tbuckley/cabot-search huggingface dataset:
PATH-13. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW-GRADE GLIOMAS
Authors: Margot Lazow, Austin Schafer, Lindsey Hoffman, Diana Osorio, Daniel Boué, Sarah Rush, Erin Wright, Adam Lane, Mariko DeWire, Teresa Smolarek, Jared Sipple, Heather Taggert, Jaime Reuss, Ralph Salloum, Trent Hummel, Peter de Blank, Natasha Pillay-Smiley, Mary Sutton, Anthony Asher, Charles Stevenson, Rachid Drissi, Jonathan Finlay, Maryam Fouladi, Christine Fuller
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, exome analyses, and/or targeted sequencing were performed on paired tumor samples from diagnostic and subsequent surgeries. RESULTS Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status occurred in 10 patients (40%), with acquisition of CDKN2A deletion in seven (including three who received chemotherapy [two with temozolomide] and one who received radiation) and loss in three (including one who received targeted therapy and radiation). A trend toward shorter time to progression was observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration (median: 5.5 versus 14.0 months [p=0.078]). CONCLUSIONS Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
LINC-16. MEDULLOBLASTOMA IN A BOY WITH RUBINSTEIN-TAYBI SYNDROME: A CASE REPORT
Authors: Regina M Navarro-Martin del Campo, Juan Luis Soto-Mancilla, Luis A Arredondo-Navarro, Ana L Orozco-Alvarado, Fernando A Sanchez-Zubieta
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Rubinstein–Taybi syndrome (RTS) is characterized by multiple congenital anomalies and associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of benign and possibly also malignant tumors, but the correlation remains unclear. Here we present a case of a patient with RTS and medulloblastoma. CLINICAL CASE: A 5-year-old male presented with increased intracranial pressure. An MRI revealed a 4.2 x 4.7 cm mass in the midline of cerebellum arising from the floor of 4th ventricle. The patient underwent a complete resection and pathology revealed medulloblastoma, classic histology. Staging established no disseminated disease. At diagnosis, a peculiar phenotype consisting in mild mental retardation, microcephaly, down-slanting palpebral fissures, broad nasal bridge, highly arched palate, mild micrognathia, screwdriver incisors and wide thumbs and toes was noted. Clinical genetics evaluation was consistent with RTS. Karyotype was performed and normal. Further genetics testing was not done. Treatment consisted in 8 cycles of chemotherapy and craniospinal radiation (2300 cGy to spine, 5500 cGy Total). At the end of treatment, there was no evidence of disease. He was under surveillance for 33 months free of disease, but relapsed with a supratentorial meningeal disease that ultimately resulted in death. CONCLUSION This report highlights the fact that pediatric medulloblastoma can be associated to RTS, in this case associated to classical histology and recurrent disease.
MODL-30. DISSECTING THE ROLE OF MULTI-CILIOGENESIS NETWORK IN CHOROID PLEXUS TUMOR
Authors: Haotian Zhao, Tasneem Zahran
Journal: Neuro-Oncology (2020)

Abstract The choroid plexus (CP) in brain ventricles consists of a fibro-vascular core encapsulated by epithelial cells that possess clusters of primary cilia on cell surface. CP tumors are rare primary brain neoplasms that most commonly occur in young children. Compared to the benign CP papilloma, choroid plexus carcinoma (CPC) is poorly understood and highly lethal with few treatments available. Molecular, cytogenetics and genomics studies uncovered complex alterations in CPC including frequent chromosomal loss and recurrent focal aberrations, whereas abnormal NOTCH signaling is observed in many CP tumors. We showed that activation of both NOTCH and Sonic Hedgehog (SHH) signaling in mice drives the formation of aggressive CP tumor. Molecular and histology analyses demonstrated that these murine CP tumors closely resemble their human counterparts, which also display aberrant SHH and NOTCH signaling, suggesting they may represent potential therapeutic avenues. Indeed, treatment with vismodegib, an FDA-approved SHH pathway inhibitor, suppresses CP tumor growth. Unlike multi-ciliated CP epithelial cells, tumor cells in these animal models are characterized by a solitary primary cilium. Though key genes of the multi-ciliogenesis circuit driven by Geminin coiled-coil domain-containing protein 1 (GEMC1) are expressed in CP epithelium, GEMC1-dependent transcriptional program is suppressed in NOTCH-driven CP tumors. Importantly, CPCs in humans consist of tumor cells with a solitary primary cilium and exhibit profound defects multi-ciliogenesis program. Together, these results indicate that a solitary primary cilium is crucial for CPC development, whereas multi-ciliogenesis circuit possesses tumor suppressive functions and may represent a novel therapeutic target in CPC.
