tbuckley/cabot-search huggingface dataset:
RONC-09. PSEUDOPROGRESSION AFTER PROTON THERAPY OF PEDIATRIC SPINAL PILOCYTIC ASTROCYTOMA AND MYXOPAPILLARY EPENDYMOMA
Authors: Susan McGovern, Jason Johnson, Stephen Kralik, David Grosshans, Mary Frances McAleer, Wafik Zaky, Patricia Baxter, Frank Lin, Murali Chintagumpala, Arnold Paulino
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pseudoprogression after proton therapy of CNS tumors is a challenging clinical situation. The rate of pseudoprogression after proton therapy of pediatric spinal tumors is unknown. METHODS Records of pediatric patients with spinal pilocytic astrocytoma (sPA; n = 9) or myxopapillary ependymoma (MPE; n = 6) with gross disease treated with proton therapy with at least 6 months of follow up from completion of proton therapy were retrospectively reviewed for demographics, treatment characteristics, and occurrence of pseudoprogression. Pseudoprogression was defined as a post-radiation increase in tumor size with subsequent decrease in size without additional tumor-directed therapy. RESULTS The median age at radiation for sPA patients was 10.1y (range, 7.0 – 16.2y) and 12.7y (range, 7.9 – 14.4y) for MPE patients. The median prescribed dose was 45 GyRBE (range, 39.6 – 50.4 GyRBE) for sPA patients and 50.4 GyRBE (range, 45 – 54 GyRBE) for MPE patients. One sPA patient received concurrent vincristine. Median follow up after proton therapy was 44 months (range, 9 – 99 months). Six of nine sPA patients (67%) had pseudoprogression occurring at a median of 81 days (range, 34 – 136 days) after proton therapy; no MPE patients developed pseudoprogression (0%; p &amp;lt; 0.03). Two sPA patients with pseudoprogression were symptomatic and improved with medical therapy. CONCLUSION Preliminary analysis suggests that pseudoprogression occurs frequently within 6 months after proton therapy for sPA and infrequently after proton therapy for MPE.
Comorbidities Drive the Majority of Overall Mortality in Low-Risk Mucinous Pancreatic Cysts Under Surveillance
Authors: Ankit Chhoda, Muhammad N. Yousaf, Kamraan Madhani, Harry Aslanian, Priya A. Jamidar, Alejandro L. Suarez, Ronald R. Salem, Thiruvengadam Muniraj, John W. Kunstman, James J. Farrell
Journal: Clinical Gastroenterology and Hepatology (2020)
Pancreatic Iron and Bone Health in Thalassemia Major
Authors: Antonella Meloni, Silvia Maffei, Laura Pistoia, Cristina Vassalle, Maria Caterina Putti, Angelo Peluso, Calogera Gerardi, Cristina Paci, Elena Facchini, Maria Grazia Sanna, Aurelio Maggio, Vincenzo Positano, Alessia Pepe
Journal: Blood (2017)
NIMG-47. METABOLIC CHARACTERIZATION OF IDH MUTANT LOWER GRADE GLIOMA USING SPECTROSCOPIC IMAGING OPTIMIZED FOR 2-HYDROXYGLUTARATE DETECTION
Authors: Marisa LaFontaine, Adam Autry, Elizabeth Philips, Llewellyn Jalbert, Javier Villanueva-Meyer, Susan Chang, Yan Li
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Mutations in isocitrate dehydrogenase (IDH1/2) genes are both diagnostic and prognostic biomarkers for lower grade gliomas, which can be noninvasively evaluated via MRS detection of 2-hydroxyglutarate (2HG). A high percentage of lower grade gliomas harbor IDH mutations that have a major impact on tumor biology. METHODS Forty IDH-mutant lower grade glioma patients were recruited and scanned using 2HG-optimized 97ms PRESS spectroscopy prior to surgical resection, whereupon image-guided tissue samples were acquired and analyzed via histopathology. Spectra were processed and quantified using LCModel. Wilcoxon ranksum tests were used to compare the difference in metabolic parameters between patient subgroups. Cox proportional hazard models were used to evaluate the influence of metabolic parameters on progression free survival (PFS). Pearson and Kendall Tau rank correlations were used for metabolites and histopathology parameters. RESULTS Levels of 2HG were quantifiable in 37/40 (92.5%) IDH+ patients, yielding a detection rate of 92.5%. A significant difference in myoinositol/total choline was found between astrocytoma and oligodendroglioma in the newly diagnosed grade II population (N=10/13, p=0.042) and also in the overall population (N=25/15, p=0.022). 