 5 (± 2.57) hours; AUCD→∞ = 262156 (± 105424) hr*ng/mL; CL = .178 (± .088) L/hr/kg. Pexidartinib in the CSF was not detected (n=2, LLOQCSF = 5 ng/ml) or was quantifiable (n=2) with Cmax of 16.1 and 10.1 ng/ml. CSF values were lower than predicted based on steady-state rat data which showed CSF:plasma between .0015 and .0044. Plasma protein binding of pexidartinib exceeds 99% in equilibrium dialysis experiments, which is consistent with low CSF:plasma. CSF penetration of pexidartinib after oral administration in a NHP was limited and lower than predicted by a rodent steady-state model. Pexidartinib is well-tolerated in rhesus macaques. FUTURE Subsequent studies will examine pharmacokinetics of pexidartinib in plasma and CSF at steady state, and investigate intrathecal administration of pexidartinib. PLX3397 was supplied by Plexxikon Inc.
DIPG-30. A NEW TREATMENT OPPORTUNITY FOR DIPG: 5-ALA AND SONODYNAMIC AUGMENTED MEV IRRADIATION, THE ASAI PROTOCOL
Authors: Richard KAST, Michael Salacz
Journal: Neuro-Oncology (2018)

Prognosis for diffuse intrinsic pontine glioma [DIPG] has only marginally improved over the last ~40 years despite dozens of chemotherapy trials. We present the rationale for adding 5-aminolevulinic acid [5-ALA] to current palliative irradiation of DIPG, plus doxycycline and unfocused 1 MHz ultrasound, the ASAI Regimen. 5-ALA enhances meV radiation of gliomas. 5-ALA is currently used in intraoperative demarcation of overt glioblastoma margins by virtue of glioblastoma cells’ selective uptake of 5-ALA and selective conversion to protoporphyrin IX [PpIX], a fluorescent molecule. 5-ALA is also useful in treating gliomas by virtue of PpIX’s emission of a photon that creates singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective cancer cell cytotoxicity after illumination with 410 nm [blue] light. Shallow penetration of excitation light required for PpIX generation of cytotoxicity, and inaccessibility of central structures like the pons or thalamus to blue light excitation lead to 5-ALA phototherapy not being considered for DIPG. But DIPGs selectively take up 5-ALA as do other gliomas and meV irradiation induced cytotoxicity also is enhanced by pre-irradiation oral 5-ALA. The old antibiotic doxycycline enhances glioma cell uptake of 5-ALA. Low power unfocused 1 MHz ultrasound, not neurotoxic or damaging to brain structures, augments 5-ALA glioma cell cytotoxicity. Both doxycycline and ultrasound are therefore added to ASAI Protocol. A pilot study of uptitration of oral 5-ALA plus doxycycline, and ultrasound delivered through a bone window prior to each standard palliative irradiation session - the ASAI Protocol - is warranted.
RETRACTED ARTICLE: Systematic analyses reveal long non-coding RNA (PTAF)-mediated promotion of EMT and invasion-metastasis in serous ovarian cancer
Authors: Haihai Liang, Xiaoguang Zhao, Chengyu Wang, Jian Sun, Yingzhun Chen, Guoyuan Wang, Lei Fang, Rui Yang, Mengxue Yu, Yunyan Gu, Hongli Shan
Journal: Molecular Cancer (2018)

Abstract Background A deeper mechanistic understanding of epithelial-to-mesenchymal transition (EMT) regulation is needed to improve current anti-metastasis strategies in ovarian cancer (OvCa). This study was designed to investigate the role of lncRNAs in EMT regulation during process of invasion-metastasis in serous OvCa to improve current anti-metastasis strategies for OvCa. Methods We systematically analyzes high-throughput gene expression profiles of both lncRNAs and protein-coding genes in OvCa samples with integrated epithelial (iE) subtype and integrated mesenchymal (iM) subtype labels. Mouse models, cytobiology, molecular biology assays and clinical samples were performed to elucidate the function and underlying mechanisms of lncRNA PTAF-mediated promotion of EMT and invasion-metastasis in serous OvCa. Results We constructed a lncRNA-mediated competing endogenous RNA (ceRNA) regulatory network that affects the expression of many EMT-related protein-coding genes in mesenchymal OvCa. Using a combination of in vitro and in vivo studies, we provided evidence that the lncRNA PTAF-miR-25-SNAI2 axis controlled EMT in OvCa. Our results revealed that up-regulated PTAF induced elevated SNAI2 expression by competitively binding to miR-25, which in turn promoted OvCa cell EMT and invasion. Moreover, we found that silencing of PTAF inhibited tumor progression and metastasis in an orthotopic mouse model of OvCa. We then observed a significant correlation between PTAF expression and EMT markers in OvCa patients. Conclusions The lncRNA PTAF, a mediator of TGF-β signaling, can predispose OvCa patients to metastases and may serve as a potential target for anti-metastatic therapies for mesenchymal OvCa patients.
ATRT-09. WHOLE GENOME AND EPIGENOME CHARACTERIZATION LINKS ATRT-MYC TO A SUBGROUP OF RENAL RHABDOID TUMORS
Authors: Pascal Johann, Elizabeth Chun, Serap Erkek, Murat Iskar, Elizabeth Perlman, Martin Hasselblatt, Stefan M Pfister, Marco Marra, Marcel Kool
Journal: Neuro-Oncology (2018)

