tbuckley/cabot-search huggingface dataset:
RARE-51. MOLECULAR INSIGHTS INTO MALIGNANT PROGRESSION OF CHOROID PLEXUS PAPILLOMA (CPP)
Authors: Maxim Yankelevich, Jonathan L Finlay, Hamza Gorsi, William Kupsky, Daniel R Boue, Carl J Koschmann, Chandan Kumar, Rajen Mody
Journal: Neuro-Oncology (2020)

Abstract Malignant transformation of CPP is rare and the mechanisms remain elusive. We report a case of progression of papilloma into carcinoma where we performed molecular sequencing of both samples. A boy was found to have a brain mass soon after birth. The gross total resection (GTR) was diagnostic of CPP. Six years later he developed a recurrent mass that demonstrated progression to a choroid plexus carcinoma (CPC). The patient received chemotherapy according to a “HeadStartII” protocol. He is 2.5 years off therapy and disease-free. A sequencing study consisting of 1700 genes and tumor transcriptome was done. The analysis of both samples revealed a germline variant of TP53(R248W) with LOH and an allele frequency of 39% in the germline sample, suggesting a mosaicism. Analysis of both samples identified extensive aneuploidy and similar pattern of gains in chromosomes 7/8/12/20/21/X. Copy number aberrations newly acquired in the carcinoma included copy gain of chromosomes 5q/12/15q/20, and copy loss of chromosomes 5q/13/22. The papilloma was found to harbor 3 somatic mutations with 4% to 21% allelic fractions, all lost in the carcinoma. These mutations were of unknown significance and with too low allelic fractions to be responsible for the transformation. More pertinently, chromosomal aneuploidy was significant with additional losses in the carcinoma. This resulted in the losses of two critical tumor suppressor genes, RB and BRCA2, playing a possible role in the observed transformation. The “HeadStart” experience suggested that the prognosis of TP53 mutant CPC may be improved in the absence of radiation therapy.
Abstract P422: Nonalcoholic Fatty Liver Disease and Cognitive Function in Middle-aged Adults: The CARDIA Study
Authors: Yariv Gerber, Lisa B Vanwagner, James G Terry, Jamal S Rana, Jared P Reis, Kristine Yaffe, Stephen Sidney
Journal: Circulation (2020)

Background: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular disease (CVD) and its major risk factors. The latter have been linked to accelerated cognitive decline. Whether NAFLD is associated with decreased cognitive performance in midlife remains uncertain. Methods: Participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study with CT-measured NAFLD and cognitive function assessment at year 25 (2010-2011; n=2,835) were included. Cognitive function was reassessed at year 30 (2015-2016; n=2,388). NAFLD was defined according to liver attenuation and categorized into 3 groups: none [&gt;51 Hounsfield Units (HU)], probable (&gt;40-51 HU), and definite (≤40 HU). Cognitive tests, including the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop were analyzed with standardized z scores. Linear models were constructed to examine (a) the cross-sectional association between NAFLD and cognitive scores (year 25) and (b) the predictive role of NAFLD in subsequent (year 30) cognitive scores. Results: The mean age at baseline was 50.1 (SD, 3.6) years (58% women; 48% blacks), with 398 (14%) and 286 (10%) having probable and definite NAFLD, respectively. In unadjusted models, an inverse association was shown between NAFLD and all cognitive tests. For DSST ( P interaction =.047) and RAVLT ( P interaction =.033), the association was stronger in whites than blacks. The association was attenuated after age and sex adjustment, and practically eliminated after further adjustment for sociodemographic and CVD risk factors (Table). NAFLD was not predictive of subsequent cognitive performance in any of the measures once baseline scores were adjusted for (all P &gt;.10). Using liver attenuation as a continuous variable yielded similar results. Conclusion: Among middle-aged adults, an inverse association of NAFLD with cognitive function -evident in whites only- was attenuated by sociodemographic and CVD risk factor adjustment.
