tbuckley/cabot-search huggingface dataset:
EXTH-06. INTEGRATED MOLECULAR PROFILING REVEALS TARGETABLE MOLECULAR ABNORMALITIES SHARED ACROSS MULTIPLE HISTOLOGIES OF BRAIN METASTASIS
Authors: Kazutaka Fukumura, Prit Benny Malgulwar, Grant Fischer, Xiao Ding Hu, Bisrat Godefay Debeb, Dihua Yu, Michael Davies, Jason Huse
Journal: Neuro-Oncology (2020)

Abstract Brain metastases (BMs) occur in approximately 20–40% of patients with advanced cancer, and the estimated prevalence of new BMs in United States is between 200,000–300,000 per year. While the incidence of BM has increased over the past decades due to improvements in brain tumor detection technology, the prognosis is still very poor with the median overall survival times from weeks to few months. Therefore, identification of the precise molecular landscape and therapeutic targets for BMs is absolutely essential in tangible improvement of patient management. Here, we performed integrated genomic, transcriptional, and proteomic profiling in a cohort of lung, breast, and renal cell carcinomas consisting of both BMs and patient-matched primary or extracranial metastatic tissues to identify shared cellular and molecular factors driving BMs across distinct primary tumor histologies. Although the comprehensive analysis identified the unique genomic, transcriptional and proteomic landscapes according to the different histopathologies, elevated PI3K/AKT and RAS/MAPK signaling was observed as a generalizable feature across the entire specimen cohort, along with relative immunosuppression and metabolic upregulation of the electron transport chain (ETC). Interestingly, immunosuppression via T cell depletion was significantly associated with unfavorable prognosis of patients with BMs, and ETC inhibition as the prospective therapeutic target for BM patients was demonstrated using in vitro and in vivo disease models. Taken together, our findings suggest that abnormalities involving oncogenic signaling, metabolism, and the immune microenvironment are shared across multiple histologies of BMs, and may be amenable to therapeutic targeting.
Proteasome activator PA200 maintains stability of histone marks during transcription and aging
Authors: Tian-Xia Jiang, Shuang Ma, Xia Han, Zi-Yu Luo, Qian-Qian Zhu, Tomoki Chiba, Wei Xie, Kui Lin, Xiao-Bo Qiu
Journal: Theranostics (2020)

The epigenetic inheritance relies on stability of histone marks, but various diseases, including aging-related disorders, are usually associated with alterations of histone marks. Whether and how the proteasome is responsible for maintaining the histone marks during transcription and aging remain unclear. The core histones can be degraded by the atypical proteasome, which contains the proteasome activator PA200, in an acetylation-dependent manner during somatic DNA damage response and spermiogenesis. Methods: By utilizing a substitute of methionine to label proteins metabolically, we analyzed histone degradation genome-wide by sequencing the DNA fragments following pulse-chase assays. The genome-wide RNA-sequencing analysis was performed to analyze transcription and chromatin-immunoprecipitation (ChIP)-sequencing was used for analyses of histone marks. The experimental models included gene-manipulated cells (including both mouse and yeast), mouse liver, and mice. Results: Degradation of H4 or the transcription-coupled histone variant H3.3 could be suppressed by deletion of PA200 or its yeast ortholog Blm10. The histone deacetylase inhibitor accelerated the degradation rates of H3, while the mutations of the putative acetyl-lysine-binding region of PA200 abolished histone degradation in the G1-arrested cells. Deletion of PA200 dramatically altered deposition of the active transcriptional hallmarks (H3K4me3 and H3K56ac) and transcription, especially during cellular aging. Furthermore, deletion of PA200 or Blm10 accelerated cellular aging. Notably, the PA200-deficient mice displayed a range of aging-related deteriorations, including immune malfunction, anxiety-like behavior and shorter lifespan. Conclusion: PA200 promotes the transcription-coupled degradation of the core histones, and plays an important role in maintaining the stability of histone marks during transcription and aging.