2HG/creatine was the only significant prognostic indicator on PFS in newly diagnosed patients (p=0.036, HR=4.435; N=33), who had a median PFS of 1472 days [95%CI 994 1950 days] (15 censored). Significantly decreased glutamate/creatine and increased (2HG+GABA)/creatine (p&amp;lt; 0.0001) were found in the T2 lesion compared to those in the normal appearing white matter. At the location where the biopsy samples were taken, there was a significant relationship between 2HG/creatine and glycine/creatine (0.93±0.01; mean±SD Tau; p=0.0005) as well as 2HG/creatine and glutathione/creatine (0.96±0.02; mean±SD Tau; p=0.001) but no significance between the metabolites and pathology parameters were found. CONCLUSIONS The non-invasive detection of 2HG can provide clinically relevant information for patient management and our study demonstrated both the feasibility of 2HG detection and its relationship with PFS.
Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective
Authors: Massimo Filippi, Paolo Preziosa, Frederik Barkhof, Declan T. Chard, Nicola De Stefano, Robert J. Fox, Claudio Gasperini, Ludwig Kappos, Xavier Montalban, Bastiaan Moraal, Daniel S. Reich, Àlex Rovira, Ahmed T. Toosy, Anthony Traboulsee, Brian G. Weinshenker, Burcu Zeydan, Brenda L Banwell, Maria A. Rocca
Journal: JAMA Neurology (2020)

Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS.
MBRS-33. TEMPORARY RESTORATION OF p53 ACTIVITY DURING FRACTIONATED RADIOTHERAPY IN A GROUP3 MEDULLOBLASTOMA GEMM REPRESENTS A POWERFUL TOOL FOR RADIOBIOLOGY STUDIES
Authors: Alaide Morcavallo, Henry Mandeville, Karen Barker, Stacey Richardson, Janet Lindsey, Nikita Lockett, Jessica K R Boult, Simon P Robinson, Uwe Oelfke, Daniel Williamson, Steven C Clifford, Louis Chesler
Journal: Neuro-Oncology (2020)

Abstract TP53 pathway alterations are well-described events in medulloblastoma (MB) and are predictive of poor clinical outcome. Alterations are rare at diagnosis in Group3 (Gr3) and Group4, but enriched in Sonic Hedgehog and WNT subgroups. However, TP53 mutations are observed in all subgroups at relapse. Radiation therapy, along with surgery and chemotherapy, represents the standard of care treatment for MB. Loss of p53 function correlates with increased resistance to radiation in several cancers conferring poor survival for patients. In this study, we exposed the MYCN-driven/Trp53kiki (with tamoxifen-inducible p53 activation) Gr3 MB GEMM to a clinically relevant fractionated radiation therapy (RT) regime, to assess the role of p53 in Gr3 radio-resistance and relapse. Mice exhibiting tumour progression (bioluminescence (BLI) signal &amp;gt;109 photons/second) were randomized to treatment groups. A small animal radiation research platform was used to deliver CT-guided cranio-spinal irradiation (CSI) and a cranial boost (CB). Mice were followed for survival and tumour burden tracked using BLI. Bodyweight was monitored to evaluate treatment tolerability. Full dose radiation therapy (54Gy CB, 36Gy CSI, α/β=10) or dose modulation (12Gy CB, 8Gy CSI) was performed. The results showed comparable primary tumour regression in response to RT in p53 inactive and active backgrounds, followed by imminent relapse or prolonged remission respectively. No significant acute toxicity was observed. Temporary activation of p53 during RT improved tumour-free survival and decreased the incidence of relapse. In conclusion, we developed a new model which will help improve understanding of the radiobiology of high-risk MB and future preclinical trials.