RARE-09. PRESERVATION OF ENDOCRINE FUNCTION AFTER OMMAYA RESERVOIR INSERTION IN CHILDREN WITH CYSTIC CRANIOPHARYNGIOMA
Authors: Laura-Nanna Lohkamp, Abhaya Kulkarni, James Drake, James T Rutka, Peter Dirks, Michael Taylor, George Ibrahim, Lorena Baroni, Jill Hamilton, Ute Katharina Bartels
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Children with craniopharyngiomas (CP) can be subjected to significant morbidities caused by radical surgery and/or radiation with severe long-term consequences. Ommaya reservoir Insertion (ORI) into cystic CP represents a minimally invasive procedure that aims to preserve endocrine, hypothalamic and neurocognitive function. The purpose of this study was to determine the relevance of upfront ORI (+/- intracystic treatment) for preservation of endocrine function. METHODS A retrospective chart review of children with CP treated at the Hospital for Sick Children between 01/01/2000 and 15/01/2020 was undertaken. Endocrine function was reviewed at the time of initial ORI or surgical resection and throughout the course of follow-up. Event free survival (EFS) was defined as the time to additional surgical resection or irradiation. RESULTS Fifty-five patients with sufficient endocrine follow-up data were included. The median age of diagnosis was 8.3 years (range 2.1–18.0 years), 31 were males. ORI was performed as upfront treatment in 30 patients, gross total or partial resection in 24 patients and radiation in 1 patient, respectively. Endocrine function remained stable after ORI with a median EFS of 19.2 (0 – 105.3) months while the majority of patients who underwent surgical resection had documented worsened endocrine function postoperatively (median of 0; range 0 – 29.4 months) (p&amp;lt; 0.001). The event most commonly related to secondary endocrine deterioration was initial or delayed surgical resection. CONCLUSIONS Endocrine function was preserved in patients with upfront ORI (+/- intracystic treatment). Further studies will elucidate the implications of ORI with respect to ophthalmological, vascular and neurocognitive long-term outcome.
MBRS-69. METABOLITE PROFILING OF SHH MEDULLOBLASTOMA IDENTIFIES A SUBSET OF CHILDHOOD TUMOURS ENRICHED FOR HIGH-RISK MOLECULAR BIOMARKERS AND CLINICAL FEATURES
Authors: Christopher Bennett, Sarah Kohe, Florence Burte, Heather Rose, Debbie Hicks, Ed Schwalbe, Stephen Crosier, Lisa Storer, Anbarasu Lourdusamy, Martin Wilson, Shivaram Avula, Dipayan Mitra, Robert Dineen, Simon Bailey, Daniel Williamson, Richard Grundy, Steven Clifford, Andrew Peet
Journal: Neuro-Oncology (2020)

Abstract SHH medulloblastoma patients have a variable prognosis. Infants (&amp;lt;3–5 years at diagnosis) are associated with a good prognosis, while disease-course in childhood is associated with specific prognostic biomarkers (MYCN amplification, TP53 mutation, LCA histology; all high-risk). There is an unmet need to identify prognostic subgroups of SHH tumours rapidly in the clinical setting, to aid in real-time risk stratification and disease management. Metabolite profiling is a powerful technique for characterising tumours. High resolution magic angle spinning NMR spectroscopy (HR-MAS) can be performed on frozen tissue samples and provides high quality metabolite information. We therefore assessed whether metabolite profiles could identify subsets of SHH tumours with prognostic potential. Metabolite concentrations of 22 SHH tumours were acquired by HR-MAS and analysed using unsupervised hierarchical clustering. Methylation profiling assigned the infant and childhood SHH subtypes, and clinical and molecular features were compared between clusters. Two clusters were observed. A significantly higher concentration of lipids was observed in Cluster 1 (t-test, p=0.012). Cluster 1 consisted entirely of childhood-SHH whilst Cluster 2 included both childhood-SHH and infant-SHH subtypes. Cluster 1 was enriched for high-risk markers - LCA histology (3/7 v. 0/5), MYCN amplification (2/7 v. 0/5), TP53 mutations (3/7 v. 1/5) and metastatic disease - whilst having a lower proportion of TERT mutations (0/7 v. 2/5) than Cluster 2. These pilot results suggest that (i) it is possible to identify childhood-SHH patients linked to high-risk clinical and molecular biomarkers using metabolite profiles and (ii) these may be detected non-invasively in vivo using magnetic-resonance spectroscopy.
