tbuckley/cabot-search huggingface dataset:
CTNI-05. NRG ONCOLOGY / RTOG 1119: PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY / STEREOTACTIC RADIOSURGERY WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASES FROM HER2-POSITIVE BREAST CANCER
Authors: In Ah Kim, Kathryn Winter, Paul Sperduto, Jennifer De Los Santos, David Peereboom, Tomi Ogunleye, Daniel Boulter, Kwan Ho Cho, Kyung Hwan Shin, Imran Zoberi, Serah Choi, Joshua Palmer, Ben Liem, Yong Bae Kim, Bethany Anderson, Anupama Thakrar, Thierry Muanza, Michelle Kim, Doo Ho Choi, Julia White, Minesh Mehta
Journal: Neuro-Oncology (2020)

Abstract Trastuzumab/pertuzumab improved outcomes for patients (pts) with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of these agents apparently contributes to increased incidence of brain metastases (BM). Lapatinib (L) crosses the BBB and demonstrates activity against BM. Based upon pre/early clinical data, it’s hypothesized that L + whole brain radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS) would improve intracranial control compared to WBRT/SRS (RT) alone. This randomized phase II trial included HER2+ breast cancer pts with ≥ 1 measurable, unirradiated parenchymal BM. Pts were randomized 1:1 to WBRT (37.5 Gy/3 weeks) or SRS +/- concurrent L (1000 mg dailyx6 weeks), andwere stratified by graded prognostic assessment (GPA), use of non-CNS penetrating anti-HER2 therapies, and previous SRS/resection. The primary endpoint was intracranial complete response (CR) rate 12weeks (wk) after RT. Secondary endpoints included objective response rate (ORR), lesion-specific response rate, CNS progression-free survival, and overall survival. 114 of 143 pts were evaluable for 12-wk CR (52 RT, 62 RT+L). Rate of grade 3 and 4 adverse events were 8% and 0% for RT and 29% and 6% for RT+L. 92% and 90% pts received concurrent and adjuvant L per protocol/acceptable variation. There were no significant differences in 12 or 4wk CR rates (p=0.97 and p=0.77); 5.8% and 0% at 12wk and 3.6% and 1.5% at 4wk for RT and RT+L, respectively. The ORR at 4 wk was 42% and 56% (p=0.059, RECIST), 40% and 58% (p=0.027, WHO) in the RT and RT+L, respectively. Although the addition of lapatinib to WBRT/SRS did not improve the 12wk CR rate, it showed meaningful clinical benefit by demonstrating a trend toward improvement of 4 wk ORR. Results of ongoing central review of MRIs using RECIST1.1, WHO and RANO-BM criteria including secondary endpointswill be reported. Support: NCI grants U10CA180868, U10CA180822, UG1CA189867, and Novartis
Tracing the Genetic Legacy of the Tibetan Empire in the Balti
Authors: Xing-Yan Yang, Allah Rakha, Wei Chen, Juzhi Hou, Xue-Bin Qi, Quan-Kuan Shen, Shan-Shan Dai, Xierzhatijiang Sulaiman, Najmudinov Tojiddin Abdulloevich, Manilova Elena Afanasevna, Khudoidodov Behruz Ibrohimovich, Xi Chen, Wei-Kang Yang, Atif Adnan, Ruo-Han Zhao, Yong-Gang Yao, Bing Su, Min-Sheng Peng, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2020)

Abstract The rise and expansion of Tibetan Empire in the 7th to 9th centuries AD affected the course of history across East Eurasia, but the genetic impact of Tibetans on surrounding populations remains undefined. We sequenced 60 genomes for four populations from Pakistan and Tajikistan to explore their demographic history. We showed that the genomes of Balti people from Baltistan comprised 22.6–26% Tibetan ancestry. We inferred a single admixture event and dated it to about 39–21 generations ago, a period that postdated the conquest of Baltistan by the ancient Tibetan Empire. The analyses of mitochondrial DNA, Y, and X chromosome data indicated that both ancient Tibetan males and females were involved in the male-biased dispersal. Given the fact that the Balti people adopted Tibetan language and culture in history, our study suggested the impact of Tibetan Empire on Baltistan involved dominant cultural and minor demic diffusion.