ATRT-19. EPIGENETIC REPROGRAMMING LEADS TO INNATE IMMUNE PATHWAY ACTIVATION IN AT/RT
Authors: Seethalakshmi Hariharan, Cem Kilic, Michelle Bowie, Zachary Reitman, David Ashley
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive brain tumors affecting early childhood and are characterized by bi-allelic inactivation of the SMARCB1 gene. Though patients benefit from multimodal therapy, there is no improvement in overall survival necessitating exploration of alternative approaches including innate-based immune therapy and epigenetic therapy, which have shown promise in treating adult brain tumors and other cancers. Though reconstitution of SMARCB1 in SMARCB1-deficient cells leads to activation of interferon-stimulated genes, the role of innate immune signaling has not been investigated in AT/RTs. METHODS Our data from a panel of AT/RT cell lines indicates loss of expression of key innate signaling components, like RIG-I, MDA-5, cGAS and STING that are required for sensing extracellular dsRNA and dsDNA. These cell lines also do not respond to dsDNA-based or dsRNA-based innate agonists. However, co-treatment of the BT-16 cell line with two epigenetic drugs, panobinostat and 5-azacytidine leads to re-expression of STING and RIG-I. Panobinostat/5-azacytidine co-treatment followed by either genomic DNA (dsDNA agonist) or poly(I:C) (dsRNA agonist) treatment results in induction of innate responses, measured by STAT1 phosphorylation and production of ISG-15 and IFIT-1. CONCLUSION Our data suggests that AT/RT cell lines are unresponsive to innate agonists possibly due to the loss of expression of key innate immune components. However, these pathways can be reactivated by epigenetic drugs and further potentiated by dsDNA/dsRNA-based innate agonists. Combined epigenetic reprogramming and innate pathway stimulation may serve as a potential therapy option for treating AT/RT.
ATRT-06. SMARCB1 LOSS DRIVEN NON-CANONICAL PRC1 ACTIVITY REGULATES DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS (ATRT)
Authors: Irina Alimova, Etienne Danis, Marla Weetall, Angela M Pierce, Dong Wang, Natalie Serkova, Ilango Balakrishnan, Krishna Madhavan, Bridget Sanford, Cole Michel, Nicholas K Foreman, John Baird, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2020)

Abstract Loss of SMARCB1 is the hallmark genetic event that characterizes ATRT. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. To identify co-operating epigenetic factors, we performed an unbiased shRNA screen targeting 408 epigenetic/chromatin molecules in patient-derived ATRT cell lines and identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as essential for ATRT cell viability. Genetic and Chemical inhibition of BMI1 inhibited clonogenic potential and induced apoptosis in vitro. In vivo PTC 596 significantly decreased growth of intracranial orthotopic ATRT tumors as evaluated by T2 MRI imaging and significantly prolonged survival compared to control animals. Using RNA-seq and ChIP-Seq our studies show that BMI1 co-operates with SMARCB1 loss to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. We then used a doxycycline-inducible SMARCB1 expression system and performed Immunoprecipitation for BMI1, followed by and mass spectrometry analysis. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. Re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. CBX4 is implicated DNA damage response, tumor angiogenesis and self-renewal. CBX8 activates lineage-specific genes during differentiation of ESC. Our data suggest that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex. These studies identify the mechanistic basis of BMI1 co-operation with SMARCB1 loss in ATRT and establish BMI1 inhibition as a novel therapeutic approach in ATRT.
