bluuebunny/crossref_metadata_2025_split huggingface dataset:
RTHP-12. NATIONWIDE DISTRIBUTION OF LINEAR ACCELERATOR VERSUS GAMMA KNIFE STEREOTACTIC RADIOSURGERY UTILIZATION FOR METASTATIC BRAIN DISEASE IN ACADEMIC VERSUS COMMUNITY HOSPITALS
Authors: McClelland III Shearwood , Degnin Catherine , Chen Yiyi , Watson Gordon , Jaboin Jerry 
Published: November 2019

Abstract

INTRODUCTION
Single-fraction stereotactic radiosurgery (SRS) is often the preferred treatment modality for metastatic brain disease, particularly when patients have a small enough volume of disease to preclude whole brain radiation therapy and its associated permanent cognitive morbidity. The two predominant SRS treatment modalities are Gamma Knife and linear accelerator (LINAC). The recent impact of SRS modality in academic versus community hospital settings in the United States (US) since the 2013 implementation of the American Tax Payer Relief Act (ATRA) has yet to be examined.

METHODS
Brain metastases patients from non-small cell lung cancer (NSCLC) throughout the United States having undergone SRS were identified using the 2010–2016 National Cancer Data Base (NCDB). SRS utilization in academic versus community (non-academic) hospitals was identified and assessed.

RESULTS
Of the 4,012 SRS patients examined, the majority (64%) were treated at academic hospitals. Beginning in 2014, LINAC SRS rapidly increased in popularity compared to GKRS, reversing an annual decline in utilization originating from 2011. The 63% LINAC composition of SRS cases at non-academic centers in 2016 was an all-time high, a 12% increase from a year earlier. This was markedly different than SRS utilization at academic hospitals, where despite a steady increase in LINAC SRS since 2013, GKRS remained the predominant SRS modality, comprising 73% of cases in 2016.

CONCLUSIONS
The implementation of LINAC over Gamma Knife SRS in the non-academic hospital setting has markedly increased in the timespan since ATRA implementation, comprising more than 60% of SRS cases compared to only 27% of academic hospital SRS cases in 2016. These findings indicate that without the substantially increased Medicare reimbursement advantage formerly associated with Gamma Knife compared to LINAC prior to ATRA, the non-academic setting may be more sensitive than academic centers to conditions optimizing reimbursement.
RTHP-13. EFFICACY OF FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR ORBITAL CAVERNOUS HEMANGIOMA: 10-YEAR EXPERIENCE AT A SINGLE INSTITUTION
Authors: Hwan Kim Kyung , Kim Seon-Hwan , Lee Jung-Il , Kong Doo-Sik , Jun Seol Ho , Nam Do-Hyun 
Published: November 2019

Abstract

This study aimed to evaluate the efficacy and safety of fractionated gamma knife radiosurgery (GKS) for the treatment of orbital cavernous hemangioma (OCH).

METHODS
From January 2007 to June 2018, 34 patients who underwent fractionated GKS (median 20 Gy in 4 fractions) for OCH at a single tertiary institution were reviewed. Ophthalmic evaluations including exophthalmometry, best corrected visual acuity with the Snellen chart and Humphrey visual field were investigated. Changes in lesion volume were also analyzed.

RESULTS
The median age was 43 years (range, 10–67 years) and 18 patients were male (53%). The median clinical follow-up time was 42 months (range, 12–132 months). The most common presenting symptom was proptosis followed by visual impairment. Proptosis improved in all 27 patients. The mean value of proptosis was reduced from 2.9 mm to 1.1 mm (P < 0.001). Of 15 patients who showed decreased visual acuity preoperatively, 12 patients (80%) had improved in vision. Preoperative visual field defects were evident in 17 patients and resolved in 15 patients (88%) after treatment. The median tumor volume at the time of GKS was 2.2 cm3 (range, 0.2–8.5 cm3). Tumor shrinkage was observed in all patients and the mean volume reduction rate was 64%. No patient experienced GKS-related ocular morbidity, though two transient GKS-related adverse events (6%) were observed.

