tbuckley/cabot-search huggingface dataset:
PATH-17. INTRAGENIC COPY NUMBER BREAKPOINT ANALYSIS OF METHYLATION DATA FROM CNS TUMOURS IDENTIFIES NOVEL SUBGROUP-SPECIFIC CANDIDATE FUSION GENE ENRICHMENTS
Authors: Alan Mackay, Yura Grabovska, Matthew Clarke, Diana Carvalho, Sara Temelso, Chris Jones
Journal: Neuro-Oncology (2020)

Abstract Methylation array-based molecular profiling has redefined the classification of brain tumours and now forms an important part of their integrated diagnosis, providing both subgroup assignment and genome wide DNA copy number profiles. These latter data can be used to identify intragenic breakpoints which are frequently associated with structural variations resulting in therapeutically targetable oncogenic fusion genes. To systematically assess the landscape of these alterations, we combined publicly available methylation datasets resulting in a total of 5660 CNS tumours, around half paediatric, and including &amp;gt;1000 high grade glioma and DIPG. These were analysed by standard methodology (MNP, conumee), and intragenic breakpoint enrichment was compared within methylation subgroups, superfamilies, and tumours with no high-scoring classification. Benchmarking included sequence-verified cases such as infant hemispheric gliomas (IHG) with ALK(15%) and ROS1(7%) fusions, and pathognomic alterations associated with specific entities such as RELA-EPN, MYB-LGG and HGNET-MN1. We identified previously unreported enrichments of well-recognised fusion targets such as NTRK2in GBM_MID and NTRK3in DMG_K27 (both 5%), METin A_IDH / A_IDH_HG (3–5%), and FGFR1/3in GBM_G34 (8–9%). Novel recurrent kinase gene candidates to be verified and explored further include IGF1Rin 2–12% cases spanning glioma subgroups, and TIE1in poorly classified tumours. This latter ‘NOS’ group were also enriched in various transcription factor targets of breakpoints, including TCF4and PLAGL2. Despite limitations due to sample quality, resolution or balanced translocations, breakpoint analysis of methylation copy number profiles provides simple screening for structural rearrangements which may directly influence targeted therapy in paediatric CNS tumours.
HGG-45. PROTEOMIC ANALYSIS OF PEDIATRIC DIFFUSE ASTROCYTOMAS YIELDS PATHWAYS ASSOCIATED WITH BOTH PROGRESSION-FREE AND OVERALL SURVIVAL
Authors: Blake Sells, Jessica Fleming, Richard Graham, Joseph McElroy, Jahar Haque, Daniel Boué, Aline Becker, Erica Bell, Jonathan Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2020)