IMMU-10. GENOMIC DIFFERENCES UNDERLIE MYELOID-DERIVED SUPPRESSOR CELL SEXUAL DIMORPHISM IN GLIOBLASTOMA
Authors: Defne Bayik, Yadi Zhou, Alice Lo, Chihyun Park, Changjin Hong, Daniel Vail, Dionysios Watson, Gustavo Roversi, Adam Lauko, Daniel Silver, Tyler Alban, Balint Otvos, Matthew Grabowski, Mia Sorensen, Peter Sims, Bjarne Kristensen, Craig Horbinski, Michael Vogelbaum, Tae Hyun Hwang, Ahmad Khalil, Antonio Iavarone, Manmeet Ahluwalia, Feixiong Cheng, Justin Lathia
Journal: Neuro-Oncology (2020)

Abstract A potently immunosuppressive tumor microenvironment facilitates progression of glioblastoma (GBM). We previously demonstrated that myeloid-derived suppressor cell (MDSC) subsets promote tumorigenesis in a sex-specific manner, contributing to sexual dimorphism in GBM incidence and prognosis. Our findings indicated that proliferating monocytic MDSCs (mMDSCs) accumulate in tumors of male mice and patients, while female tumor-bearing mice had an increase in circulating granulocytic MDSC (gMDSC) frequency, and a high gMDSC gene signature correlated with worse outcome of female patients. However, the mechanisms underlying sexual dimorphism of MDSC heterogeneity remain understudied and can provide insights for improved immunotherapy response. Using syngeneic mouse glioma models and sequencing approaches, we show that expression of Y-chromosome-linked genes correlates with upregulation of multiple RNA transcription-related pathways specifically in male mMDSCs. Consistently, adoptive transfer of male mMDSCs but not gMDSCs worsened GBM outcome in male recipients, while the transfer of sex-matched mMDSCs did not impact survival of female mice. In contrast to this cell-intrinsic regulatory pathway, sex steroids had no impact on MDSC profile, as castration or ovariectomy failed to alter MDSC subset accumulation patterns in GBM-bearing mice. Correspondingly, IL-1β, which we had identified as a female-specific drug target, was highly expressed in female but not male gMDSCs. Single-cell sequencing revealed that circulating but not tumor-infiltrating gMDSCs were the primary source of IL-1β and that its neutralization provided a female-specific survival advantage by reducing circulating gMDSCs. This was accompanied by declines in tumor infiltration of microglia, microglia activation status and tumor cell proliferation. In vitro, IL-1β inhibition reduced viability and expression of activation markers by primary microglia. These findings highlight a peripheral gMDSC-microglia communication axis mediated by IL-1β signaling in females with GBM and indicate that expression differences in MDSC subsets represent opportunities for improved immunotherapy efficacy while accounting for sex as a biological variable.
RARE-21. CANCER SPECTRUM IN GERMLINE SUFU MUTATION CARRIERS: A COLLABORATIVE PROJECT OF THE SIOPE HOST GENOME WORKING GROUP
Authors: Léa Guerrini-Rousseau, Sebastian Waszak, Franck Bourdeaut, Olivier Delattre, Nicola Dikow, Christelle Dufour, Amar Gajjar, Jacques Grill, Steffen Hirsch, Saskia Hopman, David Jones, Majoline Jongmans, Andrey Korshunov, Christian Kratz, Lucie Lafay-Cousin, Julien Masliah, Till Milde, Paul Northcott, Kristian Pajtler, Stefan Pfister, Stéphanie Puget, Marie Agnès Rame Collonge, Giles Robinson, Eric Sariban, Nicolas Sevenet, Miriam Smith, Dominik Sturm, Hélène Zattara, Pascale Varlet, Gareth Evans, Laurence Brugières
