tbuckley/cabot-search huggingface dataset:
SURG-03. COMBINATION LASER INTERSTITIAL THERMAL THERAPY PLUS SRS INCREASES TIME TO PROGRESSION FOR RECURRENT SRS-TREATED BRAIN METASTASES
Authors: Matthew Grabowski, Eric Sankey, Ethan Srinivasan, Balint Otvos, Alex Scott, Michael Olufawo, Albert Kim, Eric Leuthardt, Gene Barnett, Alireza Mohammadi, Peter Fecci
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Laser interstitial thermal therapy (LITT) has evolved as an effective treatment for brain metastases (BM) failing stereotactic radiosurgery (SRS), and an alternative to open resection/repeat SRS. We sought to evaluate the efficacy of LITT+SRS in recurrent SRS-treated BM, and compare outcomes to LITT alone vs. repeat SRS. METHODS A multicenter, retrospective study was performed of patients with biopsy-proven BM recurrence after SRS. Patients were stratified by planned LITT+SRS vs. LITT alone vs. repeat SRS. Index lesion progression was determined by RANO criteria. RESULTS Forty-five patients fit inclusion, with a median follow-up of 7.3 months (range:1.1-30.5), age of 60 (range:37-86), KPS of 80 (range:60-100), and contrasted tumor volume (CTV) of 6.1cc (range:1.4-19.4). Histologies included NSCLC (44%), breast (24%), SCLC, melanoma, colon, and oroesophageal (&amp;lt; 10% each). Sixty-three percent of patients underwent LITT alone, 18% had repeat SRS, while 27% had LITT+SRS (post-LITT SRS). Median time to index lesion progression was greatest in the LITT+SRS group compared to LITT alone or repeat SRS (&amp;gt;23, 7.5, and 3.6 months, respectively [p=0.018]), as was overall survival (23.7, 5.9, and 7.0 months, respectively [p=0.023]). Age, sex, primary histology, CTV, and treatment strategy were univariate predictors of tumor progression; patients not treated with LITT+SRS were more likely to have index lesion progression (p=0.016). When controlling for histology and CTV in a multivariate model, patients not treated with LITT+SRS were significantly more likely to have progression (p=0.001). All LITT+SRS patients who experienced subsequent radiographic progression were diagnosed with recurrent tumor, while radiation necrosis incidence in the repeat SRS arm was 25%. CONCLUSION LITT+SRS appears superior to LITT alone or repeat SRS for treatment of biopsy-proven BM recurrence after SRS when controlling for other variables known to be predictive of progression. Prospective trials should be designed to validate the utility of combination LITT+SRS after SRS failure.
GCT-53. CASE OF INTRACRANIAL GROWING TERATOMA SYNDROME WITH DIFFICULTY IN TIMING OF RESECTION
Authors: Hidenobu Yoshitake, Hideo Nakamura, Yuta Hamamoto, Yusuke Otsu, Jin Kikuchi, Motohisa Koga, Soushou Kajiwara, Yui Nagata, Yoshihisa Matsumoto, Takuro Hashikawa, Hideki Sakai, Satoru Komaki, Nobuyuki Takeshige, Naohisa Miyagi, Setsuko Nakagawa, Kenji Takahashi, Yasuo Sugita, Motohiro Morioka
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Intracranial Growing teratoma syndrome(iGTS) is a phenomenon in which a tumor with a teratoma component grows during treatment, and its pathological tissue is often a mature teratoma. Here we report a case of iGTS in which the timing of surgery was determined by tumor markers and changes in tumor size on MRI images. CASE-REPORT: 11-year-old boy with a short stature. He developed a headache and we found a pineal gland tumor on MRI. Due to obstructive hydrocephalus, an endoscopic third ventriculostomy and biopsy were performed. The pathological diagnosis was mature teratoma, but AFP was elevated at 104.2 ng/mL. Considering NGGCT, we started chemoradiation immediately. Despite the declining AFP, it gradually increased, at which point we suspected iGTS. Resection was considered, but at some point tumor growth had stopped, so radiation therapy and a second course of ICE therapy preceded the resection. Thereafter, the tumor was completely removed, and a third course of ICE therapy was performed. DISCUSSION The onset mechanism of iGTS has not been elucidated, and its prediction is difficult. Early resection of the tumor is required, but discontinuation of radiation therapy and side effects of chemotherapy also need to be considered. In our case, resection was performed after normalization of AFP and recovery of myelosuppression. The patient followed an uneventful course, but the timing of resection was controversial. CONCLUSION We experienced a case of iGTS in NGGCT, a mixed tumor with mature teratoma. The optimal timing of the resection was discussed and literature was reviewed.