CSIG-03. RECONCILING TUMOR HETEROGENEITY IN GLIOBLASTOMA USING A PATHWAY-BASED APPROACH
Authors: Alvaro Alvarado, Kaleab Tessema, Kunal Patel, Riki Kawaguchi, Richard Everson, Benjamin Ellingson, Vivek Swarup, Steven Goldman, Harley Kornblum
Journal: Neuro-Oncology (2020)

Abstract Despite efforts to gain a deeper understanding of its molecular architecture, glioblastoma (GBM) remains uniformly fatal. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has yielded little progress towards extending patient survival. In particular, the great phenotypic heterogeneity of GBM – both inter and intratumorally – has hindered therapeutic efforts. To this end, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. Gene set enrichment analysis (GSEA) was applied to gene expression data and used to provide an overview of each sample that can be compared to other samples by generating sample clusters based on overall patterns of enrichment. The Cancer Genome Atlas (TCGA) samples were clustered using the canonical and oncogenic signatures and in both cases the clustering was distinct from the molecular subtype previously reported and clusters were informative of patient survival. We also analyzed single cell RNA sequencing datasets and uniformly found two clusters of cells enriched for cell cycle regulation and survival pathways. We have validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity when E2F1, out top target, was silenced and when treated with fulvestrant and calcitriol, which were identified as potential drugs targeting this genelist. Conversely, no changes were observed in samples not enriched for this gene list. Finally, we interrogated spatial heterogeneity and found higher enrichment of the proliferative signature in contrast enhancing compared with non-enhancing regions. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.
MBRS-14. INTEGRATING CLINICAL AND GENOMIC CHARACTERISTICS IN PEDIATRIC MEDULLOBLASTOMA SUBTYPES IN A SINGLE COHORT IN TAIWAN
Authors: Kuo-Sheng Wu, Tai-Tong Wong
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Medulloblastoma (MB) was classified to 4 molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4) with the demographic and clinical differences. In 2017, The heterogeneity within MB was proposed, and 12 subtypes with distinct molecular and clinical characteristics. PATIENTS AND METHODS: PATIENTS AND METHODS We retrieved 52 MBs in children to perform RNA-Seq and DNA methylation array. Subtype cluster analysis performed by similarity network fusion (SNF) method. With clinical results and molecular profiles, the characteristics including age, gender, histological variants, tumor location, metastasis status, survival, cytogenetic and genetic aberrations among MB subtypes were identified. RESULTS In this cohort series, 52 childhood MBs were classified into 11 subtypes by SNF cluster analysis. WNT tumors shown no metastasis and 100% survival rate. All WNT tumors located on midline in 4th ventricle. Monosomy 6 presented in WNT α, but not in β subtype. SHH α and β occurred in children, while SHH γ in infant. Among SHH tumors, α subtype showed the worst outcome. G3 γ showed the highest metastatic rate and worst survival associated with MYC amplification. G4 α has the highest metastatic rate, however G4 γ showed the worst survival. CONCLUSION We identified molecular subgroups and subtypes of MBs based on gene expression and DNA methylation profile in children in our cohort series. The results may contribute to the establishment of nation-wide correlated optimal diagnosis and treatment strategies for MBs in infant and children.
Clinical, financial and academic implications of COVID-19 on a tertiary care interventional endoscopy programme
Authors: Ji Young Bang, Robert Hawes, Shyam Varadarajulu
Journal: Gut (2020)

<h3>Abstract</h3> Simple sequence repeats (SSRs) are found ubiquitously in almost all genome, and their formation mechanism is ambiguous yet. Here, the SSRs were analyzed in 55 randomly selected segments of genomes from a fairly wide range of species, with introducing more open standard for extensively mining repeats. A high percentage of repeats were discovered in these segments through that open standard and verified that they are not random. However, the current theory suggested that repeats tend to disappear over long-term evolution, which is inconsistent with such high proportion of SSRs remained in the genomes, inferring that there is most probably a mechanism for continually producing repeats during replicating process to balance continuous repeat disappearance. Therefore, the accepted straight-line slippage model is necessary to improve for explaining occurrence of simple sequence repeats. We proposed a folded slippage model to explain the high percent microsatellite occurrence with considering the geometric space of nucleotides and hydrogen bond stability, which can describe microsatellite expansion and contraction more reasonably. And analysis of external forces in the folding template strands showed the microsatellites tend to expand than contract. Our research may provide implements for the contribution of microsatellites to genome evolution and complement the semi-conservative replication.