RARE-52. <i>RB1</i> GENE DELETIONS ARE THE NOVEL MECHANISM OF CHOROID PLEXUS TUMORS (CPT) ONCOGENESIS
Authors: Alexander Druy, Liudmila Yasko, Andge Valiakhmetova, Galina Novichkova, Liudmila Papusha
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND CPTs are known to be rare TP53-dependent neoplasms, while major molecular alterations underlying tumor progression, especially in TP53-wild type cases, are still unclear. METHODS 18 primary CPT, including 16 choroid plexus carcinomas (CPC) and two atypical choroid plexus papillomas (CPP), were evaluated for copy number status of 87 major oncogenes and tumor suppressor genes by nCounter Cancer CNV assay by Nanostring and TP53 and RB1 by MLPA. Germline TP53 nucleotide substitutions were analyzed by Sanger sequencing. RESULTS Pathogenic germline TP53 variants were present in 4 cases confirming Li-Fraumeni syndrome (LFS). Two patients have somatic TP53 substitutions. Only one patient with LFS harbored somatic TP53 deletion. In 7 patients, heterozygous deletions of RB1 involving from 3 exons to the whole coding sequence detected by MLPA were discovered. All these findings were validated by nCounter CNV assay. Additionally, four patients have WT1 deletions, two patients – BRCA2, and in 1 case - NF1, concomitant with RB1 deletions in 3 cases. Interestingly, in one patient who faced a progression of CPP to CPC germline, RB1 deletion was detected, and in both subsequent tumors, the length of the deleted region progressively increased. Notably, that RB1 deletions are mostly mutually exclusive to TP53 substitutions. 3 of 4 patients with RB1 deletions having follow-up period &amp;gt;1 year faced with tumor-related adverse events. CONCLUSIONS Somatic or uncommon germline RB1 heterozygous deletions have been unraveled as a novel mechanism of aggressive CPT and could be implemented in prognosis definition schemes.
MODL-28. IMMUNE PRIMING WITH INTERFERON-Γ COMBINED WITH EPIGENETIC MODULATION IN PEDIATRIC BRAIN TUMORS
Authors: Erin Crotty, Shelli Morris, Ken Brasel, Emily Girard, Alyssa Noll, Andrew Mhyre, James Olson
Journal: Neuro-Oncology (2020)

Abstract Systemic interferon-γ (IFNγ) has been shown to induce major histocompatibility complex class I (MHC-I) and T cell infiltration in solid tumors in adult patients, demonstrating a potential strategy to abrogate tumor-intrinsic mechanisms of immune escape. Pediatric brain tumors (PBT) may be particularly sensitive to this approach but have a paucity of immunogenic tumor antigens for presentation on MHC-I. Decitabine and other DNA methyltransferase (DNMT) inhibitors promote expression of oncofetal antigens and endogenous immune responses through epigenetic alterations. We tested the convergence of these immune priming mechanisms using a novel combination of IFNγ and decitabine across a spectrum of PBT. Primary human cell lines (Med-411FH, PBT-05FH, GBM-511FH, CCHMC-GBM-1, CCHMC-GBM-4, ATRT-310FH) and murine transgenic models were treated with IFNγ alone or in combination with decitabine and evaluated expression of cell surface MHC-I and PD-L1, interferon response genes (ISGs), and oncofetal antigens. PBT showed exquisite sensitivity to IFNγ, increasing expression of MHC-1/PD-L1 along with ISGs (TAP1, MX1, IRF1). Decitabine enhanced IFNγ-induced gene expression of oncofetal antigens NY-ESO-1 and MAGE-A1. In a medulloblastoma flank tumor model, MHC-I was increased by 40-fold following intraperitoneal IFNγ treatment (p=0.01), with a 3-fold increase in PD-L1 (p=0.005) compared to untreated controls. Effect on CD8+ T cell killing and validation in humanized models is ongoing. Immune priming of PBT with IFNγ is feasible and results in more substantial MHC-I upregulation compared to hypomethylating agents alone. These results provide a strong rationale for priming prior to checkpoint inhibition as a compelling therapeutic strategy in immunologically-quiescent PBT.