Rhabdoid tumors (RTs) are pediatric cancers that account for nearly 10% of all tumors in infants. Currently, RTs are classified according to tumor location. In the central nervous system, they are called atypical teratoid/rhabdoid tumors (ATRTs) as compared to extra-cranial malignant RTs (MRTs). Regardless of the site of occurrence, RTs share histological characteristics and genetic alterations, with >95% of them showing loss of SMARCB1, a subunit of the chromatin-remodeling SWI/SNF complex. Molecularly, RTs are heterogeneous. Previous studies reported molecular subgroups within RTs of the same anatomic compartment. However, biological similarities among RT subgroups of different sites, and molecular characteristics shared among them remained unknown. To investigate the similarity of RTs from different anatomic sites at a molecular level, we compared DNA methylation, gene expression, and H3K27ac profiles of 150 MRTs and 161 ATRTs generated by WGBS, 450K/850K arrays, RNA-, and ChIP-Seq. Unsupervised clustering of DNA methylation data showed that a subset of MRTs clustered with the MYC-subgroup of ATRTs but not with SHH- and TYR-subgroups of ATRTs. Over-expression of MYC-ATRT representative genes, such as c-MYC and the non-coding regulatory RNA gene HOTAIR, was also observed in these MRTs. Furthermore, they were both characterized by global hypomethylation, high prevalence of partially methylated domains, and similar super-enhancer regions, identified by H3K27ac ChIP-seq analyses, such as those for the HOXC cluster genes. Our results indicate that MYC-ATRTs and a subset of MRTs share molecular similarities and associate with distinct developmental processes compared to other ATRT and MRT subgroups.
TBIO-03. CONSTRUCTION AND PRELIMINARY CLINICAL APPLICATION OF A HIGH-SENSITIVITY AND MULTISITE IMMUNOMAGNETIC LIPOSOME-FLUORESCENCE CTC SYSTEM FOR CTC CAPTURING IN PEDIATRIC BRAIN TUMOR
Authors: Yang Zhao, Changbin Zhu, Yipeng Han, Qifeng Li, Feng Jiang, Qianhua Wang, Xiaofei Liang, Jie Ma
Journal: Neuro-Oncology (2018)

Detection of Circulating tumor cells (CTCs) plays vital role in tumor diagnosis and dynamic assessment in various tumor spectrum. While, CTC detection in pediatric brain tumor, the most occurred solid tumor in children was still underway. Developing a highly efficient CTC capturing system for pediatric brain tumor will be certainly of great importance in clinical practice. In this study, a novel CTC system consisting high-sensitivity and multisit immunomagnetic liposome was constructed. Validation and the efficiency of this system in capturing CTCs were measured in both in vitro and in vivo. The association of the number of CTCs with clinical characters were further analyzed. The results showed that CTCs were successfully isolated by IMLs. CTCs were isolated from CSF and blood samples of 24 cases with brain tumors. It was found that the number of CTCs in CSF was significant higher than that from the blood and the number of CTCs in tumors was significantly higher than the normal control. The level of CTCs in CSF was not related to the tumor stage, instead, related to the type and location of the tumor. Therefore, IMLs isolating CTC from CSF combined immunofluorescence assay of anti-tumor markers can serve as a novel method for the identification of CTCs in CSF from children with brain tumor. As a minimally invasive biopsy, this technique is of important clinical significance in diagnosis and efficacy assessment for brain tumors in children.
RADI-07. POSTOPERATIVE PAEDIATRIC CEREBELLAR MUTISM SYNDROME- IDENTIFYING QUANTITATIVE BIOMARKERS ON LONGITUDINAL FOLLOW-UP MRI
Authors: Shivaram Avula, Michaela Spiteri, Jean-Yves Guillemaut, David Windridge, Ram Kumar, Barry Pizer, Conor Mallucci, Emma Lewis
Journal: Neuro-Oncology (2018)