MBRS-13. MiR-1253 POTENTIATES CISPLATIN RESPONSE IN PEDIATRIC MEDULLOBLASTOMA BY REGULATING FERROPTOSIS
Authors: Ranjana K Kanchan, Naveenkumar Perumal, Pranita Atri, Ramakanth Chirravuri Venkata, Ishwor Thapa, Mohd Wasim Nasser, Surinder K Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2020)

Abstract Despite improvements in targeted therapies, few group 3 medulloblastoma patients survive long-term. Haploinsufficiency of 17p13.3 is a hallmark of these high-risk tumors; included within this locus is miR-1253, which has tumor suppressive properties in medulloblastoma. Therapeutic strategies capitalizing on the anti-neoplastic properties of miRNAs can provide promising adjuncts to chemotherapy. In this study, we explored the potentiation of miR-1253 on cisplatin cytotoxicity in group 3 MB. Overexpression of miR-1253 sensitized group 3 MB cell lines to cisplatin, leading to a pronounced downregulation in cell viability and induction of apoptosis. Cisplatin is reported as an inducer of both apoptosis and ferroptosis-mediated cancer cell death. In silico analysis revealed an upregulation of several ABC transporters in high-risk MB tumors. When compared to cell lines overexpressing miR-1253, the ABC transporter ABCB7, which regulates both apoptosis and ferroptosis, was revealed as a putative target of miR-1253 with poor survival that may facilitate its chemosensitizing effects by modulating mitochondrial ROS and HIF1α-driven NFκB signaling. We observed high expression of ABCB7 and GPX4, ferroptosis regulators, in MB patients with poor overall survival. MiR-1253 negatively regulated the expression of ABCB7 in Group 3 MB cell lines and induced cytoplasmic ROS and mitochondrial O2-, suggesting ROS-mediated induction of ferroptosis through regulation of ABCB7 and GPX4. Treatment with ROS and ferroptosis inhibitors rescued miR-1253 transfected cells treated with cisplatin. We conclude that miR-1253 induced ROS and potentiated the ferroptotic effects of cisplatin via targeting miR-1253/ABCB7/GPX4/mtROS axis.
NIMG-28. VALIDATION OF MODIFIED RESPONSE ASSESSMENT IN NEURO ONCOLOGY (mRANO) DETERMINED PFS AS A STRONG PREDICTOR OF OVERALL SURVIVAL IN RECURRENT GLIOBLASTOMA TREATED WITH A TARGETED IMMUNOTOXIN
Authors: Benjamin Ellingson, Chandtip Chandhasin, Melissa Coello, Nina Merchant, Fahar Merchant
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The current study compared the modified response assessment in neuro-oncology (mRANO)(1), iRANO (2), and standard RANO criteria (3) as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM). METHODS A total of 47 patients with rGBM were enrolled in a phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and an independent radiologic faculty (IRF), then standard RANO, iRANO, and mRANO criteria were applied. Differences of PFS and the association between PFS and OS were evaluated. RESULTS 41 of 47 patients were evaluable for response. Both local site and IRF-determined PFS was significantly shorter using standard RANO compared to iRANO (log-rank, P&amp;lt; 0.0001; HR=0.3) and mRANO (P&amp;lt; 0.0001; HR=0.3). No difference in PFS was observed between iRANO and mRANO (Local, P=0.67; IRF, P=0.59). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (Local, P=0.47; IRF, P=0.34). Using the iRANO, a weak association driven by a few outliers was observed between confirmed PFS and OS via local site measurements (P=0.017), but not central IRF measurements (P=0.18). Importantly, 24 of 41 patients (59%) were censored using iRANO and not included because they did not have confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2=0.66, P&amp;lt; 0.0001) and IRF-determined reads (R2=0.57, P=0.0007). CONCLUSION No correlation between PFS and OS was observed for standard RANO or iRANO, but a strong correlation was identified between both locally-determined and centrally-determined PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
EPEN-33. PHARMACOGENOMICS REVEALS SYNERGISTIC INHIBITION OF ERBB2 AND PI3K SIGNALING AS A THERAPEUTIC STRATEGY FOR EPENDYMOMA