CONCLUSION
Fractionated GKS is an effective and safe option for the treatment of OCH, with significant reduction in tumor volume and improvement of ophthalmic outcomes.
RTHP-18. PROSPECTIVE PHASE II RANDOMIZED TRIAL COMPARING PROTON THERAPY VS. PHOTON IMRT FOR NEWLY DIAGNOSED GBM: SECONDARY ANALYSIS COMPARISON OF GENDER AND NEUTROPHIL-LYMPHOCYTE RATIO (NLR) IN GBM OUTCOMES
Authors: Randall James , Al Feghali Karine , Wefel Jeffrey , Grosshans David , Dibaj Seyedeh , Milton Denai , McAvoy Sarah , Li Jing , McGovern Susan , McAleer Mary , Ghia Amol , Paulino Arnold , Sulman Erik , Penas-Prado Marta , Wang Jihong , DeGroot John , Heimberger Amy , Armstrong Terri , Gilbert Mark , Mahajan Anita , Brown Paul , Chung Caroline 
Published: November 2019

Abstract

BACKGROUND
While glioblastoma (GBM) is more prevalent in males, studies show that females with GBM tend to have longer overall survival (OS) than males. Pretreatment neutrophil to lymphocyte ratio (NLR) has also proven to be prognostic in GBM, with lower NLR having favorable outcomes. This secondary analysis of a prospective randomized trial of proton vs. photon intensity modulated radiotherapy aims to explore the interaction of gender and NLR on GBM outcomes.

METHODS
Analysis was performed on the full patient population. Kaplan-Meier methods estimated OS with censoring at last follow-up for those who were alive. Univariate (UVA) and multivariate (MVA)Cox proportional hazards models assessed predictors of OS.

RESULTS
Of 90 patients, 77 were included (43 males; 34 females) with median age of 52 years (range: 26–82 years). Median OS was longer for females than males (30.7 vs 18.2 months, p=0.004). On UVA, patients with NLR below median value (NLR= 3.1) tended to have longer OS than those above median, though not meeting statistical significance (23.1 vs. 17.9 months, p=0.051). Difference in OS was statistically significant in females (OS 36.4 months NLR >median vs. 16.7 months NLR< median, p=0.002), but not in males (OS 17.8 months NLR >median vs. 19.1 NLR< median, p=0.95). MVA analysis was consistent, with female gender predicting reduced hazard ratio (HR) (0.28, p=0.034) and females with below median NLR showing a reduced HR over those with above median (0.28, p=0.005). Again, males did not benefit (HR 0.90, p=0.77).

CONCLUSION
Consistent with prior publications, females and all patients with lower pre-treatment NLR with newly diagnosed GBM had longer OS. However, combining these two factors revealed that the benefits from lower pre-treatment NLR were conferred only in females with no impact on males. This different impact of NLR between genders may suggest innate immune differences in gender during response to malignancy.
RTHP-33. A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS ON SURVIVAL BASED ON TREATMENT PARADIGMS FOR PATIENTS WITH ANAPLASTIC OLIGODENDROGLIOMA
Authors: Young Jacob , Zhang Yalan , Molinaro Annette , Taylor Jennie , Clarke Jennifer , Prados Michael , Chang Susan , Berger Mitchel , Butowski Nicholas , Ann Oberheim-Bush Nancy 
Published: November 2019

Abstract
Anaplastic oligodendrogliomas are a type of high grade glioma defined molecularly by the 1p19q co-deletion. Currently, there is no curative therapy, and some studies have estimated median survival is estimated to be approximately 5 years. Current standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone following surgical resection has not been shown in a randomized control trial. Given the long-term cognitive consequences of radiation therapy and the high percentage of patients who lives beyond 15 years with AO, there is an effort to balance longevity with radiation toxicity. As such we performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996–2016. Of those, 57 patients were found to have anaplastic olidodendroglioma at original diagnosis and had long term follow-up. Sixty-six percent of patients were between the ages of 30–50 and mean KPS was 87.3. At the time of analysis, 33% of patients had died. In this cohort, 60% of patients were initially treated with radiation and chemotherapy (either temozolomide or CCNU) at diagnosis and 40% were treated with chemotherapy alone. Median overall survival for the entire cohort was 142 months. The related risk of progression in the upfront chemotherapy only group is approximately 5.87 times higher than the patients who received radiation and chemotherapy (Hazard ratio=5.87, 1.92–17.90, p=0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p=0.14). On univariate analysis, there was no association between age, KPS, EOR, or upfront vs. delayed radiation and survival. As such initial treatment with chemotherapy alone may be an option for some patients with anaplastic oligodendroglioma.
RARE-33. LEPTOMENINGEAL DISEASE IN PATIENTS WITH MIDLINE GLIOMAS HARBORING HISTONE H3 K27M MUTATIONS
Authors: Eduardo Silva Correia Carlos , Pentsova Elena , Lin Andrew , Miller Alexandra 
Published: November 2019

Abstract

INTRODUCTION
The 2016 WHO classification describes a specific subtype of midline gliomas harboring histone 3 (H3) K27M mutations which compromise 15–40% of gliomas in children and young adults. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the true incidence and the clinical behavior of this group has not been well-defined.