Stillbirths and neonatal deaths fell 15% in five years, but inequalities remain, UK report finds
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Extended perinatal mortality (stillbirths and neonatal deaths) decreased by 15% between 2013 and 2018, but women in the most deprived areas, and Black and Asian babies, remained the most at risk over the period, a surveillance report has found.1

The report, produced by MBRRACE-UK (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK), looked at perinatal deaths from 22 weeks gestational age (including late fetal losses, stillbirths, and neonatal deaths) of babies born in the UK between 1 January …
Farnesoid X Receptor Activation Impairs Liver Progenitor Cell–Mediated Liver Regeneration via the PTEN‐PI3K‐AKT‐mTOR Axis in Zebrafish
Authors: Kyounghwa Jung, Minwook Kim, Juhoon So, Seung‐Hoon Lee, Sungjin Ko, Donghun Shin
Journal: Hepatology (2020)

Background and Aims Following mild liver injury, pre‐existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC‐driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end‐stage liver diseases. Despite this attention, the molecular basis of BEC‐driven liver regeneration remains poorly understood. Approach and Results By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC‐driven liver regeneration. Here we show that FXR activation blocks the process through the FXR‐PTEN (phosphatase and tensin homolog)–PI3K (phosphoinositide 3‐kinase)–AKT‐mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC‐to‐hepatocyte differentiation, but not BEC‐to‐LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena / b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC‐driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K‐AKT‐mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC‐driven liver regeneration, as did FXR activation. Conclusions FXR activation impairs BEC‐driven liver regeneration by enhancing PTEN activity; the PI3K‐AKT‐mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.
NCMP-04. INCIDENCE AND OUTCOMES OF BRAIN METASTASES IN PATIENTS WITH EXTRA-PULMONARY NEUROENDOCRINE NEOPLASMS
Authors: Zainul Abedin Kapacee, Mohammed Dawod, Jennifer Allison, Dr Melissa Frizziero, Bipasha Chakrabarty, Prakash Manoharan, Catherine McBain, Was Mansoor, Angela Lamarca, Richard Hubner, Juan Valle, Mairead McNamara
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Brain metastases (BMs) incidence in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) is unclear, with no available management recommendations. This study aimed to review the clinical presentation, management and survival outcomes of patients with EP-NENs and BMs at a European Centre of Excellence. METHODS A retrospective single-centre analysis of consecutive patients with EP-NENs (Aug 2004-Feb 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis were estimated (Kaplan Meier). RESULTS Of 786 patients, 15 (1.9%) had BMs, median age 61y (range 15–77); 8 (53%) male, primary NEN site: unknown 40%; oesophageal 13%; small bowel 13%; pancreas 13%; gastric 7%; cervix 7% and bladder 7%. Most patients with BMs had grade 3 (G3) NENs (11, 73%), 3 (20%) were G2 and 1 (7%)G1. Eight (53%) had poorly-differentiated NENs, 6 well-differentiated and 1 not recorded. Two (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. Median time to development of BMs after initial NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 4 had 2–9 lesions and 6 had &amp;gt;10 BMs. The most commonly affected sites were the cerebrum (13, 87%), cerebellum (6, 40%), leptomeninges (2, 13%) and orbit (1, 7%). The most common presenting symptoms were limb weakness, headache, confusion, visual disturbance (each n=3, 20%), seizures (2, 13%), word-finding difficulty (2, 13%) and facial weakness/ptosis (1, 7%). Median OS from initial NEN diagnosis was 23.6-months [95%-CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0-months [95%-CI 0.0–8.3]. Treatment of BMs was surgery (n=3); radiotherapy (n=6); 5 had WBRT, one localised radiotherapy (orbit). Six (40%) had best supportive care. CONCLUSION BMs in patients with EP-NENs are rare and predominantly in G3 NENs, with diverse intracranial distribution. Although uncommon, BMs from NENs behave aggressively and greater understanding is needed to improve therapeutic outcomes.