Authors: David Pauck, Eunice Paisana, Rita Cascão, Sevgi Sarikaya-Seiwert, Viktoria Marquardt, Daniel Picard, Jasmin Bartl, Lena Blümel, Mara Maue, Christian Dimitriadis, Kübra Taban, Ute Fischer, Hans Jakob Steiger, Cláudia Faria, Guido Reifenberger, Arndt Borkhardt, Thomas Beez, Marc Remke
Journal: Neuro-Oncology (2020)

Abstract Subgroups of ependymoma, especially RELA fusion-positive and posterior fossa type A tumors, are associated with poor prognosis. Curative therapeutic strategies have not yet been identified. We set up a high-throughput drug screening (HTS) pipeline to evaluate clinically established compounds (n=196) in primary ependymoma cultures (n=12). As culturing ependymoma is challenging, assay miniaturization to 1536-well microplates emerged as a key feature to process HTS despite smallest cell numbers. DNA methylation profiling showed that entity and subgroup affiliation from primary diagnosis was maintained in primary cultures, as assessed through molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). A comparison of HTS data of ependymoma and other pediatric brain tumor models (n=48) revealed a remarkable chemoresistance in vitro. However, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate which was preferentially active in a subset of the investigated ependymoma cultures (n=5). Combinatory treatment with Copanlisib, a PI3K inhibitor, was able to overcome resistance to single agent treatment using Neratinib in established cell lines of ependymoma (n=3) and 2/4 primary cultures for which combinatory treatment could be tested. Finally, we validated efficacy of Neratinib combined with Copanlisib in mice bearing ependymoma xenografts which revealed significantly reduced tumor size compared to vehicle-treated animals. In summary, our study demonstrates that HTS may reveal targeted therapies for pediatric brain tumors. Specifically, we found a synergistic interaction of Neratinib and Copanlisib for treatment of ependymoma, thereby providing a novel therapeutic approach in an otherwise largely chemoresistant entity.
EXTH-13. POTENT ANTICANCER EFFECTS OF A NEW WEARABLE NONINVASIVE ONCOMAGNETIC DEVICE: CELLULAR MECHANISMS OF ACTION
Authors: Santosh Helekar, Shashank Hambarde, David Baskin, Martyn Sharpe
Journal: Neuro-Oncology (2020)

Abstract Oscillating magnetic fields (OMF) produced by a new device with rotating magnets produces rapid apoptosis of patient derived glioblastoma (GBM) cells in culture. We have proposed that this is due to a sequence of events triggered by the well-established mT-range magnetic influence on the radical electron pair mechanism in the mitochondrial respiratory electron transport chain (ETC). Here we present results of preclinical studies in support of this mitochondrial hypothesis, accounting for the oncolytic effects of OMF. We tested a range of in vitro treatment protocols, involving changes in frequency and timing of OMF, to arrive at an optimally effective set of parameters. After hours of exposure to this optimized intermittent pattern of OMF killed not only patient derived GBM cells, but cells of 4 other malignant tumors in a cell culture dish. This treatment was not lethal to normal human astrocytes, bronchial epithelial cells, and B lymphocytes. Exposure to static magnetic fields and continuous OMF did not produce any oncolysis. The oncolytic effect of OMF was potentiated by compounds that enhance mitochondrial metabolism, e.g. β-hydroxybutyrate. The underlying cellular mechanism of OMF action involved complete arrest of ETC-dependent consumption of oxygen, accelerated upregulation of the levels of reactive oxygen species, opening of the mitochondrial membrane permeability transition pore, and disruption of the mitochondrial network, leading to caspase-dependent apoptosis of cancer cells. Daily treatment in a late-stage mouse model consisting of human GBM xenografts implanted into the brains of immunocompromised mice produced significant survival benefit. These findings document the potent oncolytic effects of OMF and specific mechanisms of action that will likely provide a novel and powerful treatment against GBM and a wide range of other solid malignant tumors. Clinical trials of this therapy are underway at our institution.