IMMU-47. PROTEIN PHOSPHATASE 2A INHIBITION IN NK CELL THERAPY FOR TREATMENT OF MEDULLOBLASTOMA
Authors: Rongze Olivia Lu, Winson Ho, Brandon Chiou
Journal: Neuro-Oncology (2020)

Abstract Checkpoint immunotherapy (ICB) thus far has shown limited efficacy against brain tumors, such as medulloblastoma (MB). Its low mutational burden is thought to result in a paucity of neoantigen to trigger an effective T-cell response. Natural killer (NK) cells, can recognize tumor cells independently of neoantigens, making them appealing against MBs. Modulation of NK cells to enhance cytotoxicity against MBs could be a novel treatment strategy. Protein Phosphatase 2A (PP2A), a ubiquitous serine/threonine phosphatase, has been shown to inhibit IFNg and Granzyme B production by NK cells. We hypothesize that NK92, a transformed human NK cell line, has intrinsic activity against human MB cells and that inhibiting PP2A pharmacologically can enhance cytotoxicity of NK92 cells. We performed NK cytotoxicity assay and granulation assay against human MB cell line D425. We also used a small molecular inhibitor, LB100, to modulate PP2A activity in NK92. NK92 cells were co-cultured with D425, in increasing E:T (Effector:Target) ratio for 4 hours. D425 cells were pre-labeled with CellTrace Violet dye. The percentage of D425 (Violet+) cells in apoptosis (Cas3/7+) or necrosis (AAD+) were compared with different ET ratios to quantify NK mediated cell cytotoxicity. We also measured CD107a expression in NK92 to assess granulation with LB100 treatment. D425 cells were sensitive to NK92 killing. Percentage of D425 cells either apoptotic or necrotic increased with increasing ET ratio, suggesting that there was NK92 mediated cytotoxicity. Percentage of killed D425 cells ranged from 18% at baseline (without NK92) to 80% at ET ratio of 20. Inhibition of PP2A using LB100, enhanced NK92 degranulation. CD107a+ NK92 cells increased from 19% to 28% with 8uM of LB100. NK92 cells are cytotoxic against MB cells in vitro and inhibition of PP2A in NK cells can enhance their activity against MB cells.
IMG-07. GADOLINIUM IS NOT NECESSARY FOR SURVEILLANCE MR IMAGING IN CHILDREN WITH CHIASMATIC-HYPOTHALAMIC LOW GRADE GLIOMA
Authors: Fatema Malbari, Murali Chintagumpala, Jack Su, Mehmet Okcu, Frank Lin, Holly Lindsay, Surya Rednam, Patricia Baxter, Guillermo Aldave, William Whitehead, Robert Dauser, Stephen Kralik
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with chiasmatic-hypothalamic low grade glioma (CHLGG) have frequent MRIs with gadolinium based contrast agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in children is a potential concern. The purpose of this research is to establish whether MRI with GBCA is necessary for determining tumor progression in children with CHLGG. METHODS Children with progressive CHLGG were identified from Texas Children’s Cancer Center between 2005–2019. Pre- and post-contrast MRI sequences were separately reviewed by one neuroradiologist who was blinded to the clinical course. Three dimensional measurements and tumor characteristics were collected. Radiographic progression was defined as a 25% increase in size (product of two largest dimensions) compared to baseline or best response after initiation of therapy. RESULTS A total of 28 patients with progressive CHLGG including 683 MRIs with GBCA (mean 24 MRIs/patient; range: 10–43 MRIs) were reviewed. No patients had a diagnosis of NF1. Progression was observed 92 times, 91 (98.9%) on noncontrast and 90 (97.8%) on contrast imaging. Sixty-seven radiographic and/or clinical progressions necessitating management changes were identified in all (100%) noncontrast sequences and 66 (98.5%) contrast sequences. Tumor growth &amp;gt;2 mm in any dimension was identified in 184/187(98.4%) on noncontrast and 181/187(96.8%) with contrast imaging. Non primary metastatic disease was seen in seven patients (25%), which were better visualized on contrast imaging in 4 (57%). CONCLUSION MRI without GBCA effectively identifies patients with progressive disease. One should consider eliminating contrast in imaging of children with CHLGG with GBCA reserved for monitoring those with metastatic disease.