Quality of dying and death in patients with interstitial lung disease compared with lung cancer: an observational study
Authors: Takafumi Koyauchi, Yuzo Suzuki, Kazuki Sato, Hironao Hozumi, Masato Karayama, Kazuki Furuhashi, Tomoyuki Fujisawa, Noriyuki Enomoto, Yutaro Nakamura, Naoki Inui, Koshi Yokomura, Shiro Imokawa, Hidenori Nakamura, Tatsuya Morita, Takafumi Suda
Journal: Thorax (2020)

Background There is limited knowledge regarding the quality of dying and death (QODD) and end-of-life interventions in patients with interstitial lung disease (ILD). Hence, differences in QODD and end-of-life interventions between patients with ILD and those with lung cancer (LC) remain poorly understood. Methods The primary aim of this study was to explore the differences in QODD and end-of-life interventions among patients dying with ILD versus those dying with LC. We performed a mail survey to quantify the QODD of a bereaved family’s perspective using the Good Death Inventory (GDI) score. Moreover, we examined the end-of-life interventions by medical chart review. Results Of 361 consecutive patients analysed for end-of-life interventions, 167 patients whose bereaved families completed questionnaires were analysed for QODD. Patients with ILD had lower GDI scores for QODD than those with LC (p=0.04), particularly in domains related to ‘physical and psychological distress relief’ and ‘prognosis awareness and participation in decision making’ (p=0.02, respectively). In end-of-life interventions, patients with ILD were less likely to receive specialised palliative care services (8.5% vs 54.3%; p&lt;0.001) and opioids (58.2% vs 73.4%; p=0.003). Additionally, lower frequencies of participation of patients with ILD in end-of-life discussion were also observed (40.8% vs 62.4%; p=0.007). Conclusion Patients with ILD had lower QODD and poorer access to palliative care and decision making than those with LC. Additional efforts to improve QODD in patients with ILD, particularly in symptom relief and decision-making processes, are urgently warranted.
Abstract 15517: Sarcopenia in Heart Failure Patients Without Dementia is Associated With Local Brain Atrophy and Predicts Poor Prognosis
Authors: Tomomi Meguro, Yuko Meguro, TOSHIO NAGAI
Journal: Circulation (2020)

Background: Sarcopenia is age-related loss of skeletal muscle volume and strength. Aged Heart failure (HF) patients without dementia may have potential risk of cognitive impairment (CI) that attenuates the effect of treatment. Patients with CI have severe brain atrophy in parahippocampal gyrus (PHG). However, it is not clear whether sarcopenia is associated with local brain atrophy and predicts prognosis. Hypothesis: Sarcopenia in HF patients without dementia is associated with local brain atrophy of PHG, a potential risk of CI, and predicts prognosis. Methods: Fifty-four HF patients (age 78+/-8 years, NYHA class II, EF47+/-18 %) were enrolled. We excluded patients with dementia using mini-mental state examination. We took 3D-T1 weighted sagittal images of whole brain using 1.5T magnetic resonance imaging. Image analysis was performed to evaluate the severity of local brain atrophy of gray matter using 2mm voxel-based morphometry by the statistical parametric mapping software. The Z-score value was calculated to evaluate the severity of atrophy in PHG. The cross-sectional area of the erector spinae muscles (CSA), an index of sarcopenia, were measured at the 12th thoracic vertebra using computed tomography. Results: Patients were divided into sarcopenia HF group (n=27) and Non-sarcopenia HF group (n=27) according to median of CSA. The severity of total brain atrophy was similar between sarcopenia HF group (8.1 +/-3.8%) and Non-sarcopenia HF group (8.9+/-3.5%). However, as shown in the representative cases (Figure A), the Z-score value in PHG (pink circle), reflecting the severity of atrophy, was prominent in sarcopenia HF group (1.57+/-0.80) (white arrows) in comparison with Non-sarcopenia HF group (0.94+/-0.63, P=0.002). Although age, gender, BNP and hemodynamic factors were similar between groups, sarcopenia HF group had a lower survival rate (Figure B). Conclusions: HF patients with sarcopenia without dementia have potential risk of CI and poor prognosis.
