tbuckley/cabot-search huggingface dataset:
LINC-30. A CLINICOPATHOLOGICAL STUDY OF IMMUNOGENICITY AND IMMUNE EVASION MECHANISMS AMONG MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA
Authors: Kavneet Kaur, Vaishali Suri, Mehar C Sharma, Ashish Suri, Chitra Sarkar
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Medulloblastomas have been well characterised in terms of genomics, epigenomics, transcriptomics and recently proteomics. However, there is limited knowledge regarding immunogenicity, immune-microenvironment and immune evasion mechanisms in different molecular subgroups of medulloblastoma. It is important to analyze these parameters to understand tumor progression, prognostic stratification as well as treatment response to available immunotherapeutic drugs. MATERIALS AND METHODS Molecular subgrouping performed by immunohistochemistry(IHC), Nanostring and 850k-methylation array. Immune profile by IHC for CD3, 20, CD8 [tumor infiltrating lymphocytes (TILs)], CD163 [tumor-associated macrophages (TAMs)], and PD-L1 and CTLA-4 [immune checkpoint proteins]. RESULTS A total of 35 cases were analyzed with age-range from 1 to 54 years (77% pediatric and 23% adult). 82% cases were located in midline, while rest in cerebellar hemispheres. On molecular subgrouping, MBs were subdivided into 8 WNT, 10 SHH, 8 Group 3 and 9 Group 4. Twenty four cases had follow up, 12 with no evidence of disease while 12 with progressive disease or death. PD-L1 expression ranged from 0% to 20% and included 5SHH, 2WNT and 1Group 3. CTLA4 positive lymphocytes ranged from 0 to 33 in 4 cases: 1WNT, 3 SHH, 1Group4. TILs ranged from 0–220/mm2 with a median of 3. TAMs ranged from 0–60/mm2 with a median of 18. Both TILs and TAMs were significantly higher in SHH subgroup. CONCLUSION PD-L1 positivity and number of TILs and TAMs were significantly more in SHH-subgroup tumors followed by WNT tumors. CTLA-4 expression did not correlate with subgroups. All parameters showed a positive trend with increasing age.
The Healthy Brain and Child Development Study—Shedding Light on Opioid Exposure, COVID-19, and Health Disparities
Authors: Nora D. Volkow, Joshua A. Gordon, Michelle P. Freund
Journal: JAMA Psychiatry (2020)

This Viewpoint describes the planned Healthy Brain and Child Development Study, which will investigate the associations of parental substance abuse, coronavirus disease 2019 infection, and exposure to health disparities with their children's health and well-being.
TAMI-11. IMPACT OF oHSV ACTIVATED NOTCH SIGNALING IN TUMOR MICROENVIRONMENT, AND ITS IMPACT ON ANTI-TUMOR IMMUNITY
Authors: Yoshihiro Otani, Ji Young Yoo, Samantha Chao, Toshihiko Shimizu, Cole Lewis, Sara Murphy, Josue Pineda, Kimberly Rivera Caraballo, Bangxing Hong, Yeshavanth Kumar Banasavadi-Siddegowda, John Heiss, Yuanqing Yan, Scott Olson, Guangsheng Pei, Zhongming Zhao, Balveen Kaur
Journal: Neuro-Oncology (2020)

Abstract NOTCH signaling is a method of cell-cell communication where membrane bound NOTCH ligands on signal-sending cells can bind to and initiate cleavage of the NOTCH receptor, releasing NICD which can initiate signal transduction in adjacent “signal-receiving” cells. We have recently shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells. RNA sequencing of GBM cells post-infection also uncovered Gene Ontology NOTCH signaling pathway to be significantly upregulated. This activation was induced by viral miRNA-H16, which represses FIH-1 expression. FIH-1 was found to be a negative regulator of Mib1, a ubiquitin ligase, which activates NOTCH ligand-mediated activation of adjacent signal-receiving cells bearing the NOTCH receptor (Otani et al Clin. Can. Res. 2020). Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment. Treatment of brain tumors in immune competent mice with oHSV and NOTCH blocking gamma secretase inhibitor (GSI) induced an anti-tumor memory immune response. Long term survivors in mice treated with the combination also completely rejected subsequent tumor re-challenge in the other hemisphere. UMAP of flow cytometry of tumor-bearing hemispheres and functional analysis of isolated cellular fractions from treated mice showed a significant influx of MDSC cells after oHSV treatment that was rescued in mice treated with oHSV and GSI. Ongoing mechanistic studies are uncovering a significant induction of NOTCH in tumor associated macrophages that aids in recruitment of MDSC cells. Overall these studies have uncovered a significant impact of oHSV therapy on GBM tumor microenvironment and presents opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity.