Abstract Brain tumors are now responsible for more deaths each year than any other childhood cancer. Current studies aim to discover key molecular drivers that can explain prognosis and serve as targets for new therapeutic approaches, reducing morbidity. In this study, we performed LC-MS/MS proteomics on a cohort of 28 primary diffuse astrocytoma formalin-fixed paraffin embedded samples (WHO Grades II-IV) from patients at Nationwide Children’s Hospital with a median follow-up time of 2.3 (0.6–20.2) years. Ingenuity Pathway Analysis was used to analyze the proteomic data after using both age and grade as covariates and only including proteins with p-values less than 0.05. The upregulation of a well-known oncogenic pathway, the Protein Kinase A signaling pathway, was significantly associated with greater risk of progression and death (P=5.5E-07 and P=4.6E-04). Integrin signaling, a pathway commonly suppressed in cancer, was similarly downregulated in those with greater risk of progression and death (P=3.3E-04 and P=1.7E-07). A global upstream analysis of the proteomic data also predicted activation of the oncogene MYCN in those who performed poorly, supporting previous studies. When comparing grade II (n=10) to grade III (n=8) and IV (n=10) primary tumors, the pathway most upregulated in higher histopathological grades was EIF2 Signaling (P=4.9E-49). This pathway has previously been associated with resistance in adult glioblastoma. These pathways, and the proteins detected within, may provide novel means by which to better understand and treat pediatric diffuse gliomas. Ongoing studies are in progress to understand how these pathways drive aggressiveness and differ from adult astrocytomas.
MBCL-28. LONG-TERM FOLLOW-UP RESULTS OF REDUCED DOSE CRANIOSPINAL RADIOTHERAPY AND TANDEM HIGH-DOSE CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK MEDULLOBLASTOMA
Authors: Ji Won Lee, Do Hoon Lim, Meong Hi Son, Ki Woong Sung, Hee Won Cho, Hee Young Ju, Ju Kyung Hyun, Keon Hee Yoo, Hye Lim Jung, Hong Hoe Koo, Yeon-Lim Suh, Yoo Sook Joung, Hyung Jin Shin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND In this study, we report the follow-up results of reduced-dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB). METHODS Newly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor &amp;gt; 1.5 cm2 or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, RT including reduced-dose CSRT (23.4 or 30.6 Gy), 4 cycles of post-RT chemotherapy and tandem HDCT were given. NanoString and DNA sequencing were done with archival tissues. RESULTS Forty patients were enrolled, and molecular subgrouping was possible in 21 patients (2 WNT, 3 SHH, 8 Group 3 and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (10-year cumulative incidence 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (4 acute TRMs and 2 late TRMs) resulting in 18.5 ± 0.5% of 10-year cumulative incidence. Taken together, the 10-year event-free survival and overall survival were 71.1 ± 8.0% and 68.9 ± 8.5%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common. CONCLUSIONS Strategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate, however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can have benefit from HDCT will be needed in the future study.
NCOG-32. THE SAFETY AND EFFICACY OF DEXAMETHASONE IN THE MANAGEMENT OF GLIOMA PATIENTS
Authors: Ravi Medikonda, Kisha Patel, Laura Saleh, Siddhartha Srivastava, Christina Jackson, Aditya Mohan, Jon Weingart, Chetan Bettegowda, Gary Gallia, Henry Brem, Michael Lim
Journal: Neuro-Oncology (2020)

Abstract Dexamethasone is routinely administered to glioma patients for the management of cerebral edema. Dexamethasone is associated with significant side effects including hyperglycemia, increased risk of infection, and impaired anti-tumor immune response. Despite these risks, there are no standardized guidelines for the effective use of dexamethasone in managing glioma. In this single-institution retrospective cohort study, we evaluate the effect of dexamethasone in glioma patients undergoing surgical resection on post-operative complications and overall survival. 436 patients met the inclusion criteria for this study. 46% of patients received pre-operative dexamethasone, and 90% of patients received post-operative dexamethasone. Pre-operative dexamethasone usage did not significantly affect the immediate post-operative T2 flair volume (p=0.53), however it was associated with a higher incidence of post-operative wound infection (4.0% vs 0%, p=0.002) and post-operative hyperglycemia ((p=0.02). Administration of dexamethasone in the post-operative setting did not affect the incidence of post-operative wound infection (p = 0.38) or hyperglycemia (p=0.18). It also did not affect the 3-month T2 flair volume (p=0.87). On cox proportional hazards analysis, pre-operative dexamethasone was associated with a greater hazard of death (HR=1.48; p=0.01), and post-operative dexamethasone was associated with a lower hazard of death (HR=0.20; p=0.04) after adjusting for several possible confounders. Our findings demonstrate significant differences in the safety and efficacy of pre-operative and post-operative dexamethasone in glioma patients. Routine use of pre-operative dexamethasone appears to increase the risk of post-operative complications and negatively impact survival, whereas post-operative dexamethasone improves survival and was not associated with a higher risk of steroid-related post-operative complications. These findings reaffirm a role for dexamethasone in managing cerebral edema in glioma patients, but also highlight the potential for serious negative consequences with dexamethasone use. This study provides a rationale for re-evaluating the role of dexamethasone, particularly in the pre-operative period.
GCT-65. INCIDENCE AND OUTCOME OF INTRACRANIAL MALIGNANT GERM CELL TUMOURS DIAGNOSED IN WESTERN DENMARK IN THE LAST DECADE
Authors: Yasmin Lassen-Ramshad, Torben Stamm Mikkelsen, Steen Rosthoej, Louise Tram Henriksen, Ruta Tuckuvienne, Ines Ackerl Kristensen, Gorm von Oettingen, Soeren Cortnum, Anne-Birgitte Als, Akmal Safwat, Mads Agerbaek
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Intracranial malignant germ cell tumours (iGCT) are rare brain tumours mainly diagnosed in children and younger adults. MATERIAL AND METHODS A retrospective analysis was performed by chart review of patients treated for iGCT in the northern and central region of Denmark. Teratoma only patients were not included in the study. RESULTS 20 patients with iGCT were diagnosed from 2008–2019 in Western Denmark. The cumulative incidence was 1.05 per 100.000. The yearly incidence was 0.1 per 100.000. Mean age at diagnosis was 18 years (range 8–36 years), 17 were males and 3 were females. 13 patients presented with germinoma and 7 patients with non germinomateous germ cell tumours (NGGCT). Three patients had disseminated disease, two with germinoma and one with NGGCT. All patients had received radiotherapy and 18 patients were treated with multidrug chemotherapy including platinum and etoposide before irradiation. Two patients experienced recurrent disease, both non disseminated at diagnosis, one patient with germinoma and one patient with NGGCT. Both received salvage treatment including high dose chemotherapy with stem cell transplantation and reirradiation. Two NGGCT patients died, one patient after development of an anaplastic astrocytoma in the radiation field five years after radiotherapy and one patient after intracranial hemorraghe 18 months after salvage treatment for recurrent disease. Overall survival was 90%, 100% for GCT and 71% for NGGCT. CONCLUSION The outcome of patients with iGCT in Western Denmark was comparable to the literature. A nationwide study of epidemiology and outcome of iGCT in Denmark is planned.
COVID‐19 Outcomes in Patients With Systemic Autoimmune Rheumatic Diseases Compared to the General Population: A US Multicenter, Comparative Cohort Study
Authors: Kristin M. D’Silva, April Jorge, Andrew Cohen, Natalie McCormick, Yuqing Zhang, Zachary S. Wallace, Hyon K. Choi
Journal: Arthritis & Rheumatology (2020)