EPEN-01. MULTIDISCIPLINARY TREATMENT IN EPENDYMOMA
Authors: Daisuke Hirokawa
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND In intracranial ependymoma, the effectiveness of chemotherapy and radiation therapy is unclear, and the degree of tumor removal contributes to the improvement of life prognosis. METHODS We examined ependymoma cases treated in our institution from July 1998 to March 2017. RESULTS There were 18 boys and 7 girls. The average age at the time of surgery is 5.3±3.6 years. The pathological diagnosis was Grade II for 8 cases and Grade III for 17 cases. Genetic analysis was performed in 16/25 cases (64%). Of the infratentorial cases, 10/11 cases (90.1%) were PFA and PFB were one case. Of the supratentorial cases, 3/5 cases (60%) were positive for RELA fusion. As chemotherapy, 19 patients were VCR + VP-16 + CDDP + CPA. Irradiation was performed in all cases, local irradiation (50.4–55.8Gy) in 22 cases (88%), and craniospinal irradiation in 2 cases (8%). The 7-year OS was 74.6±9% and the 7-year PFS was 59.7±10.5%. Grade III showed a short OS (p = 0.053). GTR and NTR were obtained in the first excision in 14 cases (56%), and OS and PFS were not significantly different from those in the STR group (p = 0.219, p = 0.248). GTR and NTR including 2nd-look surgery were obtained in 18 cases (72%), and significant improvement of OS was observed compared with STR group (p = 0.02). CONCLUSION Even if it is not GTR or NTR at the first operation, improvement of OS is expected by total excision after chemotherapy.
ProsRegNet: A deep learning framework for registration of MRI and histopathology images of the prostate
Authors: Wei Shao, Linda Banh, Christian A. Kunder, Richard E. Fan, Simon J.C. Soerensen, Jeffrey B. Wang, Nikola C. Teslovich, Nikhil Madhuripan, Anugayathri Jawahar, Pejman Ghanouni, James D. Brooks, Geoffrey A. Sonn, Mirabela Rusu
Journal: Medical Image Analysis (2020)

Magnetic resonance imaging (MRI) is an increasingly important tool for the diagnosis and treatment of prostate cancer. However, interpretation of MRI suffers from high inter-observer variability across radiologists, thereby contributing to missed clinically significant cancers, overdiagnosed low-risk cancers, and frequent false positives. Interpretation of MRI could be greatly improved by providing radiologists with an answer key that clearly shows cancer locations on MRI. Registration of histopathology images from patients who had radical prostatectomy to pre-operative MRI allows such mapping of ground truth cancer labels onto MRI. However, traditional MRI-histopathology registration approaches are computationally expensive and require careful choices of the cost function and registration hyperparameters. This paper presents ProsRegNet, a deep learning-based pipeline to accelerate and simplify MRI-histopathology image registration in prostate cancer. Our pipeline consists of image preprocessing, estimation of affine and deformable transformations by deep neural networks, and mapping cancer labels from histopathology images onto MRI using estimated transformations. We trained our neural network using MR and histopathology images of 99 patients from our internal cohort (Cohort 1) and evaluated its performance using 53 patients from three different cohorts (an additional 12 from Cohort 1 and 41 from two public cohorts). Results show that our deep learning pipeline has achieved more accurate registration results and is at least 20 times faster than a state-of-the-art registration algorithm. This important advance will provide radiologists with highly accurate prostate MRI answer keys, thereby facilitating improvements in the detection of prostate cancer on MRI. Our code is freely available at https://github.com/pimed//ProsRegNet.