NFB-02. TREATMENT OF PAIN AND TUMOR GROWTH IN NF2
Authors: Molly Hemenway, Anan Nellan, Kate McMahon, Nicholas Foreman, Kartik Reddy, Anan Nellan, Alexandra Suttman
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Neurofibromatosis Type 2 (NF2) is an autosomal dominant disorder characterized by multiple nervous system tumors. Chronic pain affects the majority of patients with NF2 and is the primary factor that contributes to decreased quality of life. There are limited therapies that effectively reduce pain in NF2, but intravenous (IV) bevacizumab has been reported to provide significant relief to patients suffering from debilitating pain. CASE STUDY James is a 24-year-old who initially presented with manifestations of NF2 at age 10, and by 15 years old had developed daily pain affecting his neck, back, and lower extremity. He has multiple CNS schwannomas, meningiomas, neurofibromas, and meets clinical NF2 criteria. While genetic testing did not reveal a mutation in his gDNA, low level skipping of exon 4 via RNA supports (likely mosaic) NF2. James’s pain was poorly controlled with multiple oral medications, including opioids. James started IV bevacizumab at age 16 that improved his pain. He was critically dependent on bevacizumab for pain control and required continuous IV pain medication when bevacizumab was held for a surgical procedure. Following five years of bevacizumab he developed worsening toxicities including hypertension, proteinuria, and elevated hemoglobin. James transitioned to therapy with trametinib, a MEK inhibitor, and was able to wean off bevacizumab six months later. Treatment of NF2 related pain with trametinib instead of bevacizumab has improved his QOL with decreased medical visits, improved pain management, and decreased side effects. FUTURE IMPLICATIONS: Treatment of NF2 tumor related pain can be managed with MEK inhibitors.
A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
Authors: Dezuo Dong, Weimin Zhang, Wenchang Xiao, Qingnan Wu, Yiren Cao, Xiaohan Gao, Lijie Huang, Yan Wang, Jie Chen, Weihu Wang, Qimin Zhan
Journal: Cancer Research (2020)

Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAM135B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC. SIGNIFICANCE: These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.
GCT-71. SIOP STRATEGY TREATMENT FOR CENTRAL NERVOUS SYSTEM GERM CELL TUMORS IN A MIDDLE INCOME COUNTRY
Authors: Agustina Oller, Claudia Sampor, Lorena Baroni, Candela Freytes, Nicolas Fernandez Ponce, Gabriela Villanueva, Daniel Alderete
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/OBJECTIVES Central nervous system (CNS) germ cell tumors (GCTs) represent 3% of primary paediatric brain tumours in occident. They can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs). The aim is to describe demographic characteristics, Event Free Survival (EFS) and Overall Survival (OS) in patients with GCTs treated at Oncology Unit of Garrahan Hospital (HG). DESIGN/METHODS Retrospective analysis of patients with GCTs admitted between September 1st,2000 to September 1st,2019. Variables analysed: age, localization, treatment, relapse and death. Patients were treated per SIOP-CNSGCTs protocol. For statically analysis SPSS (IBM), for EFS/OS Kaplan-Meyer, Long-rank for significance. RESULTS Fifty-seven patients were included, comprising 38 Germinomas and 19 NGGCTS. Median age was 146 months (range 11–228). Primary site in localized Germinomas were pineal (16p), suprasellar (7p) and bifocal (7p). Five-year EFS and OS of 100% and 88.5%, respectively. Four patients presented metastatic disease, with an EFS and OS of 60.9% and 66.6%. Tumor site in localized NGGCT were pineal(8p) and suprasellar(5p). Five-year EFS was 81.8% and OS was 80.2%. No patients presented metastatic disease. All patients with high-risk tumor markers at diagnosis relapsed. No significative differences were found in OS neither EFS between groups (Germinomas OS5y 90% vs NGGCTs 74.6%p=0.19[CI95%0.0786–1.689]), (Germinomas EFS5y 78.9% vs NGGCTs5y 81.8%p=0.85[CI95%0.3046–4.230). Global OS and EFS5y was 83% and 72.9%. CONCLUSION OS of our cohort is lower than what has been shown in current literature. This result may be related to the lack of resources and lower social economic status in our population.