LGG-24. CARBOPLATIN-INDUCED HEMATURIA IN A PEDIATRIC PATIENT WITH LOW-GRADE GLIOMA AND REVIEW OF LITERATURE
Authors: Alex Hoover, Mariko Sato
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE In this case report, we present a pediatric patient with gross hematuria and hydroureteronephrosis associated with high dose carboplatin. Given the paucity of literature on the subject, we also conduct and present a review of cases. CASE PRESENTATION: A 6-year-old Caucasian female with history of Type 1 neurofibromatosis was undergoing treatment for a low-grade glioma with monthly high dose carboplatin (560 mg/m2). After 8th dose out of 13, the patient developed severe nausea and vomiting and was admitted for dehydration. She was noted to have microscopic hematuria. After 9th dose, the patient again developed severe nausea, vomiting and gross hematuria with clots. She was admitted and treated with IV hydration. Renal ultrasound showed newly developed bilateral hydroureteronephrosis. Coagulation studies were normal. Multiple cultures and viral studies were negative. Hematuria cleared spontaneously after 4 days of aggressive hydration. RESULTS Subsequent carboplatin was given with aggressive hydration and minimized nausea/vomiting and no hematuria was observed. Literature review revealed only 4 reported cases of carboplatin-induced hematuria, including only one pediatric case that occurred in a patient with concurrent thrombocytopenia. Carboplatin may exhibit toxicity to the transitional epithelial cells of the urogenital tract causing hemorrhage from the renal pelvis and ureters. If untreated, this may lead to urinary outflow obstruction and subsequent obstructive nephropathy. CONCLUSION We present a rare toxicity, gross hematuria caused by high-dose carboplatin treatment. Providers should be aware of this rare toxicity and provide timely hydration and supportive care to prevent development of obstructive kidney injury and/or renal failure.
EPEN-20. EZHIP/CATACOMB COOPERATES WITH PDGF-A AND p53 LOSS TO GENERATE A GENETICALLY ENGINEERED MOUSE MODEL FOR POSTERIOR FOSSA A EPENDYMOMA
Authors: Emily Kagan, Daniel Brat, Ali Shilatifard, Andrea Piunti, Oren Becher
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND PFA ependymoma is a pediatric brain tumor with only 30% long-term survival. Recently a gene called CXORF67/EZHIP/CATACOMB (henceforward: CATACOMB) was found to be overexpressed in PFA ependymoma. CATACOMB’s mechanism of action has been found to be analogous to that of the H3K27M mutation as its expression reduces H3K27me3 via inhibition of PRC2 catalytic activity. METHODS We infected NESTIN- or GFAP-expressing neonatal hindbrain progenitors with wild-type CATACOMB or a loss of function (LOF) point mutant (M406K), alone, with PDGFA, and with and without p53 deletion. RESULTS CATACOMB overexpression alone or with p53 loss was insufficient to induce tumorigenesis. CATACOMB overexpression with PDGFA and p53 loss was sufficient to induce tumorigenesis using either the LOF mutant (M406K) or the wild-type CATACOMB in both cells-of-origin. The histology appeared more ependymoma-like when CATACOMB was expressed in GFAP-expressing progenitors. Median survival for the model initiated in NESTIN progenitors was 99.5 days for the CATACOMB mutant (n=26) group and 61 days for the CATACOMB wild-type (n=28; log-rank test p=0.0033). Median survival for the model initiated in GFAP progenitors were 144 days for the CATACOMB mutant (n=19) group and 65 days for the CATACOMB wild-type (n=21; log-rank test is P&amp;lt;0.0013). Immunohistochemistry for H3K27me3 demonstrated that CATACOMB wild-type tumors had reduced H3K27me3 compared to CATACOMB mutant tumors. CONCLUSIONS Disrupting CATACOMB inhibitory activity toward PRC2 significantly increases survival in mice in both models, suggesting this activity plays a critical role in accelerating tumorigenesis. Ependymoma-like histology was more commonly observed in the model initiated in the GFAP-expressing progenitors.