Postoperative paediatric cerebellar mutism syndrome (POPCMS) is a complication affecting 8%-31% of children undergoing posterior fossa tumour resection. Injury to the proximal efferent cerebellar pathway during surgery is increasingly implicated in its causation but the exact pathogenesis remains unclear. Identifying MRI changes in the brain stem and cerebellum of these children can further the understanding of the pathogenesis and anatomical substrates involved. Longitudinal analysis of follow -up MRI in 40 children with and without POPCMS following posterior fossa tumour resection was performed using a fully automated quantitative analysis of the brainstem and cerebellum in 3D space using the following steps: segmentation, registration, longitudinal interpolation of the MR images and machine learning techniques for feature selection and data classification. Longitudinal analysis and machine learning of the first 7 month MRI data following surgery identified six features at specific locations in Crus I, VI, VIIb, VIIb & IX of the anatomical right cerebellar hemisphere following surgery that are potential biomarkers of POPCMS. Three of these are identified at 1 month, two at 2 months and one at 5 months following surgery. This novel fully automated quantitative analysis of MRI in children following posterior fossa tumours resection reveals biomarkers that help to further the understanding the pathogenesis of POPCMS. This is one of the few studies that support the involvement of the right cerebellar hemisphere in the development of POPCMS. These biomarkers could also serve as imaging surrogates to the severity of the injury and prognosis.
MBRS-06. THE ROLE OF G-CSF RECEPTOR SURFACE EXPRESSION IN MEDULLOBLASTOMA PATHOGENESIS
Authors: Megan Paul, Peter Zage
Journal: Neuro-Oncology (2018)

Medulloblastoma recurrence portends a dismal prognosis. Identifying sub-populations of medulloblastoma tumors with stem cell-like properties holds promise for reducing disease recurrence, but no unifying marker of medulloblastoma cancer stem cells has been found. The granulocyte stimulating factor receptor (GCSF-R) is well understood in the context of hematopoiesis. Neuroblastoma and melanoma cells subpopulations that express the GCSF-R have cancer stem cell properties of chemoresistance and increased tumorigenicity and are enriched in tumors after after chemotherapy administration. GCSF-R activation after ligand binding leads to signaling through the JAK-STAT pathway, suggesting a potential therapeutic target. Using flow cytometry, we show that a subpopulation of medulloblastoma cells in a panel of cell lines express GCSF-R, and that the GCSF-R-positive subpopulations have a slower growth rate than GCSF-R-negative or mixed populations. Subpopulations of medulloblastoma cells that express the GCSF-R are also more chemoresistant in vitro to vincristine, etoposide, and carboplatin. We also show that Ruxolitinib, a JAK1/2 inhibitor used in the treatment of polycythemia vera, has in vitro activity against medulloblastoma cell lines, suggesting that JAK/STAT inhibition is an effective therapy against medulloblastoma. With the common use of G-CSF to promote bone marrow recovery in children with medulloblastoma and the potential role of the GCSF-R as a cancer stem cell marker, we propose that JAK inhibition may represent an adjunct therapy targeting overall tumor burden and specifically targeting slow-growing, GCSF-R-positive, cells that may drive recurrence.
Is there a prognostic effect of etiologies in patients with gastric cardia cancer during a recent decade of Korea?
Authors: W. Chung, Y. Kim, S. Oh
Journal: Annals of Oncology (2018)

Introduction: There are two different etiologies of gastric cardia cancer - Barrett's esophagus and Helicobacter pylori (H. pylori) associated atrophy/intestinal metaplasia. We aimed to evaluate the clinical characteristics and outcome between gastric cardia and non-cardia cancer. Also, we evaluated the clinical outcome according to obesity, H. pylori infection, and gastric atrophy. Methods: We performed a retrospective cohort study of 90 patients with gastric cardia cancer from Jan. 2003 to 2013. The control group was randomly selected in a 2:1 ratio compared with the case group, and 180 patients with gastric non-cardia cancer were selected as age and sex matched control during the same period. Results: The rate of curative resection (R0), disease free survival and overall survival duration were significantly lower in gastric cardia cancer. The rate of recurrence was significantly higher in gastric cardia cancer (28.4% vs 8.0%, P < 0.01). The rate of H. pylori (-) and gastric atrophy (-) of gastric cardia cancer was statistically higher than non-cardia cancer (P < 0.01), but there was no difference in the rate of obesity. Irrespective of obesity or the presence of H. pylori/gastric atrophy, there were no differences of overall survival, recurrence rate and disease-free survival. Conclusion: Gastric cardia cancer had a negative prognostic impact, compared with gastric non-cardia cancer. Although a possible heterogeneity in the pathogenesis and biological behavior of gastric cardia cancer would be present, there was no difference in prognosis.