METHODS
This is a retrospective study of patients with H3K27M/I diffuse midline gliomas at MSKCC from 01/2012 to 01/2019. Mutations were identified through next-generation sequencing (NGS).

RESULTS
We identified 24 patients. Median age was 21 (6–70) and 13 were male. Thirteen tumors were in the thalamus, 6 in the brainstem, 4 in the spinal cord, and 1 in the pineal region. H3K27M mutations were detected by NGS from tumor tissue in 21 patients, from cerebral spinal fluid (CSF) circulating tumor DNA (ctDNA) in 2 and from tissue and CSF ctDNA in one. LMD was diagnosed in 17/24 (71%) patients radiographically. Of these, 8 underwent LP: CSF cytology was positive in 2/8 and CSF ctDNA was detected in 3/3. All patients received RT and one or more lines of chemotherapy. At analysis, thirteen patients remain alive. Median time to last follow up for all patients was 14.2 months. Median time from diagnosis to LMD was 13.2 months (0–45.1), with median OS of 6.5 months (0.3–27) after diagnosis of LMD.

CONCLUSION
Our study showed that more than two-thirds of the patients with H3 K27M diffuse midline developed LMD. Neuroaxis imaging should be performed in conjunction with CSF studies to diagnose LMD. Besides, CSF ctDNA represents an important tool to identify molecular profile of tumors when biopsy is not feasible or limited for the analysis.
RARE-35. MRI FINDINGS AT PROGRESSION IN ADULT PATIENTS WITH MEDULLOBLASTOMA
Authors: Cordova Christine , Vera Elizabeth , Aboud Orwa , Antony Ramya , Boris Lisa , Bryla Christine , Burton Eric , Crandon Sonja , Leggiero Nicole , Reyes Jennifer , Siegel Christine , Theeler Brett , Vyas Yamini , Wall Kathleen , Wu Jing , Gilbert Mark , Armstrong Terri , Penas-Prado Marta 
Published: November 2019

Abstract

Progression (PD) in medulloblastoma (MB) represents a diagnostic challenge due to imaging heterogeneity among/within patients. SHH (Sonic hedgehog)-MB is thought to recur mostly within the tumor bed (TB). In children, DWI restriction (DWIr) is more sensitive than contrast enhancement(CE) for first PD. Whether this is applicable to adults is unknown.

METHODS
Retrospective review of adults (age ≥18) with MB enrolled to Natural History study at NCI-NOB. Descriptive statistics of imaging at diagnosis and PD(CE, T2/FLAIR signal without CE, DWIr) and imaging patterns for each PD. RESULTS:14 adults with MB: 5 diagnosed in childhood (8–16 yrs), 9 as adults (18–45 yrs); Subtypes: 7 SHH, 3 non-WNT/non-SHH, 4 unknown. Eleven experienced ≥1 PD (6/7 SHH, 2/3 non-WNT/non-SHH, 3/4 unknown); median PD of 5 (range 1–9). Median age at first PD 31 years (range 10–46) with 5 first PDs >5 years after diagnosis. In 10 patients with available baseline MRI, 9 had CE, and 8 DWIr (2 without DWI sequences). Of 48 total PDs, the commonest patterns were: brain LMD alone (n=14), TB alone or distant brain parenchyma alone (each n=7), distant brain parenchyma with brain LMD (n=6), and TB with either distant brain parenchyma or LMD (n=3). Of the 82 PD lesions, 23% (n=14) of brain lesions lacked DWIr, and 37% (n=23) had T2/FLAIR signal without CE. PD tissue confirmation obtained at 18 time points:16 cases with confirmed recurrence had heterogeneous characteristics; in 12 with brain PD: CE in 5, T2/FLAIR without CE in 3 (unknown: 4). 2 CE lesions revealed meningioma (one- atypical meningioma- had DWIr).

