tbuckley/cabot-search huggingface dataset:
GCT-12. INTRACRANIAL GROWING TERATOMA SYNDROME: CLINICAL IMPLICATION FROM SINGLE UNIVERSITY EXPERIENCES
Authors: Chae-Yong Kim, Ji-Yeon Kwon, Kyeong-O Go, Kihwan Hwang, Jung Ho Han, Hyoung Soo Choi, You Jung Kim, Byung Se Choi, In Ah Kim, Gheeyoung Choe, Seung-Ki Kim, Ji Hoon Phi, Kyu-Chang Wang, Byung-Kyu Cho
Journal: Neuro-Oncology (2020)

Abstract In general, intracranial germ cell tumors (GCT) are sensitive to chemotherapy, radiation therapy, and have favorable outcomes. However, a rare chemotherapeutic retro conversion phenomenon, known as intracranial growing teratoma syndrome (iGTS), shown a poorer prognosis. We analyze the diagnostic characteristics and the result of treatment response for the patients with iGTS treated in our institutes (SNUH and SNUBH, from 1997 to 2019). The electronic medical records and PACS were used for reviewing the clinical information, follow-up MRI images, tumor markers (alpha-fetoprotein, human chorionic gonadotropin, in serum or cerebrospinal fluids), and pathological findings. Out of 328 intracranial GCT patients, seventeen were finally identified as iGTS. Sixteen out of 17 patients were non-germinomatous GCTs, and 1 were germinomas. Initial pathology was common in order of immature teratoma (26.7%), other than immature teratoma (11.5%), and germinoma (0.5%). All of the tumors showed typical ‘honeycomb appearance’ in their follow-up MRI images. Sixteen out of 17 tumors were surgically resected as 2nd look surgery. Among them, 13 tumors were gross totally resected. Twelve were alive without evidence of recurrences during follow-up periods, and the other was dead from the progression of the disease. Among the other than the gross total resection group (n=4), two patients were dead, one recurred the tumor, and the other is following up with stable disease after adjuvant radiation therapy. Early detection and total resection of the tumor as possible might be meaningful for favor prognosis, especially in non-germinomatous GCTs patients.
IMMU-01. IMMUNE CHECKPOINT INHIBITION FOR PEDIATRIC CNS TUMORS: A SINGLE INSTITUTION EXPERIENCE
Authors: Chantel Cacciotti, Jungwhan Choi, Mary Ann Zimmerman, Elise Tierney, Christine Chordas, Jessica Clymer, Susan Chi, Kee Kiat Yeo
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Immune checkpoint inhibition through PD-1 and CTLA-4 blockade has shown efficacy in some adult malignancies and is being investigated in pediatrics. We describe our institutional experience with immune checkpoint inhibition in pediatric CNS tumors. METHODS We performed a retrospective chart review of patients with recurrent, progressive, or refractory pediatric CNS tumors treated with immunotherapy at Dana-Farber/Boston Children’s Hospital between 2018–2019. RESULTS Eleven patients were identified, with median age of 11 years (range:3–9). Diagnoses included DIPG (n=3), HGG (n=4), ependymoma (n=1), craniopharyngioma (n=1), HGNET (n=1) and NGGCT (n=1). Eight patients had recurrent disease (5 local; 3 disseminated); three had refractory disease (non-recurrent). Nine patients were treated with combination therapy (ipilimumab/nivolumab); two patients received monotherapy with either nivolumab or pembrolizumab. Median time from initial diagnosis-to-treatment was 8 months (range 0.8–156). Ten patients received radiation therapy (RT) prior to immunotherapy, with one receiving concurrent RT. Median duration of treatment was 6.1 months (range:1–19). Therapy was discontinued in nine patients: seven due to disease progression and two due to adverse events (colitis, transaminitis). Other pertinent toxicities included type 1 diabetes, hypothyroidism and skin toxicity. Based on iRANO criteria, best responses included partial (n=4), stable (n=6) and progressive disease (n=1). Durable response (&amp;gt;12months) was noted in two patients (HGG and progressive NGGCT). CONCLUSION Immune checkpoint inhibition appears to have clinical benefit and is relatively well tolerated in this cohort of patients. Results from recently completed prospective clinical trials will be critical to inform clinical decisions.
MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents
Authors: Arnold Bolomsky, Meike Vogler, Murat Cem Köse, Caroline A. Heckman, Grégory Ehx, Heinz Ludwig, Jo Caers
Journal: Journal of Hematology & Oncology (2020)

Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
RADT-19. EFFECTS OF RADIATION DOSE-RATE AND TUMOR CHARACTERISTICS ON LOCAL CONTROL AND TOXICITY AFTER RADIOSURGERY FOR ACOUSTIC NEUROMAS
Authors: Conrad Josef Villafuerte, Fred Gentili, David Shultz, Alejandro Berlin, Robert Heaton, Monique van Prooijen, Michael Cusimano, Michael Schwartz, Gelareh Zadeh, David Payne, Derek Tsang
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The effect of stereotactic radiosurgery (SRS) dose-rate on tumor control for acoustic neuroma (AN, or vestibular schwannoma) is unclear. METHODS This was a retrospective study of all patients treated for AN with frame-based cobalt-60 SRS at the Toronto Western Hospital between 2005-2019. Dose rates on the day of SRS were calculated from the calibration dose-rate while accounting for the cobalt-60 half-life of 5.2713 years. Local failure was defined as continued tumor growth &amp;gt;36 months post-SRS, tumor resection for LF, or use of any repeat SRS for LF. Cumulative incidence of LF was reported after accounting for competing risks of death, on a per-lesion basis. Comparisons of actuarial LF were made using Gray’s test. Multivariable analysis of LF was performed using a proportional hazards model. RESULTS A total of 607 patients were treated for 617 acoustic neuromas. Median follow-up was 5.0 years. 158 tumors (26%) were cystic. 71 tumors (12%) had previous resection. Nine patients received 10-11 Gy due to large tumor size; all remaining patients received 12 Gy to approximately the 50% isodose line. Median dose rate was 2.4 Gy/min (range, 1.3-3.7). There was no association between dose rate and LF (≥ 2.4 Gy/min vs. &amp;lt; 2.4 Gy/min, 6.07% vs. 6.12% at 5-year follow-up, p = 0.75). The adjusted local failure-specific hazard ratio (HR) for dose rate (per Gy/min) was 1.2 (95% CI 0.69-2.1, p = 0.52). Patients with previous surgery had higher LF, with a HR of 3.6 (95% CI 1.7-7.8, p = 0.0012), after adjusting for presence of cysts (HR 0.27, p = 0.034) and maximum tumor diameter (HR 1.055 per cm, p = 0.071). CONCLUSIONS In a large cohort of patients with acoustic neuromas, radiosurgery dose-rate was not associated with tumor control. Previous resection was a strong risk factor for local failure after SRS.
The virtual fishbowl: bringing back dynamic debates to medical conferences
Authors: Felix Muehlensiepen, Johanna Mucke, Martin Krusche, Sandra Kurkowski, Gerlinde Bendzuck, Ina Koetter, Vanessa Lemarié, Manuel Grahammer, Martin Heinze, Hendrik Schulze-Koops, Johannes Knitza
Journal: Annals of the Rheumatic Diseases (2020)

‘A good discussion increases the dimension of everyone who takes part’—Randolph Bourne (American writer, 1886–1918).

COVID-19 is changing clinical routines of healthcare providers worldwide. This also affects communication and knowledge exchange. Webinars and virtual conferences have become the ‘new normal’.1 Although digital conferences enable the transfer of research results and medical knowledge, opportunities for participation and discussion are very limited.2 Dynamic debates and panel discussions have become scarce during COVID-19 lockdown.

Recently, the fishbowl technique has been successfully implemented in rheumatology conferences.3 It is a validated method, fostering open group discussions and engagement of all audience members.3 4 By including an expert panel (inner circle) and one empty chair for an alternating audience member, the technique promotes a dynamic and direct exchange with the audience.

