tbuckley/cabot-search huggingface dataset:
GCT-69. VOLUMETRIC CHANGE BEFORE CHEMORADIOTHERAPY AND INFLUENCE OF DIAGNOSTIC RADIATION EXPOSURE IN INTRACRANIAL GERMINOMAS
Authors: Naoki Kagawa, Ryuichi Hirayama, Chisato Yokota, Yasuyoshi Chiba, Yasunori Fujimoto, Tomoyoshi Nakagawa, Toru Umehara, Noriyuki Kijima, Manabu Kinoshita, Haruhiko Kishima
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Spontaneous regression in intracranial germ cell tumors has been reported in some literatures, but the mechanism has not been well known. We retrospectively measured the tumor volume before chemoradiotherapy and analyzed factors that influence reduction of tumor volume. PATIENTS AND METHODS Plural MRI scans were done before the first course of chemotherapy regimen in 27 patients with primary intracranial germinomas. Their age ranged from 8 to 31 years. 35 lesions from them were enrolled and included 13 pineal, 4 neurohypophyseal, 4 basal ganglia, 4 bifocal type, and 2 multiple lesions. All regions were verified as pure germinoma or HCG-producing germinoma by histopathological examination. Tumor volume of 35 lesions was analyzed by volumetric assessment based on MRI. Ratio of volumetric change between the first MRI and the scan immediately before chemotherapy was defined as shrinking rate (%). Period between disease onset and the first chemotherapy was 20 to 47 days. Diagnostic radiation dose was calculated in each case. RESULTS Initial tumor volume ranged from 0.962 to 72.356 cubic centimeters (mean: 8.27). Diagnostic radiation dose: 40.5 to 910.1 mGy. Shrinking rate ranged from -57.8 to 85.4% (mean: 30.8). In 10 regions, shrinking rate was within 30%. Shrinking rate was significant positively influenced by diagnostic radiation dose (p&amp;lt;0.05) and negatively influenced by initial volume (p&amp;lt;0.05). But, other factors such as age, sex, histopathological parameters did not influence tumor shrinkage. CONCLUSION This study shows that the volume of intracranial germ cell tumors is changing dynamically before chemoradiotherapy in many cases. Diagnostic exposure to low-dose radiation influences tumor shrinkage of intracranial germinomas.
Clonal Somatic Mutations Are a Biomarker for Inferior Prognosis in Diffuse Large B-Cell Lymphoma
Authors: Nicholas J. Boddicker, Pinkal Desai, Mithun Vinod Shah, Vivekananda Sarangi, Matthew J. Maurer, Elliot J. Cahn, Peter Martin, Brian K. Link, Thomas E. Witzig, Andrew L. Feldman, Grzegorz S. Nowakowski, Thomas M. Habermann, Susan L. Slager, C. Chris Huang, Fadi Towfic, Yan Asmann, Anita K Gandhi, Anne J. Novak, James R. Cerhan
Journal: Blood (2020)
CTNI-79. PRICOTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Sied Kebir, Lazaros Lazaridis, Teresa Schmidt, Christoph Oster, Daniela Pierscianek, Nika Guberina, Christoph Kleinschnitz, Martin Proescholdt, Peter Hau, Anca-Ligia Grosu, Ulrich Sure, Björn Scheffler, Martin Stuschke, Martin Glas
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Survival rates were significantly improved when adding TTFields to adjuvant chemotherapy with temozolomide in patients with newly diagnosed glioblastoma (nGBM) in the phase 3 EF-14 trial. TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In preclinical studies, the combination of TTFields and radiotherapy demonstrated synergistically enhanced efficacy in GBM cells. Here, we present the PriCoTTF trial, which is currently enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. METHODS After surgery and complete wound-healing, TTFields therapy will be initiated in newly diagnosed GBM patients. TTFields therapy will continue throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. Radiotherapy will be conducted through the arrays, by which TTFields therapy is delivered. Totally, thirty-three patients will be enrolled in two arms. In arm A, 20 adult patients will be enrolled to receive normo-fractionated radiotherapy and in arm B, 13 elderly patients will be treated by hypo-fractionated radiotherapy. The patients will receive chemotherapy according to institutional standard and interdisciplinary tumor conference. RESULTS Safety and tolerance based on the frequency of pre-specified treatment-limiting toxicities is defined as primary endpoint of the trial. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. To date, 13 patients were included (May 2020). Initial practical experiences will be presented. CONCLUSION The combination of TTFields and radiotherapy is an encouraging approach to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in newly diagnosed GBM will be assessed. In addition, initial efficacy data (phase II) can serve as a rationale for a randomized phase III trial.