CONCLUSIONS
Imaging findings in adult patients with MB are highly heterogeneous. Despite high specificity of DWIr for PD in children, it failed for 23% of brain lesions across multiple patients. Most SHH-MB had PD outside the TB, unlike what is widely accepted in the literature.
RARE-45. ACTIVITY OF LAROTRECTINIB IN TRK FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
Authors: Doz Francois , Geoerger Birgit , DuBois Steven G , Grilley-Olson Juneko E , van Tilburg Cornelis M , Italiano Antoine , Lissat Andrej , Jin Kang Hyoung , Tahara Makoto , Boni Valentina , Perreault Sebastien , Capra Michael , Nanda Shivani , Brega Nicoletta , Holynskyj Ariadna , Ziegler David S , Hong David S , Hyman David M , Drilon Alexander 
Published: November 2019

Abstract

BACKGROUND
TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion cancers (Drilon et al., NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors.

METHODS
Patients with primary CNS tumors harboring a TRK fusion treated with larotrectinib on two clinical trials (NCT02637687 and NCT02576431) were identified by local molecular testing. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019.

RESULTS
18 patients with various histological types of glial tumors (11 high-grade, 4 low-grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n=13), NTRK1 (n=2) and NTRK3 (n=2); one was not determined. Median age was 10 years (range 1–79); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR, 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. One patient (3.7 years old) with glioblastoma progressed after 5.5 months on larotrectinib. Sequencing revealed a solvent front mutation and the patient was subsequently enrolled in compassionate use protocol for BAY2731954 (formerly known as LOXO-195).

CONCLUSION
Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Confirmed responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors.
RARE-55. RIT1 MUTATION ASSOCIATED WITH SPINAL NEUROFIBROMATOSIS
Authors: Anderson Mark , Shaikh Nawal , Long Eugene , Maher Joseph 
Published: November 2019

Abstract
Neurofibromatosis type 1 is defined clinically and molecularly by the presence of a mutation in neurofibromin, resulting in typical cutaneous, peripheral nerve and nerve root neurofibromas through the changes in regulation of the RAS pathway. A 33-year-old right-handed African-American female presented with a complaint of back pain, radiating down the legs and arms worsening over several years. On physical exam, the patient had no cutaneous neurofibromas, café-au-lait spots, or axillary freckling. MRI spine revealed diffuse symmetric fusiform nerve sheath tumors throughout the cervical, thoracic, and lumbar spine favored to represent neurofibromatosis. Genetics evaluation with pedigree revealed no family history of genetic disorders. Genetic testing was positive solely for a c.293A >G transition in exon 5 of the RIT1 gene, previously reported as a cause of the RASopathy Noonan syndrome, type-8. RASopathies are conditions caused by mutations in the proteins of the RAS-MAPK pathway. Noonan Syndrome can present with some combination of abnormalities of the ears, webbing of the neck, developmental delay, and cardiac abnormalities. This patient was without external phenotypic characteristics of Noonan Syndrome, yet was found to have a mutation in this pathway. RIT1 mutation has been previously described rarely with glioma development. Alternate mutations in the RAS-MAPK pathway should be considered in the differential for patients with spinal neurofibromatosis when typical neurofibromatosis mutations are absent.
STEM-08. GENE THERAPY USING IL-24-EXPRESSING UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS AGAINST GLIOMA
Authors: Fan Shaochen , Gao Yilu 
Published: November 2019

Abstract
Despite many advances have been made in treatment of gliomas, patients prognosis remains poor. Stem cell-based therapy has been thought to be a promising option for gliomas and many studies have reported that umbilical cord-derived mesenchymal stem cells (UC-MSCs) are ideal gene vectors for tumor gene therapy. Interleukin 24 (IL-24) is a pleiotropic immunoregulatory cytokine which has an apoptotic effect on many kinds of tumor cells and can inhibit the growth of tumors specifically without damaging normal cells. However, there are still some challenges in its clinical application, such as the half-life, toxicity caused by high-dose application, and so on. Therefore, we hypothesize that combination of gene transfer with stem cell transplantation could overcome the problems. In this study, we investigated UC-MSCs transduced with lentiviral vectors carrying IL-24 complementary DNA as a vehicle for the targeted delivery of IL-24 to local tumor sites. The engineered UC-MSCs selectively migrated to glioma cells and showed the antitumor effect in vitro and in vivo. The restrictive efficacy of these UC-MSCs was related to the inhibition of proliferation and induction of apoptosis in tumor cells. These findings indicate that UC-MSCs-based IL-24 gene therapy can obviously suppress the growth of glioma xenografts, thereby suggesting the potential for future therapeutic interventions in the treatment of gliomas. Keywords: Glioma, Gene therapy, Umbilical cord-derived mesenchymal stem cells (UC-MSCs), Interleukin 24 (IL-24)
STEM-17. LOW GRADE ASTROCYTOMA MUTATIONS COOPERATE TO DISRUPT SOX2 GENOMIC ARCHITECTURE AND BLOCK DIFFERENTIATION VIA PREVIOUSLY UNIDENTIFIED ENHANCER ELEMENTS
Authors: Bready Devin , Modrek Aram , Guerrera Adler , Frenster Joshua , Skok Jane , Placantonakis Dimitris 
Published: November 2019