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Little is known about cancer risk associated with pathogenic germline SUFU variants. METHODS Data of all previously published and 25 still unpublished patients with a pathogenic germline SUFU mutation were compiled. RESULTS 124 patients in 67 families were identified, most of them ascertained after the occurrence of a medulloblastoma (MB) or as part of Gorlin syndrome cohorts. Overall, 30 patients were healthy carriers and 94 patients developed a total of 129 tumors (up to 4 tumors/patient): 68 MBs, always as first tumor (median age at diagnosis: 1.5yr [0.1–5]), 22 patients with at least 1 basal cell carcinoma (BCC) (median 10/patient) (median age at first BCC: 43yr, [17–52]), 15 meningiomas (median age 43yr, [13–72]), 7 ovarian stromal/fibrous tumors (median age 12yr [5–34]), and 17 other tumors including 5 sarcomas (median age: 50yr [7–79]). Median age at last follow-up was 30yr. Nineteen patients died, including 11 from MB. Second malignancies were diagnosed in 21 patients including 13 in MB survivors. Mutations were inherited in 58/66 (88%) of cases in which inheritance could be tested and de novo in 8. In 6/67 families (9%), &amp;gt;2 children were diagnosed with a MB. CONCLUSION In this large cohort of germline SUFU mutation carriers, MB in infants is the most frequent tumor but the spectrum also includes typical Gorlin syndrome tumors (BCC, meningiomas, and ovarian stromal/fibrous tumors) either as first tumors or as second malignancies. This broad tumor spectrum and the high risk of second malignancies justify the implementation of specific cancer surveillance programs.
EPEN-11. ONGOING RESPONSE IN A MULTIPLY RELAPSED METASTATIC POSTERIOR FOSSA EPENDYMOMA A AFTER VORINOSTAT AND CONCOMITANT IRRADIATION
Authors: Hamza S Gorsi, Stephanie Toll, Maxim Yankelevich
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Among the nine molecular subgroups of ependymoma identified, posterior fossa ependymoma A (PF-EPN-A) confers the worst prognosis. These tumors often relapse despite aggressive resection and irradiation, resulting in limited therapeutic options. Although the genomic profile of PF-EPN-A does not typically show any recurrent alterations; they demonstrate distinct epigenetic changes which can be targeted with modulators such as histone deacetylase (HDAC) inhibitors. These inhibitors have shown efficacy in pre-clinical studies in both their anticancer and radio-sensitizing properties. CASE: We describe a male diagnosed with a posterior fossa ependymoma at 3 years of age. After initial therapy with resection and focal irradiation, he went on to have a number of recurrences requiring multimodal therapy. Most recently, he developed diffuse intraventricular and leptomeningeal disease not amenable to surgical intervention. Genetic evaluation demonstrated a BCOR mutation and methylation profile was consistent with PF-EPN-A. He received 23.4 Gray craniospinal irradiation with a 30.6 Gray boost to the nodular lesions. Vorinostat was given concomitantly for radio-sensitization in 2 week intervals for a total of 6 weeks. Serial imaging after irradiation revealed decreased tumor burden with almost complete resolution of disease at 15 months. Unfortunately, MRI at 18 months exhibited mild interval growth of 2 lesions. CONCLUSIONS To our knowledge, this is the first report of a clinical response in a pediatric patient with PF-EPN-A following irradiation administered concomitantly with vorinostat therapy. This response highlights the importance of further studies evaluating this combination therapy and its potential use in this population.