Anti-VEGF Therapy or Vitrectomy Surgery for Vitreous Hemorrhage From Proliferative Diabetic Retinopathy
Authors: Gavin Siew-Wei Tan, Usha Chakravarthy, Tien Yin Wong
Journal: JAMA (2020)

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Erratum to ‘Silk fibroin for skin injury repair: Where do things stand?’. [Advanced Drug Delivery Reviews 153 (2020) 28-53]
Authors: Mazaher Gholipourmalekabadi, Sunaina Sapru, Ali Samadikuchaksaraei, Rui L. Reis, David L. Kaplan, Subhas C. Kundu
Journal: Advanced Drug Delivery Reviews (2020)
IMMU-45. CUSTOMIZED LIPID NANOPARTICLES DELIVER NUCLEIC ACIDS TO IMMUNE CELLS IN BRAIN TUMORS
Authors: Adam Grippin, Brandon Wummer, Hector Mendez-Gomez, Tyler Wildes, Kyle Dyson, Jon Dobson, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Brain tumors are notoriously difficult to treat in part due to their isolation behind the blood brain barrier and their power to suppress antitumor immune responses. We have previously reported cationic liposome formulations capable of delivering immune modulatory nucleic acids to immune cells in various peripheral organs, but there is currently no reliable method to deliver nucleic acids into brain tumors without direct injection into the tumor site. OBJECTIVE Here, we report the development of a customized lipid nanoparticle to deliver immune modulatory nucleic acids to immune cells in brain tumors. APPROACH Cationic liposomes composed of varying lipid combinations were evaluated for their ability to deliver functional mRNA and siRNA to innate immune cells in vitro and in intracranial tumor models. Nucleic acids were labelled with Cy3 to monitor particle distribution in vivo. RESULTS Lipids composed of DOTAP and cholesterol selectively delivered mRNA and siRNA to intracranial GL261 and KR158b tumors. Interestingly, these particles selectively delivered these nucleic acids to CD45+ white blood cells with minimal delivery to CD45- tumor cells or normal brain tissue. Encapsulation of siRNA blocking programmed death ligand 1 (PDL1) significantly reduced PDL1 expression on innate immune cells in brain tumors, with the greatest effects on tumor-associated macrophages. Co-administration of systemic checkpoint blockade with intravenous administration of these lipid nanoparticles bearing PDL1 siRNA enabled systemic and intratumoral checkpoint blockade, leading to 37% long term survivorship in an otherwise fatal intracranial tumor model. CONCLUSIONS Our customized lipid nanoparticles enable potent intratumoral immune modulation via delivery of nucleic acids to immune cells in brain tumors.