To determine whether the fishbowl technique is …
RARE-18. GENETIC EVALUATION IN PATIENTS WITH CHOROID PLEXUS TUMORS
Authors: Milena Oliveira, Nasjla Silva, Andrea Cappellano, Daniela Almeida, Sergio Cavalheiro, Patrícia Dastoli, Frederico Silva, Fernanda Lima
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Choroid plexus tumors (CPT) are rare intraventricular neoplasms of epithelial origin. They usually occur in the 2nd year of life, corresponding to 0.4–0.6% of intracranial tumors in this age group. They are sub classified, according to WHO 2016, in choroid plexus carcinoma (CPC), atypical choroid plexus papilloma (ACPP) and choroid plexus papilloma (CPP). Li-Fraumeni syndrome (LFS) is present in 50% of patients with CPC. In Brazil, the TP53 p.R337H mutation affects 0.3% of the population in the South/Southeast. OBJECTIVE Evaluate the incidence of genetic mutations in patients with choroid plexus tumors and therefore the importance of genetic evaluation. PATIENTS AND METHODS Between 1992–2019, 38 patients were diagnosed with CPT in our institution, 23 with CPC. From 2012, 21 patients were referred for genetic evaluation, 16 of which had CPC (2 had previously CPP). Positive family history for neoplasms was present in 87.5%; 37.5% compatible with LFS, 50% of them with mutations. All the patients with positive, but unspecific, family history of neoplasms, had pathogenic mutation. The molecular investigation of the TP53 gene in patients with CPC was performed and positive in 56.2%: R337H (5 patients), R110C, R158H, H179R, R196* (1 patient each). Of those with R337H, p53 protein immunohistochemistry resulted in 90–100% positivity. One of the patients with CPP that evolved to CCP had the H179R mutation. Clinical course was similar among them, and with those without mutations. CONCLUSION These results confirm the need for genetic evaluation in patients with choroid plexus tumors for adequate therapeutic management and long-term follow-up.
CBIO-22. p53 GAIN-OF-FUNCTION MUTATIONS DRIVE SEX SPECIFIC EFFECTS ON GLIOMA TUMORIGENESIS
Authors: Nathan Rockwell, Nicole Warrington, Joshua Rubin
Journal: Neuro-Oncology (2020)

Abstract Sex differences in malignant brain tumors are well-established: Males exhibit greater incidence and poorer survival. Understanding the biology behind these sex differences requires investigation of the pathways known to drive gliomagenesis. The transcription factor TP53 (p53) is one of the most commonly mutated genes in glioblastoma. Most p53 mutations are missense mutations in the DNA-binding domain that lead to the expression of a full length mutant p53 protein. These mutations can endow p53 with oncogenic gains-of-function through aberrant DNA binding and regulation of noncanonical cancer-promoting target genes. Previously, we analyzed patient mutation data and identified six p53 mutations with sex differences in prevalence. In this study, we developed an in vitro mutant p53 glioma model to investigate the sex specific effects of three p53 point mutations: R175H, Y205C, and Y220C (Mm R172H, Y202C, and Y217C respectively). Male and female astrocytes isolated from p53flox/- mouse pups were transduced with a retrovirus expressing mutant p53, followed by a lentivirus expressing CRE recombinase to remove the endogenous WTp53. We then assessed cell proliferation, clonogenicity, and in vivo tumorigenesis in these cells. All three mutations assayed displayed sex differences in proliferation, with male cells overexpressing p53:Y202C and p53:Y217C growing faster than female cells, and female cells overexpressing p53:R172H growing faster than male cells. Male Y202C and Y217C expressing astrocytes also exhibited a trend toward greater clonogenicity compared to female astrocytes. This observation is supported by higher expression of the stem cell markers SOX2 and NESTIN in the male cells. We performed parallel flank injections of male and female astrocytes expressing each mutation or p53 KO. Only male astrocytes expressing p53:Y202C or p53:Y217C and female astrocytes expressing p53:R172H mutation were able to form tumors in vivo. Together, these data support a sex specific gain-of-function phenotype for three different p53 mutations observed in glioma.
Switching Monopolar No-Touch Radiofrequency Ablation Using Octopus Electrodes for Small Hepatocellular Carcinoma: A Randomized Clinical Trial
Authors: Sae-Jin Park, Eun Ju Cho, Jeong-Hoon Lee, Su Jong Yu, Yoon Jun Kim, Jung-Hwan Yoon, Hyo-Jin Kang, Jeong Hee Yoon, Dong Ho Lee, Se Hyung Kim, Jae Young Lee, Jeong Min Lee
Journal: Liver Cancer (2020)