CTNI-54. LONG-TERM USE OF EVEROLIMUS PLUS OCTREOTIDE FOR RECURRENT INTRACRANIAL OR SPINAL MENINGIOMA: A SINGLE INSTITUTION EXPERIENCE
Authors: Michael Youssef, Lily Pham, Mehmet Demirhan, Rebecca Harrison, Monica Loghin, Jennifer Johnson, Kristin Alfaro-Munoz, Krishna Bhat, Debra Yeboa, Sujit Prabhu, Shaan Raza, John de Groot, Franco Demonte, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Selection of systemic therapy for recurrent meningiomas with progression after resection and/or radiation therapy represents a challenge. The combination of everolimus, an mTOR inhibitor, plus octreotide long-acting repeatable (LAR), a somatostatin agonist, suggests synergistic activity in preclinical studies. Its long-term clinical impact in recurrent meningiomas warrants further study. METHODS We reviewed the records of adult patients with recurrent intracranial or spinal meningioma (WHO grade I, II, or III), not candidates for further surgery or radiation therapy, who were treated with everolimus and octreotide, between 1/1/2015 and 06/1/2020 at MD Anderson Cancer Center. Patients received everolimus (10 mg PO daily) each 28-day cycle and octreotide 30 mg SC once monthly. Molecular features were determined by next generation sequencing (T-200–1, Oncomine). RESULTS A total of 18 patients were identified, including WHO grade I tumors (n=4), grade II (n=10), and grade III (n=4); furthermore, 8 patients harbored NF2 mutation, followed by mutations in CREBBP (n=2), NOTCH2 (n=1), MHL1 (n=1), PTEN (n=1), SETD2 (n=1), and TP53 genes (n=1). One patient had spinal meningioma. The 6- and 12-month PFS were 77.8% and 61.1%, 6- and 12-month OS were 94.4% and 83.3% respectively. Seven (38.9%) patients had tolerated treatment for more than 12 cycles, 3 (16.7%) remain on treatment for more than 24 cycles and 1 patient is still on treatment for 31 cycles. Only 1 patient required dose reduction to 7.5 mg daily due to pneumonitis, otherwise there is an acceptable toxicity profile. Four patients had resolution of trigeminal neuralgia. CONCLUSIONS In our patient population, combination treatment with everolimus and octreotide seems to have antitumor activity and proved to be safe without major side effects from long-term exposure. It also contributed to control of neuralgia. Further tissue analysis of the role of mTOR pathway and SSTR2A expression is ongoing.
Distal Embolization After Percutaneous Coronary Interventions: Prediction, Prevention, and Relevance⁎⁎Editorials published in the Journal of American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Prediman K. Shah
Journal: Journal of the American College of Cardiology (2007)
CTNI-56. A PHASE II CLINICAL TRIAL USING ACCELERATOR-BASED BNCT SYSTEM FOR REFRACTORY RECURRENT HIGH-GRADE MENINGIOMA
Authors: Shin-Ichi Miyatake, Masahiko Wanibuchi, Shinji Kawabata, Naonori Ko, Koji Ono
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Boron neutron capture therapy (BNCT) is tumor-selective particle radiation. Recently accelerator-based neutron sources (ABNS) have been developed for clinical trials to obtain on-label use, i.e. new drug approval for malignant gliomas. Recently Japanese regulatory authority has just given this permission for H&amp;N cancers. Recurrent high-grade meningiomas (HGM) are difficult to control. We have applied reactor-based BNCT for 46 cases of refractory HGM. All cases showed good tumor shrinkage with good local control. PURPOSES Based on these situations, we proposed “A phase II clinical trial using accelerator-based BNCT system for refractory recurrent HGM” for AMED in Japan which is similar to NIH in USA. This proposal was successfully accepted. DESIGN We prepared 2 study groups, BNCT test treatment group and control best supportive care group, for RCT. PFS and OS were set-up as primary and secondary endpoints, respectively. Rescue BNCT is allowed for control group patients, if they showed PD during observation. Modified Macdonald criteria is adopted for assessment. Hypothesized PFS of treatment group and control group was 5 months and 24 months, respectively. The trial started in August 2019. METHODS Twelve BNCT and 6 control subjects will be included. Patients’ eligibility criteria is recurrent HGM after some radiotherapy. Cyclotron-based ABNS system is used for neutron source. Neutron-irradiation time is determined not to exceed to 7.5 Gy-Eq for scalp dose which was referencing preceding phase I trial for malignant gliomas. PROGRESS As of April 2020, 4 subjects were included, 3 for BNCT treatment group, 1 for control best supportive care group. The control subject showed PD during one month observation and rescue treatment showed PR. Treatment group 3 cases showed more than SD. CONCLUSION We started this RCT and will introduce the interim report of this clinical trial in the meeting.