PATH-42. COMBINED NEXT GENERATION SEQUENCING AND IMMUNOHISTOCHEMISTRY IN THE DIFFERENTIAL DIAGNOSIS OF A PROGRESSIVE NEURONAL-GLIAL TUMOR: A COMPOSITE NEOPLASM
Authors: M Kelly Nicholas, Tibor Valyi-Nagy, Louis Coleman, Konstantin Slavin, Matthew Kpshy, Edward Michals, Jean Arzbaecher, Clinton Miller, Gayatry Mohapatra
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Neuronal-Glial tumors (NGT) are rare neoplasms typically benign, and characterized by various admixtures of neuronal and glial components. Occasionally these tumors transform to higher grades and rarely develop other histologic features inconsistent with a neuroepithelial origin, raising the question of histogenesis. We present a case of World Health Organization (WHO) grade I ganglioglioma (GG) diagnosed in a 28 year old man whose tumor, over a period of 8 years, progressed to anaplastic ganglioglioma (AGG, WHO grade III) and ultimately AGG with high grade sarcomatoid features. The sarcomatoid component eventually outgrew the NGT components, resulting in the patient’s death. We used next generation sequencing (NGS) and immunohistochemistry to characterize the genetic changes associated with these events. METHODS Tissues representing NGT and sarcomatoid components were macrodissected from 6 samples representing the tumor during its evolution from low to higher grades. DNA and RNA were extracted from these samples and NGS performed using the Oncomine Comprehensive Panel. Whole exome sequencing was performed using DNA from the 6 tumor samples and adjacent non-neoplastic tissue. RESULTS The original tumor, WHO grade I ganglioglioma had a BRAF V600E mutation. Seven years later, the AGG component had the BRAF V600E, absent in the sarcomatoid component, which had a CDKN2A homozygous deletion. The following year, the sarcomatoid component appeared to predominate and had an additional PIK3CA activating mutation. The NGT component retained the original BRAF mutation but no others. Hierarchical clustering of genome-wide variants identified two distinct cell populations emerging over time: GG progressing to AGG and sarcomatoid tumor. CONCLUSIONS Based on these results, we propose two distinct tumor cell populations: GG/AGG and sarcomatoid component, evolving over time and resulting in what is commonly considered a collision tumor, two independent tumors adjacent to each other.
CSIG-02. R-RAS SUBFAMILY PROTEINS ELICIT DISTINCT PHYSIOLOGIC EFFECTS AND PHOSPHOPROTEOME ALTERATIONS IN NEUROFIBROMIN-NULL MPNST CELLS
Authors: Shannon Weber, Nicole Brossier, Amanda Prechtl, Stephanie Brosius, Stephen Barnes, Landon Wilson, Steven Carroll
Journal: Neuro-Oncology (2020)

Abstract Loss of the Ras GTPase-activating protein neurofibromin promotes the development of aggressive spindle cell neoplasms known as Malignant Peripheral Nerve Sheath Tumors (MPNSTs) in patients with the genetic disorder neurofibromatosis type 1 (NF1). Currently, the available chemotherapeutic regimens and radiotherapy are ineffective against MPNSTs, so the prognosis for patients with these neoplasms is poor. Neurofibromin loss dysregulates multiple Ras proteins in the classic (H-Ras, N-Ras, K-Ras) and R-Ras (R-Ras, R-Ras2/TC21, R-Ras3/M-Ras) subfamilies. Consequently, it is unclear which Ras proteins or pathways regulated by these Ras proteins should be therapeutically targeted in MPNSTs. We have previously shown that classic Ras proteins drive MPNST cell proliferation and survival. However, the role(s) of the R-Ras subfamily of proteins in MPNSTs have not been elucidated. To determine how R-Ras proteins contribute to the pathogenesis of neurofibromin-null MPNSTs, we introduced dominant negative (DN) R-Ras mutants, which are pan-inhibitors of the R-Ras subfamily, into MPNST cells and assessed the impact of R-Ras subfamily inhibition on mitogenesis, migration and the phosphoproteome. A panel of MPNST cell lines (STS-26T, YST-1, ST88-14, 90–8, NMS2, NMS-PC, S462, T265-2c) was used. Methodologies utilized include immunoblotting, PCR, Transwell migration, 3H-thymidine incorporation, and mass spectrometric analysis of phosphoprotein-enriched specimens. We found that R-Ras and R-Ras2 are widely expressed and can be activated in neurofibromin-null MPNST cells. In contrast to classic Ras proteins, we found that R-Ras proteins drive MPNST both mitogenesis and migration. Using mass spectrometry-based phosphoproteomics, we identified thirteen protein networks that were regulated by DN R-Ras, including networks affecting cellular movement via effects on microtubules. We chose to further study changes in ROCK1 phosphorylation and found that R-Ras subfamily proteins function, at least in some part, through the same pathways as ROCK1. We conclude that R-Ras proteins promote tumorigenesis by regulating distinct signaling pathways that regulate MPNST mitogenesis and migration.