GCT-31. DIAGNOSTIC CAPABILITY OF CSF-PLAP ON INTRACRANIAL GERM CELL TUMOR
Authors: Michinari Okamoto, Shigeru Yamaguchi, Yukitomo Ishi, Hiroaki Motegi, Yukayo Terashita, Shinsuke Hirabayashi, Minako Sugiyama, Yuko Cho, Akihiro Iguchi, Atushi Manabe, Kiyohiro Houkin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Since the majority of intracranial germ cell tumor(GCT) is sensitive for chemoradiation, biopsy specimens are usually tiny and not enough for accurate pathological diagnosis. To supply complementary diagnostic information, a-fetoprotein or human chorionic gonadotropin-b are important biomarkers. Recently CSF-placental alkaline-phosphatase(PLAP) is also reported as an additional biomarker in intracranial GCT. This study’s purpose is to evaluate the significance of CSF-PLAP. METHODS CSF-PLAP was obtained from the patients with the intraventricular and periventricular tumor before any adjuvant therapy. Definitive diagnoses were made by histopathological information and/or their clinical courses; GCT(germinoma or non-germinomatous GCT(NGGCT)) or other tumors. In GCT, the relationship between CSF-PLAP and tumor reduction volume was evaluated. Tumor volumes were calculated on gadolinium-enhanced T1-weighted magnetic resonance imaging before and after initial chemoradiotherapy. RESULTS Between 2005 and 2019, 42 patients were studied: 24 with GCT and 18 with others. CSF-PLAP value in patients with GCT was significantly higher than those with others: the Specificity was 88% and the sensitivity was 95% at the cutoff value of 8.0 pg/ml. For GCT patients, CSF-PLAP value tended to be higher in germinoma(n=12, mean 4756 pg/ml), compared to the value in NGGCT(n=7, mean 332 pg/ml), although there was no statistical difference. There was a significant positive correlation between initial CSF-PLAP value and tumor reduction volume. CONCLUSION CSF-PLAP is a useful tumor marker for GCT differentiating from the other tumors located in intraventricular and periventricular region and CSF-PLAP value might correlate with the volume of germinomatous component of the tumor.
Clinical relevance of extracellular vesicles in hematological neoplasms: from liquid biopsy to cell biopsy
Authors: Stefania Trino, Daniela Lamorte, Antonella Caivano, Luciana De Luca, Alessandro Sgambato, Ilaria Laurenzana
Journal: Leukemia (2020)

Abstract In the era of precision medicine, liquid biopsy is becoming increasingly important in oncology. It consists in the isolation and analysis of tumor-derived biomarkers, including extracellular vesicles (EVs), in body fluids. EVs are lipid bilayer-enclosed particles, heterogeneous in size and molecular composition, released from both normal and neoplastic cells. In tumor context, EVs are valuable carriers of cancer information; in fact, their amount, phenotype and molecular cargo, including proteins, lipids, metabolites and nucleic acids, mirror nature and origin of parental cells rendering EVs appealing candidates as novel biomarkers. Translation of these new potential diagnostic tools into clinical practice could deeply revolutionize the cancer field mainly for solid tumors but for hematological neoplasms, too.
TAMI-13. IMPORTANCE OF CD38 INHIBITION IN PRE-RECURRENT GLIOBLASTOMA
Authors: Renee Hirte, Ian E Olson, Masum Rahman, Moustafa Mansour, Amanda Munoz Casabella, Terry C Burns
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM) is the most aggressive CNS neoplasm with a mere 15 month progression-free survival following current standards-of-care. Furthermore, conventional therapies have been effective, in part, by inducing a senescent-like phenotype in at least a proportion of glioma, as well as within the tumor-adjacent, healthy brain cells. Through an N-glyco-capture large-scale screening method, we were able to identify 25 genes exclusively overexpressed on glioma cell surfaces. Of those 25 targets, CD38 was an attractive target due to pre-existing FDA approved therapeutics. Recent studies have shown, however, that senescent cells, such as those induced via chemo- and radiotherapies, secrete a pro-inflammatory array of cytokines, known collectively as senescence associated secretory phenotype (SASP), that are capable of increasing CD38 expression in monocytes. CD38 functions as an ectoenzyme to convert extracellular NAD+ to nicotinamide (required for glioma cell salvage pathway NAD+ synthesis) and ADPR/cADPR (a cellular proliferation signal). To examine the effects of radiation on human glioma tissue, we performed reverse cyclase assays (RCA) on paired primary and recurrent human glioma tissue samples and found an increase in CD38 activity in post-irradiated tissues (recurrent glioma) compared to pre-irradiated (primary glioma). Through proliferation assays, we also found an increase in glioma cell growth following treatment with cADPR compared to untreated. Our results demonstrate that CD38 activity is tumorgenic, and furthermore that conventional chemo- and radiotherapies increase this CD38 activity. This indicates that treating CD38 with previously FDA approved therapeutics may provide hope for increasing progression free survival in our GBM patient population, and moreover emphasize the importance of leveraging novel large scale screening methods for identifying additional opportunities for treatment.