TMOD-08. PRIMARY AND RECURRENT GLIOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFTS (PDOX) REPRESENT RELEVANT PATIENT AVATARS FOR PRECISION MEDICINE
Authors: Anna Golebiewska, Ann-Christin Hau, Anais Oudin, Daniel Stieber, Yahaya A Yabo, Yong-Jun Kwon, Barbara Klink, Alexander Skupin, Frank Hertel, Rolf Bjerkvig, Simone P Niclou
Journal: Neuro-Oncology (2020)

Abstract Patient-derived cancer models are essential tools for studying tumor biology and for preclinical interventions. Although numerous clinical cancer trials are being conducted, many fail due to inappropriate selection of compounds at the preclinical stage. Therefore, better preclinical models are crucial for predicting successful clinical impact. Orthotropic patient-derived xenograft (PDOX) models are of particular importance for brain cancers, as they allow to better recapitulate the brain tumor environment and the blood brain barrier. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1. PDOX models were based on 3D organoids, derived from mechanically minced patient material. Organoids were implanted in the brain of immunodeficient mice and further propagated by serial intracranial transplantations. High grade glioma PDOX models, starting with viable patient-derived organoids, have generally a high tumor take rate, a reproducible phenotype and tumor development time. PDOXs retain histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models confirmed limited evolution of gliomas upon treatment observed in patient tumors. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. These data indicate that glioma PDOXs represent clinically relevant avatars for personalized treatment. The use of these models should lead to a more realistic evaluation of the efficacy of novel drugs, thereby increasing the success of clinical studies.
Abstract P307: Trends In Racial And Ethnic Disparities In Metabolic Syndrome Among Us Women Of Reproductive Age: 1988-2016
Authors: Erin Delker, Matthew A Allison
Journal: Circulation (2020)

Objective: To compare trends in the prevalence of metabolic syndrome (MetS) by race/ethnicity among US women ages 18-49 years between 1988 and 2016. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES), we classified MetS according to AHA/NHLBI criteria and calculated age-standardized prevalence of MetS in the following periods: 1988-94, 1999-04, 2005-10, and 2011-16. Our sample included nonpregnant women 18-49 years of age who self-reported as non-Hispanic White, non-Hispanic Black, or Mexican American. For each period, we estimated relative (prevalence ratio, PR) and absolute (prevalence difference, PD) differences by race/ethnicity. We tested heterogeneity of these estimates using ANOVA to determine if the differences between groups significantly widened or narrowed over time. All analyses were stratified by gravidity (nulligravida vs. primi- and multigravida). Results: Between 1988-94 and 2011-16, the age-standardized prevalence of MetS for nulligravida and primi-/multigravida women increased from 10% to 19% and 16% to 28%, respectively. Among nulligravida women , the relative differences in MetS between NH Black and NH White women decreased (PR 1988-94 =1.6, PR 1999-04 =1.4, PR 2005-10 =1.4, PR 2011-16 =1.0), while the difference between Mexican American and NH White women declined in 1999-04, but increased after (PR 1988-94 =2.2, PR 1999-04 =1.0, PR 2005-10 =1.5, PR 2011-16 =1.7). Compared to NH White women, the absolute differences for NH Black (PD 1988-94 =5.8%, PD 1999-04 =9.2%, PD 2005-10 =7.5%, PD 2011-16 =-0.5%) and Mexican American women (PD 1988-94 =11.1%, PD 1999-04 =-0.2%, PD 2005-10 =9.3%, PD 2011-16 =11.9%) followed similar patterns. Moreover, and among primi-/multigravida women , the relative differences between NH Black and NH White women remained stable (PR 1988-94 =1.3, PR 1999-04 =1.3, PR 2005-10 =1.5, PR 2011-16 =1.3), while the differences between Mexican American and NH White women declined (PR 1988-94 =1.8, PR 1999-04 =1.6, PR 2005-10 =1.3, PR 2011-16 =1.3). Again, compared to NH White women, absolute differences for NH Black (PD 1988-94 =4.4, PD 1999-04 =8.5, PD 2005-10 =10.7, PD 2011-16 =7.0) and Mexican American women (PD 1988-94 =12.2, PD 1999-04 =15.4, PD 2005-10 =5.7, PD 2011-16 =7.1) were similar. We found no evidence of significant heterogeneity of PRs and PDs across time for any group. Conclusions: Since 1988, prevalence of MetS among US women ages 18-49 has nearly doubled. The increase in prevalence was similar across NH White, NH Black and Mexican American women. Among nulligravida women, those that self-reported as Mexican American had the highest burden of MetS, while among primi-/multigravida women, the prevalence of MetS was consistently higher among both Mexican American and non-Hispanic Blacks.