RARE-24. LARGE CONGENITAL MELANOCYTIC NEVI AND NEUROCUTANEOUS MELANOCYTOSIS: A RETROSPECTIVE CASE SERIES
Authors: Ugur Sener, Elsie Ennin, Stephanie Suser, Ashfaq Marghoob, Sofia Haque, Yasmin Khakoo
Journal: Neuro-Oncology (2020)

Abstract Neurocutaneous melanocytosis (NCM) is a rare disease characterized by excessive proliferation and deposition of melanocytes in the leptomeninges and brain parenchyma, occurring in children with large congenital melanocytic nevi (LCMN). Manifestations of NCM range from asymptomatic CNS melanin deposition to cranial neuropathies, seizures, and hydrocephalus. Patients with NCM are at risk for malignant melanoma. We conducted a retrospective, single-institution study of patients with LCMN evaluated at Memorial Sloan Kettering Cancer Center from June 2000 to January 2020. Of 55 patients studied, 15 had no radiographic NCM, and 40 had radiographic NCM at initial evaluation. MRI findings included: focal melanocytosis (33), diffuse leptomeningeal disease (4), solid melanoma (3). Malformations were identified in 13, including arachnoid cyst (4), congenital hydrocephalus (4), Dandy-Walker malformation (3), and tethered cord (1). Twenty-one patients completed imaging once and were followed clinically. Seventeen with serial imaging (10 with focal melanocytosis, 7 with normal MRI) remained stable over a median 24-month follow up (range: 1–124). Six had suspected radiographic progression of NCM without melanoma. Malignant melanoma developed in 11 patients, 5 with focal melanocytosis on initial imaging. Median time from focal melanocytosis identification to melanoma diagnosis was 80 months (range: 18–200). Median age at melanoma diagnosis was 9.9 years (range: 1.1–25.3). Median survival from melanoma diagnosis was 9.1 months (range: 1–60.4). Focal NCM on neuroaxis imaging does not predict time to transformation to malignant melanoma. Serial imaging is not indicated in absence of disease-modifying treatment. Clinical follow up of at-risk individuals is essential in early identification of complications.
Abstract P374: Associations Of Renin-angiotensin System Blockade Discontinuation With End-stage Kidney Disease, Major Adverse Cardiovascular Events, And Death Among People With Chronic Kidney Disease
Authors: Yao Qiao, Jung-im Shin, Teresa Chen, Lesley Inker, Josef Coresh, G Caleb Alexander, John Jackson, Alex R Chang, Morgan Grams
Journal: Circulation (2020)

Introduction: Among individuals with impaired kidney function, whether and when angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) should be discontinued is unclear. We investigated the associations of ACE-I/ARB discontinuation with end-stage kidney disease (ESKD), major adverse cardiovascular events (MACE), and mortality in individuals who had an eGFR decline to below 30 ml/min/1.73m 2 . Hypothesis: Patients with ACE-I/ARB discontinuation after an eGFR decline to below 30 ml/min/1.73m 2 are at higher risks of ESKD, MACE, and mortality. Methods: Using electronic health records data from the Geisinger Health System, we identified individuals who initiated ACE-I/ARB between 01/01/2004 and 02/28/2019 and had an eGFR decline to below 30 ml/min/1.73m 2 . We classified patients based on whether they discontinued ACE-I/ARB within six months following the eGFR decline. We assessed the associations of ACE-I/ARB discontinuation with ESKD, MACE, and mortality over the subsequent five years in a propensity-score matched sample. Results: Among the 3879 patients who met eligibility criteria, 1219 discontinued ACE-I/ARB within six months after eGFR decline to below 30 ml/min/1.73m 2 . The propensity-score matched sample contained 1190 patients under each arm. ACE-I/ARB discontinuation was associated with higher risks of mortality (hazard ratio (HR): 1.45 [95% confidence interval (CI): 1.26-1.67]) and MACE (HR: 1.37 [95% CI: 1.20-1.57]), but no significant difference in risk of ESKD (HR: 1.31 [95% CI: 0.95-1.81]). Similar patterns held when evaluating ACE-I/ARB discontinuation following a 40% or greater decline in eGFR within a year. Conclusions: Our findings suggest there may be benefits of continued use of ACE-I/ARB in individuals who had an eGFR decline to below 30 ml/min/1.73m 2 .