MBRS-51. MUTATIONS IN BRPF1 FOUND IN SHH MEDULLOBLASTOMA PREVENT INTERACTION WITH TP53 AND LEADS TO RADIORESISTANCE IN VITRO
Authors: Mikaela Vouri, Audrey Mercier, Patricia Benites Goncalves da Silva, Konstantin Okonechnikov, Antoine Forget, Hua Yu, Anais Chivet, Marcel Kool, Stefan Pfister, Olivier Ayrault, Daisuke Kawauchi
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is one of the most common pediatric tumors in children. Among them, SHH subgroups of MB (MBSHH) is characterized by constitutive activation of SHH pathway. Somatic mutations in BRPF1, a chromatin modifier, is found in more than 5% of MBSHH and accounts for almost 20% of adult MBSHH but its potential role in MBSHH pathophysiology is still unknown. In this study, we first examined the function of Brpf1 on pro-tumorigenic features of MBSHH and evaluated molecular pathways regulated by Brpf1 using Brpf1floxed::Atoh1-Cre conditional knockout mice, in which Brpf1 is conditionally deleted in cerebellar granule neuron progenitors (GNPs). While RNA-seq analysis on GNPs from Brpf1 WT and KO mice showed significant differences in the pathways related with cell cycle and cell death, deletion of Brpf1 did not cause acceleration of tumorigenesis in the Ptch1 heterozygous tumor-prone. Background: Co-immunoprecipitation followed by mass spectrometry analysis identified interaction partners of BRPF1 including MOZ, MORF and ING5, known partners of BRPF1. Gene ontology analysis also depicted pathways important for cell cycle progression, cell death and response to DNA damage. Consistent with these observations, TP53 was identified as a novel co-factor of BRPF1. Of note, some of MBSHH-relevant BRPF1 mutations prevented interaction with TP53. According to the previous finding that cytosolic TP53 is required for apoptotic cell death, GNPs expressing the BRPF1-R600X mutant gene exhibited the resistance to irradiation-induced cell death. In conclusion, our data revealed that BRPF1 mutants found in MBSHH could prevent the complex formation with TP53, leading to enhanced resistance to cell apoptosis.
Persistence of intrahepatic hepatitis B virus DNA integration in patients developing hepatocellular carcinoma after hepatitis B surface antigen seroclearance
Authors: Jeong Won Jang, Jin Seoub Kim, Hye Seon Kim, Kwon Yong Tak, Heechul Nam, Pil Soo Sung, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Lewis R. Roberts
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: The role of hepatitis B virus (HBV) integration into the host genome in hepatocarcinogenesis following hepatitis B surface antigen (HBsAg) seroclearance remains unknown. Our study aimed to investigate and characterize HBV integration events in chronic hepatitis B (CHB) patients who developed hepatocellular carcinoma (HCC) after HBsAg seroclearance.&lt;br/&gt;Methods: Using probe-based HBV capturing followed by next-generation sequencing technology, HBV integration was examined in 10 samples (seven tumors and three non-tumor tissues) from seven chronic carriers who developed HCC after HBsAg loss. Genomic locations and patterns of HBV integration were investigated.&lt;br/&gt;Results: HBV integration was observed in six patients (85.7%) and eight (80.0%) of 10 tested samples. HBV integration breakpoints were detected in all of the non-tumor (3/3, 100%) and five of the seven (71.4%) tumor samples, with an average number of breakpoints of 4.00 and 2.43, respectively. Despite the lower total number of tumoral integration breakpoints, HBV integration sites in the tumors were more enriched within the genic area. In contrast, non-tumor tissues more often showed intergenic integration. Regarding functions of the affected genes, tumoral genes with HBV integration were mostly associated with carcinogenesis. At enrollment, patients who did not remain under regular HCC surveillance after HBsAg seroclearance had a large HCC, while those on regular surveillance had a small HCC.&lt;br/&gt;Conclusions: The biological functions of HBV integration are almost comparable between HBsAg-positive and HBsAgserocleared HCCs, with continuing pro-oncogenic effects of HBV integration. Thus, ongoing HCC surveillance and clinical management should continue even after HBsAg seroclearance in patients with CHB.