Patients with systemic autoimmune rheumatic diseases (ARDs) continue to be concerned about risks of severe coronavirus disease 2019 (COVID-19) outcomes. This study was undertaken to evaluate the risks of severe outcomes in COVID-19 patients with systemic ARDs compared to COVID-19 patients without systemic ARDs.
A blood circulation-prolonging peptide anchored biomimetic phage-platelet hybrid nanoparticle system for prolonged blood circulation and optimized anti-bacterial performance
Authors: Peipei Jin, Liansheng Wang, Rui Sha, Liu Liu, Jieying Qian, Nestor Ishimwe, Wenbin Zhang, Jing Qian, Yunjiao Zhang, Longping Wen
Journal: Theranostics (2020)

Phage therapy holds great promise for resolving the ever-worsening crisis of antibiotic resistance, but it also faces many challenges. One of the issues hampering phage therapy is the short blood residence time of bacteriophages. We have previously identified, through in vivo phage display, a blood circulation-prolonging peptide (BCP1) that was capable of significantly prolonging the blood retention time of a doxorubicin-loaded human ferritin nanocage, leading to enhanced therapeutic efficacy against tumors. Herein, we aimed to extend the application of BCP1 to anti-bacterial phage therapy. Methods: A genetically engineered M13 phage, BCP1-BGL, that displayed the BCP-1 peptide and expressed the restriction endonuclease Bgl II, was constructed. Taking advantage of the fact that BCP1 harbors an RGD motif (a three amino-acid sequence Arg-Gly-Asp with the ability to bind to integrins) and exerts its circulation-prolonging activity primarily through interaction with platelets, we further designed and fabricated a biomimetic phage-platelet hybrid nanoparticle (PPHN) via the physical binding of the BCP1-BGL phage to the platelet membrane nanoparticles derived via a repeated freeze-thaw procedure. A series of experiments in vitro and in vivo were conducted to reveal the long circulation and anti-bacterial capacities of BCP1-BGL phages and PPHNs. Results: The resulting PPHNs possessed a hydrodynamic size of 368 nm in deionized water, with each spherical membranous nanoparticle harboring approximately 12 rod-shaped phage particles stably bound to its surface. PPHNs, which were superior to the BCP1-BGL phages that displayed significantly prolonged anti-bacterial action in vivo against Escherichia coli infection, exhibited further extended blood retention time and optimal anti-bacterial performance in both the prophylactic and treatment approaches. Conclusion: Our work demonstrated a novel strategy in engineering biomimetic phage-based nanoparticles with improved blood retention and anti-bacterial performance and may have implications in phage therapy.
18F-Fluciclovine PET/CT in Therapeutic Decision Making for Prostate Cancer
Authors: Alexandra D. Dreyfuss, Grace S. Ahn, Andrew R. Barsky, Jennifer A. Gillman, Neha Vapiwala, Austin R. Pantel
Journal: Clinical Nuclear Medicine (2020)