CTLA4Ig Primed Donor Lymphocyte Infusions (DLI): A Novel Approach to Natural Killer Cell Immunotherapy Following Haploidentical PBSC Transplantation for Advanced Hematological Malignancies
Authors: Sarita Rani Jaiswal, Prakash Bhakuni, Priyanka Bharadwaj, Shamsuz Zaman, Suparno Chakrabarti
Journal: Blood (2017)
BIOM-08. TARGETSELECTORTM CEREBROSPINAL FLUID (CSF) CIRCULATING TUMOR CELLS AND BIOMARKER ANALYSIS: IMPROVING SENSITIVITY AND TARGETED TREATMENT OPTIONS IN BREAST AND NSCLC CANCER PATIENTS WITH CNS INVOLVEMENT
Authors: Veena Singh, Deanna Fisher, Robbie Schultz, Julie Mayer, Smitha Boorgula, Jaya Gill, Minhdan Nguyen, Judy Troung, Lucia Dobrawa, Jose Carrillo, Naveed Wagle, Santosh Kesari
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Liquid biopsy has emerged as a minimally invasive and cost-effective strategy to assess cancer biomarkers without the risk of complications associated with biopsies. Once a tumor has metastasized to the brain, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) can be found in the cerebrospinal fluid (CSF). We analyzed CSF samples from patients(pts) with primary lung or breast cancer with either brain (BM) or leptomeningeal disease (LMD). Here we report the analytical and clinical validation of Target Selector™ CSF assays. METHODS CSF was collected prospectively from pts with a prior solid tumor diagnosis and confirmed or clinical/ radiological suspicion of BM or LMD. CTCs were captured in microfluidic channel and classified as either CK+ or CK-. Cell-free total nucleic acids (cfTNA) was extracted from CSF supernatant and underwent both Target Selector™ single gene and next-generation sequencing (NGS) NSCLC and breast multi-gene testing. For NGS, data analysis was performed using Torrent Suite with annotation and curation by Ion Reporter and Oncomine Knowledgebase Reporter software. RESULTS The Target Selector™ CTC platform assays performed on clinical samples (n = 89) resulted in clinical sensitivity = 80.0%, clinical specificity = 96.6%, positive predictive value (PPV) = 98%, negative predictive value (NPV) = 70.0% at a limit of detection of 2 CTCs. For molecular analyses, Target Selector™ platform assays resulted in clinical sensitivity = 85.2%, clinical specificity = 88.3%, PPV = 76.7%, and NPV = 93.0%. CONCLUSIONS Target Selector™ is a viable and sensitive platform for CTC detection and molecular analysis of CSF samples from patients with NSCLC or breast cancer with CNS metastases compared to the current standard of care (CSF cytology) and when imaging findings are equivocal. Identifying CTCs and actionable biomarkers can help to confirm CNS involvement when clinically suspected, guide targeted therapy selection and potentially monitor treatment response.