Sweetened beverages and risk of frailty among older women in the Nurses’ Health Study: A cohort study
Authors: Ellen A. Struijk, Fernando Rodríguez-Artalejo, Teresa T. Fung, Walter C. Willett, Frank B. Hu, Esther Lopez-Garcia
Journal: PLoS Medicine (2020)

Background Consumption of sugar-sweetened beverages (SSBs) has been consistently associated with a higher risk of obesity, type 2 diabetes, cardiovascular disease, and premature mortality, whereas evidence for artificially sweetened beverages (ASBs) and fruit juices on health is less solid. The aim of this study was to evaluate the consumption of SSBs, ASBs, and fruit juices in association with frailty risk among older women. Methods and findings We analyzed data from 71,935 women aged ≥60 (average baseline age was 63) participating in the Nurses’ Health Study (NHS), an ongoing cohort study initiated in 1976 among female registered nurses in the United States. Consumption of beverages was derived from 6 repeated food frequency questionnaires (FFQs) administered between 1990 and 2010. Frailty was defined as having at least 3 of the following 5 criteria from the FRAIL scale: fatigue, poor strength, reduced aerobic capacity, having ≥5 chronic illnesses, and weight loss ≥5%. The occurrence of frailty was assessed every 4 years from 1992 to 2014. During 22 years of follow-up, we identified 11,559 incident cases of frailty. Consumption of SSBs was associated with higher risk of frailty after adjustment for diet quality, body mass index (BMI), smoking status, and medication use, specifically, the relative risks (RRs) and 95% confidence interval (95% CI) for ≥2 serving/day versus no SSB consumption was 1.32 (1.10, 1.57); p -value &lt;0.001. ASBs were also associated with frailty [RR ≥2 serving/day versus no consumption: 1.28 (1.17, 1.39); p -value &lt;0.001]. Orange juice was associated with lower risk of frailty [RR ≥1 serving/day versus no consumption: 0.82 (0.76, 0.87); p -value &lt;0.001], whereas other juices were associated with a slightly higher risk [RR ≥1 serving/day versus no consumption: 1.15 (1.03, 1.28); p -value &lt;0.001]. A limitation of this study is that, due to self-reporting of diet and frailty, certain misclassification bias cannot be ruled out; also, some residual confounding may persist. Conclusions In this study, we observed that consumption of SSBs and ASBs was associated with a higher risk of frailty. However, orange juice intake showed an inverse association with frailty. These results need to be confirmed in further studies using other frailty definitions.
Abstract P421: Alternate Health Eating Index &amp; Cognitive Function Among Middle-aged and Older Hispanics/ Latinos: The Hispanic Community Health Study/ Study of Latinos
Authors: Mayra L Estrella, melissa lamar, Ramon A Durazo-Arvizu, Josiemer Mattei, Yasmin Mossavar-Rahmani, Krista M Perreira, Ana M Siega-Riz, Daniela Sotres-Alvarez, Hector M Gonzalez, Linda C Gallo, Martha L Daviglus
Journal: Circulation (2020)

Introduction: A healthy diet may promote healthy cognitive aging; however, little is known about associations between diet quality and cognition in Hispanics/Latinos. Hypothesis: Higher diet quality (2010 Alternative Healthy Eating Index; AHEI-2010) is associated with better global cognition and performance on specific cognitive tests (verbal learning, memory, verbal fluency, and processing speed) in Hispanics/Latinos. Methods: Data from HCHS/SOL Visit 1 (2008-2011; n=8461; ages 45-74 years) were analyzed. The global cognition score was computed as the sum of z-scores for the individual tests. Dietary intake was assessed via two 24-hour recalls. Total AHEI-2010 score was categorized into quintiles (Q); higher Q represents higher diet quality. Cross-sectional associations between AHEI-2010 and each cognitive test were examined using survey-weighted linear regression models adjusted for age, sex, education, and total daily energy intake (Model 1); and Model 1 plus Hispanic/Latino heritage, annual household income, language preference, type 2 diabetes, smoking, and depressive symptoms (Model 2). Results: In minimally-adjusted models (Table 1), global cognition, verbal learning, verbal memory, verbal fluency, and processing speed scores were significantly higher by 1.32, 2.38, 1.40, 2.33, and 1.34 units for Q5 (vs. Q1). In fully-adjusted models, global cognitive function scores were significantly higher by 0.28, 0.52, and 0.48 units for Q2 through Q4 (vs. Q1; p -trend= 0.042). Verbal learning scores were significantly higher by 0.60, 0.62, 0.92, and 0.88 units for Q2 through Q5 (vs. Q1; p -trend= 0.020). Verbal memory scores were significantly higher by 0.33, 0.40, 0.52, and 0.46 units for Q2 through Q5 (vs. Q1; p -trend= 0.007). AHEI-2010 was not associated with verbal fluency and processing speed in Model 2. Conclusions: Among middle-aged and older Hispanics/Latinos, higher diet quality was associated with better global cognition, verbal learning, and memory, but not with verbal fluency, or processing speed.