A switching monopolar no-touch radiofrequency ablation (RFA) technique is used for small hepatocellular carcinoma (HCC); however, there have not been any randomized clinical trials comparing this technique to the conventional RFA technique.This study aims to compare the results of two RFA techniques, and to comparatively identify more effective methods to reduce the progression of local tumors associated with small HCC (≤2.5 cm).This prospective randomized clinical trial (NCT03375281) recruited a total of 116 participants (M:F, 93:23; 68.3 ± 8.4 years) between October 2016 and September 2017. The primary outcome was the cumulative incidence of local tumor progression (LTP) after RFA. Secondary outcomes included technical success rate, technique efficacy, and RFA procedure characteristics. Kaplan-Meier analysis and the Cox proportional hazard regression model were used.The mean follow-up period was 24.1 months. A sufficient ablative margin was more frequently achieved in the no-touch RFA group (57/60 = 95%) than in the conventional RFA group (50/64 = 78.1%) on immediate follow-up CT (p = 0.01). The cumulative incidence of LTP in the no-touch RFA group was significantly lower than that in the conventional RFA group (p = 0.02). In multivariable analysis, no-touch RFA was the only predictive factor for LTP (p = 0.04, hazard ratio = 0.2, 95% confidence interval = 0.04-0.94).A switching monopolar no-touch RFA technique is a favorable treatment option and provides lower LTP after RFA compared with conventional RFA for small HCC.
Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A
Authors: Brian R. Long, Philippe Veron, Klaudia Kuranda, Romain Hardet, Nina Mitchell, Gregory M. Hayes, Wing Yen Wong, Kelly Lau, Mingjin Li, M. Benjamin Hock, Stephen J. Zoog, Christian Vettermann, Federico Mingozzi, Becky Schweighardt
Journal: Molecular Therapy (2020)

Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures.
EPCO-27. GLIOMA SINGLE CELL MULTI-OMIC ANALYSES REVEALS REGULATORS OF PLASTICITY AND ADAPTIVE STRESS RESPONSE
Authors: Kevin Johnson, Kevin Anderson, Elise Courtois, Floris Barthel, Frederick Varn, Diane Luo, Eunhee Yi, Hoon Kim, Marcos Estecio, Ming Tang, Nicholas Navin, Rahul Maurya, Chewyee Ngan, Ketan Bulsara, Michael Samuels, Sunit Das, Paul Robson, Roel Verhaak
Journal: Neuro-Oncology (2020)

Abstract Extensive intra- and intertumoral heterogeneity in glioma contributes to therapeutic resistance and poor patient outcomes. Alterations to DNA methylation (DNAme) modulate epigenetic homeostasis, allowing tumor cells to sample alternative cell states to promote tumorigenesis. However, the epigenetic mechanisms that promote cellular plasticity and regulate cell states are still poorly understood. To characterize the epigenetic mechanisms underlying glioma heterogeneity we profiled 914 single-cell methylomes, 55,284 single-cell transcriptomes, and bulk whole genomes across 11 patient samples spanning initial and recurrent time points and 3 molecular subtypes delineated by IDH mutation status. Local DNAme disorder, defined as epimutation burden, was increased in tumor cells relative to nontumor cells, higher in IDH wild-type than in IDH mutant glioma and was positively associated with copy number alteration (CNA). Epimutation was positively associated with transcriptional variability and enriched at genes involved in cellular differentiation. Epimutation was also increased in the binding sites of transcription factors (TFs) associated with response to extracellular stimuli, suggesting that stochastic DNAme alterations enable cellular plasticity and diverse responses to microenvironmental stressors. Integrative clustering of DNAme and scRNAseq profiles defined stem-like and differentiated-like cell states which exhibited differences in TF activity. Stem-like cells were enriched for differentially methylated binding sites of TFs associated with hypoxia response. scDNAme and scRNAseq-derived copy number profiles were compared with bulk copy number profiles and inferred tumor phylogenies to assess how the timing of CNAs impact epigenetic instability, with results suggesting that early CNA events propagate both genetic and epigenetic heterogeneity. Bulk longitudinal data was used to validate the relationship of epigenetic instability with CNA burden as well as differentially methylated binding sites of cell stress response TFs. Our work suggests that local DNAme disorder promotes cellular plasticity and enables adaptive response to cellular stress such as hypoxia.
Vitamin D status and seroconversion for COVID-19 in UK healthcare workers
Authors: Aduragbemi A. Faniyi, Sebastian T. Lugg, Sian E. Faustini, Craig Webster, Joanne E. Duffy, Martin Hewison, Adrian Shields, Peter Nightingale, Alex G. Richter, David R. Thickett
Journal: European Respiratory Journal (2020)