We carried out a retrospective cohort study of patients with BR after primary treatment of PC who received imaging with 18F-fluciclovine PET/CT at our institution between January 2010 and January 2019. PET/CT results were compared with biopsy, conventional imaging results, and/or response to PC therapy. 18F-Fluciclovine PET/CT performance statistics and effects on treatment planning were calculated.A total of 328 patients with a median age of 71 years (range, 47-90 years) and median serum prostate-specific antigen level of 1.6 ng/mL (0.02-186.7 ng/mL) were included. Three hundred thirty-six 18F-fluciclovine PET/CT scans were analyzed and classified as positive (65%), negative (25%), or equivocal (10%) based on radiology reports. Sensitivity was 93% (95% confidence interval, 86%-96%) and specificity was 63% (95% confidence interval, 45%-77%). Of patients with known management recommendations post-PET/CT, scan results changed or influenced pre-PET/CT management plans in 73%, and 58% of recommendations involved treatment modality decisions. Overall, 82% of patients' actual management was concordant with post-PET/CT recommendations. Of evaluable patients, 116 (35%) had some form of post-PET radiotherapy included in their care plans, with 95% receiving radiotherapy at a PET-avid target.In the largest single-institutional cohort to date, 18F-fluciclovine PET/CT showed value in the workup of PC in the setting of BR, with noteworthy influence over clinical management decisions. Further studies are needed to evaluate whether PET/CT-based changes in management are associated with improved outcomes.
EPEN-34. THE CRISPR-Cas9 SYSTEM-MEDIATED ENDOGENOUS GENE REARRANGEMENT INDUCED C11orf95-RELA FUSION IN VITRO AND IN VIVO THAT LED TO THE DEVELOPMENT OF EPENDYMOMA-LIKE TUMOR
Authors: Mutsumi Takadera, Tatsuya Ozawa, Kaishi Satomi, Tetsuya Yamamoto, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract Recent large-scale genomic studies of ependymal tumors have identified recurrent RELA and YAP1 fusion genes in supratentorial ependymomas. The formation of the C11orf95-RELA fusion gene has been attributed to massive genomic rearrangement involving chromosome 11q termed Chromothripsis in many cases. However, the causal relationship has not been clarified experimentally. In this study, we developed a system to reproduce the oncogenic gene rearrangement using the CRISPR-Cas9 system and examined whether consequent endogenous ependymoma fusion genes are competent to form brain tumors in mice. Initially, to investigate whether C11orf95-RELA fusion can be formed by inducing the relevant gene rearrangement in vitro, we designed multiple guide RNAs on the human and mouse genomic loci and introduced them into cultured cells. RT-PCR and immunoblot analyses detected endogenous C11orf95-RELA fusion transcript and protein in both human and mouse cultured cells. Subsequently, we lentivirally introduced the gRNAs into a mouse brain. Brain tumor formation was observed from around 2 months after the lentivirus injection, thus indicating successful gene rearrangement followed by C11orf95-RELA fusion expression in vivo. Analysis of the tumor tissue confirmed the expression of the endogenous C11orf95-RELA fusion gene. These results suggested that a gene rearrangement is a primary mechanism to form the C11orf95-RELA fusion which is the direct driver of tumorigenesis. Our system to simulate a genomic event will provide significant insights into the understanding of the tumorigenic mechanism in ependymomas.
Mesenchymal stem cell-mediated immunomodulation of recruited mononuclear phagocytes during acute lung injury: a high-dimensional analysis study
Authors: Jingqi Liu, Pan Li, Jiaqi Zhu, Feiyan Lin, Jiahang Zhou, Bing Feng, Xinyu Sheng, Xiaowei Shi, Qiaoling Pan, Jiong Yu, Jianqing Gao, Lanjuan Li, Hongcui Cao
Journal: Theranostics (2020)