Surgical Delay and Pathological Outcomes for Clinically Localized High-Risk Prostate Cancer
Authors: Leilei Xia, Ruchika Talwar, Raju R. Chelluri, Thomas J. Guzzo, Daniel J. Lee
Journal: JAMA Network Open (2020)

<h3>Importance</h3> There is a lack of data evaluating the association of surgical delay time (SDT) with outcomes in patients with localized, high-risk prostate cancer. <h3>Objective</h3> To investigate the association of SDT of radical prostatectomy and final pathological and survival outcomes. <h3>Design, Setting, and Participants</h3> This cohort study used data from the US National Cancer Database (NCDB) and identified all patients with clinically localized (cT1-2cN0cM0) high-risk prostate adenocarcinoma diagnosed between 2006 and 2016 who underwent radical prostatectomy. Data analyses were performed from April 1 to April 12, 2020. <h3>Exposures</h3> SDT was defined as the number of days between the initial cancer diagnosis and radical prostatectomy. SDT was categorized into 5 groups: 31 to 60, 61 to 90, 91 to 120, 121 to 150, and 151 to 180 days. <h3>Main Outcomes and Measures</h3> The primary outcomes were predetermined as adverse pathological outcomes after radical prostatectomy, including pT3-T4 disease, pN-positive disease, and positive surgical margin. The adverse pathological score (APS) was defined as an accumulated score of the 3 outcomes (0-3). An APS of 2 or higher was considered a separate outcome to capture cases with more aggressive pathological features. The secondary outcome was overall survival. <h3>Results</h3> Of the 32 184 patients included in the study, the median (interquartile range) age was 64 (59-68) years, and 25 548 (79.4%) were non-Hispanic White. Compared with an SDT of 31 to 60 days, longer SDTs were not associated with higher risks of having any adverse pathological outcomes (odds ratio [OR], 0.95; 95% CI, 0.80-1.12;<i>P</i> = .53), pT3-T4 disease (OR, 0.99; 95% CI, 0.83-1.17;<i>P</i> = .87), pN-positive disease (OR, 0.79; 95% CI, 0.59-1.06;<i>P</i> = .12), positive surgical margin (OR, 0.88; 95% CI, 0.74-1.05;<i>P</i> = .17), or APS greater than or equal to 2 (OR, 0.90; 95% CI, 0.74-1.05;<i>P</i> = .17). Longer SDT was also not associated with worse overall survival (for SDT of 151-180 days, hazard ratio, 1.12; 95% CI, 0.79-1.59,<i>P</i> = .53). Subgroup analyses performed for patients with very high-risk disease (primary Gleason score 5) and sensitivity analyses with SDT considered as a continuous variable yielded similar results. <h3>Conclusions and Relevance</h3> In this cohort study of patients who underwent radical prostatectomy within 180 days of diagnosis for high-risk prostate cancer, radical prostatectomy for high-risk prostate cancer could be safely delayed up to 6 months after diagnosis.
Cognitive Impairment in Older Adults and Therapeutic Strategies
Authors: Thomas J. Montine, Syed A. Bukhari, Lon R. White, Vivian Hook
Journal: Pharmacological Reviews (2020)

Cognitive impairment and its severe form dementia are increasingly prevalent in older adults and loom as a public health disaster unless effective interventions are developed. Cognitive impairment is a convergent trait caused by damage from an idiosyncratic mix of four prevalent diseases (Alzheimer disease; vascular brain injury; Lewy body diseases, such as Parkinson disease and dementia with Lewy bodies; and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy) that is counterbalanced by individually varying resilience, which is comprised of reserve and compensation. Brain regional damage from each of these four prevalent diseases is generated by the net effect of injury and (mal)adaptive response and is accompanied by characteristic lesions. Existing therapeutics enhance resilience, whereas most agents under development target mechanisms of damage with only suppression of vascular brain injury yet to show therapeutic promise. We hope to anticipate future tailored interventions that target mechanisms of damage and thereby avert the oncoming surge of cognitive impairment and dementia in older adults. <h3>Significance Statement</h3> Brain regional damage is generated by the net effect of injury and (mal)adaptive response. The extent to which signs and symptoms of such damage occur is influenced by an underlying resilience comprising reserve and compensation. Finding tailored interventions that target specific mechanisms of damage likely yields the most effective therapies.