Anti-invasive efficacy and survival benefit of the YAP-TEAD inhibitor verteporfin in preclinical glioblastoma models
Authors: Anne Marie Barrette, Halle Ronk, Tanvi Joshi, Zarmeen Mussa, Meenakshi Mehrotra, Alexandros Bouras, German Nudelman, Joe Gerald Jesu Raj, Dominique Bozec, William Lam, Jane Houldsworth, Raymund Yong, Elena Zaslavsky, Constantinos G Hadjipanayis, Marc R Birtwistle, Nadejda M Tsankova
Journal: Neuro-Oncology (2021)

Abstract Background Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of glioma growth in disease progression and recurrence. Here, we use the FDA-approved drug and small molecule Hippo inhibitor Verteporfin (VP) to target YAP-TEAD activity, known to mediate convergent aspects of tumor invasion/metastasis, and assess the drug’s efficacy and survival benefit in GBM models. Methods Up to 8 low-passage patient-derived GBM cell lines with distinct genomic drivers, including 3 primary/recurrent pairs, were treated with VP or vehicle (VEH) to assess in vitro effects on proliferation, migration, invasion, YAP-TEAD activity, and transcriptomics. Patient-derived orthotopic xenograft (PDX) models were used to assess VP’s brain penetrance and effects on tumor burden and survival. Results VP treatment disturbed YAP/TAZ-TEAD activity; disrupted transcriptome signatures related to invasion, epithelial-to-mesenchymal, and proneural-to-mesenchymal transition, phenocopying TEAD1-knockout effects; and impaired tumor migration/invasion dynamics across primary and recurrent GBM lines. In an aggressive orthotopic PDX GBM model, short-term VP treatment consistently diminished core and infiltrative tumor burden, which was associated with decreased tumor expression of Ki67, nuclear YAP, TEAD1, and TEAD-associated targets EGFR, CDH2, and ITGB1. Finally, long-term VP treatment appeared nontoxic and conferred survival benefit compared to VEH in 2 PDX models: as monotherapy in primary (de novo) GBM and in combination with Temozolomide chemoradiation in recurrent GBM, where VP treatment associated with increased MGMT methylation. Conclusions We demonstrate combined anti-invasive and anti-proliferative efficacy for VP with survival benefit in preclinical GBM models, indicating potential therapeutic value of this already FDA-approved drug if repurposed for GBM patients.
CSIG-13. TRPM7 INDUCES TUMORIGENESIS AND STEMNESS THROUGH NOTCH ACTIVATION IN GLIOMA
Authors: Jingwei Wan, Alyssa Guo, Mingli Liu
Journal: Neuro-Oncology (2020)

Abstract Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling. However, which Notch component(s) is crucial for its activity regulated by TRPM7, and its relationship with other GSC markers, such as CD133 and ALDH1, remain unclear. In the current project, we elucidate the mechanisms of TRMP7’s regulation of Notch signaling pathway that contribute to the development and progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using multiple glioma cell lines (GC) with different molecular subtypes and GSCs derived from the GC lines. 1) We first analyzed TRPM7 expression using the Oncomine database (https://www.oncomine.org) and found that the TRPM7 mRNA expression is significantly increased in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissue controls. 2) TRPM7 is expressed in GBM, and its channel activity is correlated with Notch1 activation. Inhibition of TRPM7 downregulates Notch1 signaling, while upregulation of TRPM7 upregulates Notch1 signaling. 3) GSC markers, CD133 and ALDH1, are correlated with TRPM7 in GBM. 4) Targeting TRPM7 suppresses the growth and proliferation of glioma cells through G1/S arrests and apoptosis of glioma cells. 5) Targeting Notch1 suppresses the TRPM7-induced growth and proliferation of glioma cells, as well as the expression of GSC markers CD133 and ALDH1. In summary, TRPM7 is responsible for sustained Notch signaling activation, enhanced expression of GSC markers, and regulation of glioma stemness, which contribute to malignant glioma cell growth and invasion. Notch1 and ligand DII4 are key components that contribute GSC stemness.
RARE-45. SARCOMAS INVOLVING THE CENTRAL NERVOUS SYSTEM AT INITIAL PRESENTATION IN CHILDREN AND YOUNG ADULTS: A CASE SERIES
Authors: Yen-Lin Liu, Shu-Mei Chen, Hsin-Lun Lee, Jia-Hui Huang, Shu-Huey Chen, Yu-Chien Kao, Hsi Chang, Min-Lan Tsai, Sung-Hui Tseng, Kevin L C Hsieh, Chia-Yau Chang, Jinn-Li Wang, James S Miser, Tai-Tong Wong
Journal: Neuro-Oncology (2020)

Abstract Sarcomas of bone, soft tissue, or neural origin may occasionally invade the central nervous system (CNS), causing diagnostic and therapeutic challenges. We aim to investigate the clinical features of sarcomas involving the CNS at initial presentation. During 2015/01–2019/12, nine consecutive patients (4 Males and 5 Females) younger than 30 years of age treated at a University Healthcare System in Northern Taiwan were included. The median age was 8.7 years (range, 2–24 years); diagnoses were Ewing Sarcoma with EWSR1 rearrangements (n=4), CIC-NUTM1 Sarcoma (n=1), Osteosarcoma (n=2), Malignant Peripheral Nerve Sheath Tumor (MPNST; n=1), and extramedullary myeloid sarcoma (n=1). The tumors originated from the skull (n=1), dura (n=1), vertebra (n=4), spinal canal (n=1), or extra-CNS sites (n=2). Four patients had metastases (1 Ewing sarcoma, 2 osteosarcoma, and 1 extramedullary myeloid sarcoma). The main symptom at diagnosis was facial/eye pain (n=2), back pain (n=3), arm weakness (n=1), or gait disturbance (n=3). Upfront neurosurgical decompression (n=7) or urgent radiotherapy (n=1) was performed in most patients. At a median follow-up duration of 20.1 months, the overall survival rate was 70%. All patients with Ewing sarcoma (n=4) and CIC-NUTM1 sarcoma (n=1) achieved Complete Response after surgery, interval-compressed chemotherapy, radiotherapy, and adjuvant chemotherapy. Patients with stage IV osteosarcoma (n=2) had Partial Response; the patients with MPNST and extraskeletal myeloid sarcoma died of Progressive Disease at 18 and 3 months after diagnosis, respectively. We conclude that timely decompression, early diagnosis, and histology-driven multimodality treatment are effective strategies in managing sarcomas involving the CNS.