DIPG-02. USEFULNESS OF BEVACIZUMAB IN MAINTAINING QUALITY OF LIFE AT THE TIME OF DIFFUSE INTRINSIC PONTINE GLIOMA RELAPSE
Authors: Akira Gomi, Taku Uchiyama, Hirofumi Oguma, Takashi Yamaguchi, Kensuke Kawai
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Even in the age of molecular diagnosis, diffuse intrinsic pontine glioma (DIPG) is still a dismal disease. The usefulness of bevacizumab for DIPG relapse is reported. SUBJECTS AND METHODS The treatment and outcomes of 10 patients with DIPG who were treated at our institute since 2001 were retrospectively reviewed. All patients were diagnosed with DIPG by MRI imaging and underwent radiation therapy first. Three cases did not receive chemotherapy at the time of relapse (Untreated Group). In 7 cases, chemotherapy was performed at the time of relapse with ACNU/vincristine or interferon beta (Other Treatment Group), and 2 cases with bevacizumab (Bv Group). The change in the Karnofsky Performance Status Scale (KPS) from the time of relapse was compared. RESULTS The average overall survival (OS) for all 10 cases was 10.0 months. No prolongation of OS by bevacizumab was observed. However, it was only in the Bv Group that the KPS increased from the time of relapse. Comparison of the KPS at the time of relapse and the KPS after 4 months showed that the Bv Group remained unchanged or increased, while the Untreated Group and the Other Treatment Group decreased. In the Other Treatment Group, hospitalization was required for treatment, and side effects of bone marrow suppression were observed. However, in the Bv Group, outpatient treatment was possible, there were no side effects, and all could be observed at home. CONCLUSION From the above results, bevacizumab appears useful for palliative treatment for maintaining quality of life after DIPG relapse.
NCOG-04. PRETREATMENT VOLUME OF MR-DETERMINED WHITE MATTER INJURY (WMI) PREDICTS NEUROCOGNITIVE DECLINE AFTER HIPPOCAMPAL AVOIDANT (HA) WBRT+MEMANTINE FOR BRAIN METASTASES: SECONDARY ANALYSIS OF NRG ONCOLOGYCC001
Authors: Joseph Bovi, Stephanie Pugh, Paul Brown, Vinai Gondi, Jeffrey S Wefel, Wolfgang A Tome, Mark Gilbert, Cliff Robinson, Tammie L S Benzinger, David Sabsevitz, Karen Lee, Eric Paulson, Vijayananda Kundapur, David Roberge, Isaac Kaufman, Sunjay A Shah, Kenneth Y Usuki, Baldassarre D Stea, Harold A Yoon, Lyudmila DeMora, Minesh Mehta, Lisa Kachnik
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p&amp;lt; 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.
MBRS-67. ROLE OF CYCLIN DEPENDENT KINASE-9 IN <i>Myc</i>-ENHANCED MEDULLOBLASTOMA
Authors: Krishna Madhavan, Bethany Veo, Etienne Danis, Ilango Balakrishnan, Angela Pierce, Dong Wang, Ahmed Abdel-Hafiz, Natalie Serkova, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2020)

Abstract Myc is highly expressed in group 3 medulloblastoma (Myc-MB) and influences cell growth, proliferation and oncogenesis by directly promoting the activity of RNA polymerases (RNA Pol). Myc driven RNA Pol II activity is mediated by Positive Transcription Elongation Factor b (pTEFb). pTEFb’s catalytic core consists of cyclin dependent kinase-9 (CDK9) and Cyclin T, that phosphorylate and release RNA Pol II into active elongation. CDK9 is over expressed in group 3 MB suggesting that MB may be vulnerable to inhibition of CDK9 (CDK9i). The exact mechanism is not completely known in MB. Genetic depletion of CDK9 suppressed Myc-MB cell clonogenicity in vitro and tumor growth in vivo. CDK9i by two clinically relevant inhibitors, Atuveciclib and AZD4573, suppressed clonogenicity and cell self-renewal of Myc-MB cell lines. CDK9i in Myc-MB cell lines downregulated Myc and RNA Pol II phosphorylation at Ser2 and Ser5, and, upregulated P21. Further, mice with orthotopic xenografts treated with CDK9 inhibitors survived significantly longer than control mice. RNA-Seq-based gene set enrichment analysis showed that CDK9i decreased c-Myc driven transcriptomic programs and enhanced differentiation networks. ChIP-Seq for Pol2 and Myc, demonstrated that the Myc-driven aberrant transcriptional input can be reversed via CDK9i. These findings highlight the role of CDK9 in Myc-driven pathogenesis and that its inhibition is critical to the treatment of Myc-MB.