Abstract
Neomorphic mutations in isocitrate dehydrogenase I (IDH1) result in the formation of the oncometabolite 2-hydroxyglutarate (2HG) in a significant subset of gliomas and other tumors including acute myeloid leukemias. Preclinical evidence suggests that gliomas harboring IDH1 mutations undergo widespread, long-lasting modifications to the epigenome that persist following inhibition of 2HG production. However, the exact mechanism underlying gliomagenesis remains unclear. To address difficulties in growing these tumors in culture, our group generated a model of low-grade astrocytoma in human neural stem cells (NSCs). This model, referred to as 3-Hit NSCs, suggested a block in differentiation potential underlies gliomagenesis at the cellular level. This block is rescued by restoration of expression of the transcription factor (sex determining region Y)-box 2 (SOX2), which is transcriptionally downregulated during IDH mutant gliomagenesis. We believe that these changes occur secondary to profound alterations in 3-dimensional chromatin organization around the SOX2 genomic locus. Our preliminary data suggest SOX2 expression in control NSCs depends on 3-dimensional association of its promoter to an uncharacterized, distal enhancer located 600 kb telomeric to the SOX2 gene. We believe this association is disrupted in 3-Hit NSCs due to eviction of chromatin organizer CTCF from its motifs in the SOX2 topologically associating domain (TAD). To test this hypothesis, we used CRISPR-Cas9 technology to excise CTCF motifs immediately upstream of the SOX2 promoter and in the region of the putative enhancer in control NSCs. Excision of such motifs significantly reduced SOX2 mRNA levels and impaired growth of control NSCs. We are currently working on characterizing this novel SOX2-enhancer interaction in native stem cells, as well as tumors that depend on SOX2 expression. This works aims to elucidate the core epigenetic mechanisms underlying IDH mutant gliomagenesis. Our findings will be used to improve therapy in IDH-mutant glioma.
STEM-21. INVESTIGATING DOT1L AS AN EPIGENETIC VULNERABILITY IN BRAIN TUMOR STEM CELLS
Authors: Bozek Danielle , MacLeod Graham , Hao Xiaoguang , Rajakulendran Nishani , Ahmadi Moloud , Dirks Peter , Angers Stephane , Luchman Artee , Weiss Sam 
Published: November 2019

Abstract
Glioblastoma (GBM), the most common and aggressive primary adult brain cancer, is thought to be driven by a small subpopulation of brain tumor stem cells (BTSCs). BTSCs exhibit shared properties with normal stem cells such as self-renewal and multilineage differentiation. These stem cell properties have been proposed to underlie GBM tumorigenicity, treatment evasion and contribute to tumor heterogeneity. To investigate the biology underlying the stem cell properties of GBM, we compared gene essentiality profiles for a panel of BTSCs, fetal neural stem cells and non-GBM cell lines using a CRISPR Cas9 knockout library. Interestingly, from these screens, we identified the histone methyltransferase disrupter of telomeric silencing-1-like (DOT1L) as an essential gene for the growth of BTSCs and fetal neural stem cells but not for non-GBM cell lines. DOT1L is the only known histone methyltransferase responsible for histone 3 lysine 79 methylation, an epigenetic mark associated with active gene transcription. The role of this epigenetic regulator in BTSCs was investigated in depth using EPZ-5676, a clinically relevant small molecule inhibitor. Short-term treatment with EPZ-5676 in BTSCs showed minimal effects on cell viability but led to striking morphological changes, increased neuronal and astrocytic differentiation and a reduction in self-renewal. Longer treatment periods with EPZ-5676 led to a decrease in BTSC proliferation and an increase in apoptosis. Furthermore, BTSCs pretreated with EPZ-5676 led to slowed orthotopic tumor growth and improved overall survival in a SCID mouse model. Overall, these findings suggest DOT1L epigenetically regulates GBM stem cell properties and tumor growth. We are further investigating the mechanisms underlying DOT1L regulation of gene expression in BTSCs with the goal of improving the field’s understanding of epigenetics and the therapeutic implications of targeting epigenetic processes in GBM.