The coronavirus disease 2019 (COVID-19) pandemic is a global health emergency, resulting in over 50 million infections and over 1.2 million deaths as of mid-November 2020 [1]. Healthcare workers are at a high risk of COVID-19 with large numbers of deaths reported around Europe and the UK, particularly among staff in the Black, Asian and minority ethnic (BAME) demographic group [2]. COVID-19 has disproportionately affected BAME individuals even after accounting for age, sex, social deprivation and comorbidity [3]. NHS staff with vitamin D deficiency were more likely to have developed COVID-19, with staff from BAME ethnicity being the most vitamin D deficient <https://bit.ly/2J3kVTc> We thank the staff of University Hospitals Birmingham NHS Foundation Trust who kindly volunteered for this study. We would also like to thank the research staff of the Birmingham Wellcome NIHR Clinical Research Facility who undertook the staff facing assessments. We would like to thank colleagues at the Clinical Immunology Service for overseeing recruitment and sample processing. We also thank our colleagues Prof Adrian Martineau from Queen Mary University of London, Prof Elizabeth Sapey, Dr Dhruv Parekh, both from University of Birmingham and Prof Jon Rhodes from University of Liverpool, who have given helpful feedback on the study results and manuscript.
DIPG-28. REPEATED LOW DOSE RT FOR PEDIATRIC DIPG – LESS DISEASE BURDEN WITH COMPARABLE OUTCOMES
Authors: Yao Yu Wu, Chen Kan Tseng
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Pediatric diffuse intrinsic pontine glioma (DIPG) is the most dismal prognosis pediatric brain tumor. Six weeks radiation therapy (RT) remains the mainstay of treatment. The aim of the current study was to compare the results of firstly reported repeated low dose RT (rLRT) with conventional RT (CRT). METHODS AND MATERIALS: This retrospective review included 24 children with DIPG, aged 3 -18 years, underwent CRT (52- 60.0 Gy in 1.8- 2.0 Gy, n = 16) or rLRT (18 - 30 Gy in 1.5–2.0 Gy per cycle for 1–3 cycles, n = 8). All children had typical symptoms and MRI features of DIPG, or biopsy-proven DIPG. RESULTS The median overall survival (OS) was 12.6 months in rLRT group and 11.4 months in CRT group (p =0.347), progression-free survival (PFS) was 3.6 months in rLRT group and 6.5 months in CRT group (p = 0.821), no significant survival difference was observed between two groups. Temporary discontinuation or tapering of steroids rate was significantly higher in rLRT group (100% vs 60%, p = 0.028). Although not statistically significant, mean non-hospitalized days were longer in the rLRT group, 403 days versus 305 days in the CRT group, as were mean cumulative progression-free days, 276 days versus 163 days and 1-year free from CSF diversion rate was higher, 100% versus 64.9%. CONCLUSIONS For patients with newly diagnosed DIPG, repeated low dose RT, given over 3 to 4 weeks per cycle for 1 to 3 cycles, offers comparable survival outcome with less disease burden compared with conventional RT.