Rationale: Acute lung injury (ALI)-recruited mononuclear phagocytes play a pivotal role in lung injury and repair. This study investigated the types of recruited mononuclear phagocytes and the immunotherapeutic effects of allograft mesenchymal stem cells (MSCs) in a mouse model of lipopolysaccharide (LPS)-induced ALI. Methods: C57BL/6 mice were orotracheally instilled with LPS (20 mg/kg). Compact bone-derived MSCs were administered orotracheally 4 h after LPS inhalation. Mononuclear phagocytes recruited in the lung tissues were characterized at different timepoints by high-dimensional analysis including flow cytometry, mass cytometry, and single-cell RNA sequencing. Results: Eight mononuclear phagocyte subsets recruited to LPS-challenged lungs were precisely identified. On day 3 after LPS administration, both Ly6ChiCD38+ and Ly6ClowCD38+ monocytes were recruited into acutely injured lungs, which was associated with increased secretion of neutrophil chemokines. Ly6ChiCD38+ monocytes differentiated into M1 macrophages on day 3, and subsequently differentiated into CD38+ monocyte-derived dendritic cells (mo-DCs) on day 7, while Ly6ClowCD38+ monocytes differentiated into CD11b+CD38+ DCs on day 7. When ALI mice were treated with MSCs, the mortality significantly reduced. Notably, MSCs reduced the amount of M1 macrophages and reduced the secretion of neutrophil chemokines on day 3. Furthermore, MSCs reduced the number of CD38+ mo-DCs and CD11b+CD38+ DCs on day 7, suppressing the antigen presentation process. Recruited mononuclear phagocyte subsets with a high level of CD38 exhibited an activated phenotype and could secrete higher levels of cytokines and chemokines. Conclusions: This study characterized the dynamic functions and phenotypes of recruited mononuclear phagocytes in ALI mice and MSC-treated ALI mice.
Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington’s disease
Authors: Filipe B. Rodrigues, Lauren M. Byrne, Rosanna Tortelli, Eileanoir B. Johnson, Peter A. Wijeratne, Marzena Arridge, Enrico De Vita, Naghmeh Ghazaleh, Richard Houghton, Hannah Furby, Daniel C. Alexander, Sarah J. Tabrizi, Scott Schobel, Rachael I. Scahill, Amanda Heslegrave, Henrik Zetterberg, Edward J. Wild
Journal: Science Translational Medicine (2020)

Longitudinal analysis in 80 patients shows that mutant huntingtin and neurofilament light could predict Huntington’s disease progression.
NCMP-22. SECOND MALIGNANCIES FOLLOWING TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM TUMORS IN PEDIATRIC PATIENTS: A SINGLE-INSTITUTIONAL RETROSPECTIVE REVIEW
Authors: Nicholas Pytel, Erik Dedekam, Shahriar M Salamat, Diane Puccetti
Journal: Neuro-Oncology (2020)

Abstract Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.
MBRS-22. SIGNIFICANCE OF <i>RNF213</i> IN TUMORGENICITY OF MEDULLOBLASTOMA
Authors: Yohei Mineharu, Yuki Oichi, Takahiko Kamata, Yasuzumi Matsui, Takaaki Morimoto, Masahiro Tanji, Hatasu Kobayashi, Hiroko Okuda, Kouji H Harada, Akio Koizumi, Yoshiki Arakawa, Susumu Miyamoto
Journal: Neuro-Oncology (2020)

Abstract RNF213 gene, initially identified as a disease-causing gene for moyamoya cerebrovascular disease, has recently been recognized as a tumor regulator. The gene is known to be associated with WNT signaling, lipid metabolism, angiogenesis and genomic instability. The purpose of this study was to investigate the association of RNF213 in tumorgenicity of medulloblastoma. Incidence of medulloblastoma and histopathological findings were compared among ptch1+/-, ptch1+/- rnf213+/-, and ptch1+/- rnf213-/- mice. Knockout of rnf213 in ptch1+/- transgenic mouse model increased the incidence of spontaneous generation of medulloblastoma from 19.8% (ptch1+/-) to 76.5% (rnf213+/- ptch1+/-) at 9 months (p &amp;lt; 0.001). Heterozygous knockout was equivalent to homozygous knockout. Haploinsufficiency of rnf213 seems to be associated with tumorgenicity in medulloblastoma. Molecular mechanism of medulloblastoma generation needs to be further investigated.