PATH-15. PROTEOMIC SIGNATURES PREDICT GRADE IN PEDIATRIC AND YOUNG ADULT INFILTRATIVE ASTROCYTOMAS
Authors: Richard T Graham, Blake E Sells, Jessica Fleming, Joseph P McElroy, Erica H Bell, S Jaharul Haque, Aline P Becker, Daniel R Boué, Jonathan L Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Infiltrative astrocytomas in children and young adults pose a treatment challenge due to the difficulty of achieving gross total resection and tumor resistance to irradiation and chemotherapy. Histopathologic grade is an essential part of determining prognosis and treatment, but it is subjective and provides limited understanding of the molecular mechanisms underlying tumor development and progression. METHODS We performed liquid chromatography/mass spectrometry (LC/MS-MS) on 28 FFPE samples of primary infiltrative astrocytomas (10 grade II, 8 grade III and 10 grade IV – WHO classification) from Nationwide Children’s Hospital (NCH). Initial unsupervised clustering was performed. Lasso regression yielded a protein signature separating low- and high-grade tumors which was validated using a similar cohort of pediatric and young adult infiltrative astrocytomas from the Proteomic Data Commons (PDC) (n=28) of the National Cancer Institute. RESULTS Unsupervised clustering of NCH samples essentially recapitulated grade and lasso regression yielded a 10-protein signature that distinguished grade II from grade III/IV tumors. This 10-protein signature when applied to the PDC validation dataset, accurately predicted grade for 89.3% of the tumors (p=0.00014). CONCLUSIONS We identified a quantitative protein signature that can reliably distinguish between low- and high-grade infiltrative astrocytomas from FFPE tissue. Further validation will enable the development an objective prognostic proteomic clinical test that complements and may outperform current histopathological strategies. Additionally, proteomic profiling of tumors will clarify the molecular mechanisms contributing to treatment resistance and tumor progression and help identify novel treatment targets. Independent functional validation and characterization of proteins is ongoing.
B型壁内血腫患者における限局性内膜破壊の臨床的意義【Powered by NICT】
Authors: Moral Sergio, Cuellar Hug, Avegliano Gustavo, Ballesteros Esther, Salcedo Maria Teresa, Ferreira-Gonzalez Ignacio, Garcia-Dorado David, Evangelista Arturo
Journal: Journal of the American College of Cardiology (2017)
LINC-20. INFANT BRAIN TUMOURS IN HONG KONG
Authors: Matthew M K Shing, Dennis T L Ku, Godfrey C F Chan, C W Luk, Jeffrey P W Yau, Eric Fu, Carol L S Yan, Alvin S C Ling
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES To review the clinical features, pathology and survivals of infants with brain tumours. METHODS A retrospective review of the clinical findings, pathology, treatment and survival outcome in infants with brain tumours. RESULTS From 1999 to 2018, there were 507 children (&amp;lt;18 years) who were diagnosed to have brain tumours in Hong Kong. The patients were treated in five public hospitals. The clinical data were collected by the Hong Kong Paediatric Haematology and Oncology Study Group, and were cross-checked with the data of the Hong Kong Cancer Registry. In this group of patients, there were 36 infants (birth to 365 days of age) i.e. 7.1% of the whole group. Both benign and malignant brain tumours were included, while non-neoplastic lesions were excluded. On average, there was 1.89 cases per year. The pathology of the tumours were astrocytoma (n= 8), medulloblastoma (n=6), germ cell tumour (n=6), PNET (n=5), ATRT (n=4), choroid plexus tumours (n=3), ependymoma (n=2), craniopharyngioma (n= 1) and ganglioglioma (n= 1). These infants were treated according to their clinical conditions and prognosis, with operation, chemotherapy or both. Radiotherapy was withheld or postponed to older age. Some patients only received palliative care due to the poor neurological status or prognosis. The overall survivals of children younger than 18 years old vs infants were 67.3% (±2.3) vs 50.5%(±9.2) respectively, while the event free survivals were 64.4% (±2.4) and 43.5% (±8.8) at 10-years respectively. CONCLUSION Infants with brain tumours have different pathology and inferior outcome.
PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19
Authors: Min-Seok Rha, Hye Won Jeong, Jae-Hoon Ko, Seong Jin Choi, In-Ho Seo, Jeong Seok Lee, Moa Sa, A Reum Kim, Eun-Jeong Joo, Jin Young Ahn, Jung Ho Kim, Kyoung-Ho Song, Eu Suk Kim, Dong Hyun Oh, Mi Young Ahn, Hee Kyoung Choi, Ji Hoon Jeon, Jae-Phil Choi, Hong Bin Kim, Young Keun Kim, Su-Hyung Park, Won Suk Choi, Jun Yong Choi, Kyong Ran Peck, Eui-Cheol Shin
Journal: Immunity (2020)