PATH-37. IDENTIFYING HIGH-RISK PATIENTS FOR WHO GRADE I MENINGIOMA RECURRENCE USING HISTOPATHOLOGICAL FEATURES AND THE MIB-1 INDEX
Authors: Alexander Haddad, Jacob Young, Ishan Kanungo, Sweta Sudhir, Jia-Shu Chen, David Raleigh, Stephen Magill, Michael McDermott, Manish Aghi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence. METHODS A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007-2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (greater than 24 months post-treatment) recurrence. RESULTS A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy or gamma knife treatment. The incidence of recurrence was 10.9%, with an average time to recurrence of 33.2 months (6-105 months). Posterior fossa tumor location (p=0.004), MIB-1 staining (p=0.008), nuclear atypia (p=0.003), and STR (p&amp;lt; 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 &amp;gt;4.5% had a similar incidence of recurrence as those with STR (18.8vs.18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR (p=0.002) and nuclear atypia (p=0.019). RPA confirmed STR as associated with early recurrence. MIB-1 index (p=0.010) was identified as an independent predictor of post-median recurrence using similar methods. CONCLUSIONS STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index &amp;gt;4.5% is prognostic for recurrence in patients with GTR.
MBCL-22. EFFICACY OF DOUBLE-CONDITIONING REGIMEN COMPRISING THIOTEPA AND MELPHALAN FOR RELAPSED MEDULLOBLASTOMA – A SINGLE INSTITUTION EXPERIENCE
Authors: Kai Yamasaki, Kazuki Tanimura, Yuki Okuhiro, Kota Hira, Chika Nitani, Keiko Okada, Hiroyuki Fujisaki, Noritsugu Kunihiro, Yasuhiro Matsusaka, Hiroaki Sakamoto, Junichi Hara
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The prognosis of relapsed medulloblastoma was dismal. Recently, we published the promising outcome of metastatic medulloblastomas treated with a double-conditioning regimen comprising high-dose thiotepa and melphalan (HD-TM). Here, we report a single-center study of HD-TM for relapsed medulloblastomas. MATERIALS AND METHODS From April 2006 to January 2019, 17 consecutive medulloblastoma patients with the first relapse were identified, and of which 10 received HD-TM were retrospectively reviewed. RESULTS The median age at first relapse was 11.9 years (range 1.8–31.7). The median follow-up period was 23.5 months after 1st relapse. Four localized relapses at the posterior fossa and 6 metastatic relapses including 3 with multiple sites were observed. Surgical resection and re-irradiation were administered in 5 and 9 patients, respectively. Two-year PFS and OS after relapse were 21±18.1% and 60±21.9%, respectively, and significantly better than in patients who did not receive HD-TM. Among 7 evaluable patients, tumor shrinkage was observed in 6 after HD-TM administration including 3 patients who were resistant to prior chemotherapy. At the present time, 5 patients are alive with no evidence of disease (NED). The last 5 patients received re-irradiation including 12 Gy craniospinal irradiation (CSI), and 4 are alive with NED. In multivariate analysis for all patients, both HD-TM and re-irradiation were associated with improved OS and PFS, but disseminated relapse had no prognostic value (p=0.56). CONCLUSION HD-TM contributes to prolonged survival when combined with re-irradiation. HD-TM might become a curative approach for relapsed medulloblastoma, especially when combined with CSI.