Factors That Might Affect SARS-CoV-2 Transmission Among Foreign-Born and U.S.-Born Poultry Facility Workers — Maryland, May 2020
Authors: Beth L. Rubenstein, Stefanie Campbell, Alysha R. Meyers, David A. Crum, Clifford S. Mitchell, Jeré Hutson, D’Ann L. Williams, Schabbethai S. Senesie, Zunera Gilani, Steven Reynolds, Bianca Alba, Stephanie Tavitian, Kristian Billings, Lina Saintus, Stephen B. Martin, Hugh Mainzer
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Numerous recent assessments indicate that meat and poultry processing facility workers are at increased risk for infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1-4).Physical proximity to other workers and shared equipment can facilitate disease transmission in these settings (2-4).The disproportionate number of foreign-born workers employed in meat and poultry processing reflects structural, social, and economic inequities that likely contribute to an increased COVID-19 incidence in this population* (5).In May 2020, the Maryland Department of Health and CDC investigated factors that might affect person-to-person SARS-CoV-2 transmission among persons who worked at two poultry processing facilities.† A survey administered to 359 workers identified differences in risk factors for SARS-CoV-2 infection between workers born outside the United States and U.S.-born workers.Compared with U.S.-born workers, foreign-born workers had higher odds of working in fixed locations on the production floor (odds ratio [OR] for cutup and packaging jobs = 4.8), of having shared commutes (OR = 1.9), and of living with other poultry workers (OR = 6.0).They had lower odds of participating in social gatherings (OR for visits to family = 0.2; OR for visits to friends = 0.4), and they visited fewer businesses in the week before the survey than did their U.S.-born coworkers.Some workplace risk factors can be mitigated through engineering and administrative controls focused on the production floor, and this will be of particular benefit to the foreign-born workers concentrated in these areas.Employers and health departments can also partner with local organizations to disseminate culturally and linguistically tailored messages about risk reduction behaviors in community settings, including shared transportation § and household members dwelling in close quarters.¶ During a 2-day period in May 2020, interviews were conducted with a convenience sample of on-duty workers selected by management from two poultry processing facilities during the morning * According to the Migration Policy Institute, immigrants represent 17% of all civilian-employed workers in the United States and 37% of meat processing industr y workers.https://www.migrationpolicy.org/content/essential-role-immigrants-us-food-supply-chain.
Esophagectomy With Three-Field Versus Two-Field Lymphadenectomy for Middle and Lower Thoracic Esophageal Cancer: Long-Term Outcomes of a Randomized Clinical Trial
Authors: Bin Li, Yawei Zhang, Longsheng Miao, Longfei Ma, Xiaoyang Luo, Yiliang Zhang, Ting Ye, Hecheng Li, Jie Zhang, Yuan Li, Kuaile Zhao, Min Fan, Zhengfei Zhu, Jialei Wang, Jie Xu, Youjia Deng, Qiong Lu, Hang Li, Yang Zhang, Yunjian Pan, Shilei Liu, Longlong Shao, Yihua Sun, Jiaqing Xiang, Hong Hu, Haiquan Chen
Journal: Journal of Thoracic Oncology (2020)
Transition From Temporary to Durable Circulatory Support Systems
Authors: Diyar Saeed, Evgenij Potapov, Antonio Loforte, Michiel Morshuis, David Schibilsky, Daniel Zimpfer, Julia Riebandt, Federico Pappalardo, Matteo Attisani, Mauro Rinaldi, Assad Haneya, Faiz Ramjankhan, Dirk W. Donker, Ulrich P. Jorde, Julia Stein, Dmytro Tsyganenko, Khalil Jawad, Radi Wieloch, Rafael Ayala, Jochen Cremer, Michael A. Borger, Artur Lichtenberg, Jan Gummert
Journal: Journal of the American College of Cardiology (2020)
EPCT-16. A PHASE IB STUDY OF PTC596 IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA AND HIGH GRADE GLIOMA
Authors: Natasha Pillay Smiley, Patricia Baxter, Shiva Kumar, Eugene Hwang, John Breneman, Adam Lane, Renee Doughman, Michelle Deutsch, Charles Stevenson, Clinton Stewart, Jim Leach, Xiao-Nan Li, Sonia Romero, Pius Maliakal, Lan Gao, Maryam Fouladi, Rachid Drissi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND BMI-1 is highly expressed in DIPG. Downregulation leads to inhibition of cell proliferation, cell cycle signaling, self-renewal, telomerase expression, activity, and suppression of DIPG cell migration. Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and drug-induced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.) is a novel, orally available drug that inhibits microtubule polymerization, resulting in G2/M cell cycle arrest and post-translational modification of BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years of age with newly diagnosed diffuse intrinsic pontine glioma and high-grade gliomas. METHODS PTC596 is administered twice per week orally during radiotherapy and as maintenance for up to two years. The starting dose of PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose. Pharmacokinetics are performed in Cycles 1 and 2. RESULTS This study is currently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable, have been enrolled. At dose level 1, 200 mg/m2, three evaluable patients were enrolled and experienced no DLTs. At dose level 2, among 5 evaluable patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has been otherwise well tolerated. Five patients remain in Cycles 2–11. CONCLUSION This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow whole tablets.