QOL-26. I’VE GOT FRIENDS NOW: PAEDIATRIC PATIENTS’ EXPERIENCES OF METHYLPHENIDATE TREATMENT FOR NEUROCOGNITIVE LATE-EFFECTS ASSOCIATED WITH BRAIN TUMOUR
Authors: Sarah Verity, Rebecca Hill, Gail Halliday, Jade Ryles, Simon Bailey
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Whilst rates of survival following paediatric brain tumour have increased, quality of survival continues to present a significant challenge to children and their families. The neurocognitive impact of cranial radiotherapy (CRT) in childhood upon future intellectual development is well established. Both CRT and chemotherapy are associated with medium-term slowed speed of cognitive processing, attention, and memory impairment, and with longer-term failure to achieve pre-morbid intellectual potential and low Health-Related Quality of Life (HRQoL).Methylphenidate is a psychostimulant drug shown to be effective in alleviating some of the neurocognitive symptoms of cancer treatment, however the subjective experience of paediatric participants is not reported. AIM: The current study aimed to explore the subjective experience of HRQoL in paediatric neuro-oncology patients currently receiving methylphenidate. METHODS A retrospective audit was conducted on 12 paediatric neuro-oncology patients in receipt of methylphenidate. Both standardised and novel measures were used to assess aspects of HRQoL, specifically; social life, perceived independence, mood, confidence, school life, self-esteem, interpersonal relationships and fatigue levels. Data collected were analysed using Thematic Analysis. RESULTS Five key themes were identified; physical, emotional, social, academic and neuropsychological impact. CONCLUSION The current findings evidence the perception of patients that methylphenidate supported them to regain previously lost functionality. Methylphenidate has the potential to increase HRQoL in this population and to provide children with the opportunity to regain a sense of normality in their lives.
EPID-08. FINDING THE NEEDLE IN THE HAY STACK – POPULATION-BASED STUDY OF PREDIAGNOSTIC SYMPTOMATIC INTERVAL IN CHILDREN WITH CNS TUMORS
Authors: Clare Lambert, Ran Goldman, Douglas Cochrane, Anita Dahiya, Heidi Mah, Arsh Buttar, Sylvia Cheng
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Delay in diagnosis of central nervous system (CNS) tumors in children is well documented. The aims of this study were to characterize the symptomatology of CNS tumors and the time to diagnosis in a large pediatric hospital in Canada. METHODS Retrospective chart review of children diagnosed with a CNS tumor between 2000 and 2016 in Vancouver, British Columbia, Canada was performed. Data collected included demographics, symptomatology, tumor type, age at diagnosis, known visits to healthcare professionals, neuroimaging, therapy and post treatment relapse or progression. RESULTS 148 children with complete medical records were reviewed. The average age at diagnosis was 87.8 months (standard deviation (SD) = 59.7; median = 72). 50.7% of patients had posterior fossa tumors and 49.3% had supratentorial tumors. 30% of patients were diagnosed after a single visit to a health care provider. 7.7% of children needed more than 4 visits. Median total time to diagnosis (PSI) was 62 days (range = 0-2047 days). The longest prediagnostic interval was first symptom onset to first healthcare provider visit (PSI1, median 37 days). Patients with posterior fossa tumors, presence of metastases, and symptoms of ataxia and paresis were associated with shorter PSI. CONCLUSIONS CNS tumors in children continue to pose a diagnostic challenge with significant variability in time to diagnosis. Our population-based study found that median time from symptoms to seeking medical advice by parents was over a month. It is essential to uncover the reasons for delay and address them where possible.