DIPG-21. INDUCTION OF MITOTIC ABNORMALITIES AND BMI-1 MODULATION TO TREAT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Shiva Senthil Kumar, Satarupa Sengupta, Xiaoting Zhu, Deepak Kumar Mishra, Christine Fuller, Maryam Fouladi, Rachid Drissi
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor with a median survival of less than one year. No effective therapy is currently available, and no therapeutic advances have been made in several decades. BMI-1 is a member of the multimeric protein complex Polycomb repressor complex 1 (PRC1). It has been implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of histone 3 subtype. In the present study, we show that the modulation of BMI-1 leads to DNA damage, M phase cell cycle arrest, chromosome abnormalities and cell death. Furthermore, modulation of BMI-1 sensitizes DIPG patient-derived stem-like cells to ionizing radiation (IR). Treatment of DIPG stem-like cells with PTC596, a BMI-1 modulator, and IR, impairs the kinetics of DNA damage response (DDR). Both DDR foci formation and resolution were delayed, resulting in further reduction in cell viability compared with either treatment alone. In vivo, treatment of mice bearing DIPG xenografts with PTC596 leads to decreased tumor volume and growth kinetics, increased in-tumor apoptosis and sustained animal survival benefit. Gene expression analysis indicates that BMI-1 expression correlates positively with DIPG stemness and BMI-1 signature. Together our findings indicate that BMI-1 modulation is associated with mitotic abnormalities, impaired DDR and cell death, supporting the combination of BMI-1 modulation and radiation as a promising novel therapy to treat children with DIPG.
EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT
Authors: Mariko DeWire, Christine Fuller, Olivia Campagne, Tong Lin, Haitao Pan, Tina Young-Pussaint, Patricia Baxter, Eugene Hwang, Andrew Bukowinski, Kathleen Dorris, Lindsey Hoffman, Angela Waanders, Matthias Karajannis, Clinton Steward, Arzu Onar-Thomas, Ira Dunkel, Maryam Fouladi
Journal: Neuro-Oncology (2020)

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.
DIPG-32. AKT SIGNALING DRIVES RESISTANCE TO ONC201 IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Evangeline R Jackson, Ryan J Duchatel, Abdul Mannan, Esther Hulleman, Angel M Carcaboso, Michelle Monje, Geoff B McCowage, Frank Alvaro, Matthew D Dun
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive, childhood brainstem cancer with a median overall survival of 10 months post diagnosis. Remarkably, 80–90% of patients harbor recurring point mutation in histone H3, which induces a lysine for methionine substitution at amino acid 27 (H3K27M) in either H3.1 (HIST1H3B ~25%) or H3.3 (H3F3A ~65%) variants. Using the blood-brain barrier (BBB) permeable DRD2 antagonist, ONC201 (in clinical trials for DIPG and H3K27M-mutant gliomas – NCT03416530), we hypothesized that DRD2 antagonism would induce TRAIL expression via indirect inhibition of AKT and ERK signaling, to drive apoptosis in both H3.1K27M and H3.3K27M patient-derived DIPG cell lines alike. For the first time, we reveal that ONC201 shows efficacy in 100% of WT-H3 and H3.1K27M mutant DIPG cell lines (n=5), compared to 50% of H3.3K27M mutant DIPGs (n=6). Investigations to identify the mechanisms of resistance to ONC201, revealed that cell lines with decreased sensitivity upregulated the PI3K/AKT/MTOR signaling axis to drive phosphorylation of AKT and increase metabolic activity. Combined administration of ONC201 and the BBB-permeable PI3K/AKT inhibitor, paxalisib (previously GDC-0084, in clinical trials for newly diagnosed DIPG – NCT03696355), showed synergistic cytotoxicity, reduced PI3K/AKT signaling and metabolic reprogramming to drive apoptosis in all DIPG cell lines tested. This combination was used to treat a 3-year-old DIPG patient, commencing 14 weeks post disease progression, completing 40 weeks of therapy prior to her passing, December 2019. These studies highlight the potential of combined administration of two safe, BBB penetrant, oral targeted therapies and supports testing under clinical trial conditions.
CTNI-77. EF-19, A POST-APPROVAL REGISTRY STUDY OF TUMOR TREATING FIELDS (TTFIELDS) IN RECURRENT GLIOBLASTOMA (rGBM)
Authors: Jay-Jiguang Zhu, Robert T O’Donnell, Samuel Goldlust, Zvi Ram
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are an anti-mitotic therapy of alternating electric fields delivered non-invasively to the tumor. In phase 3 studies leading to FDA-approvals, TTFields plus temozolomide (TMZ) significantly extended survival in newly diagnosed GBM, and achieved comparable survival to best standard of care (BSC) as monotherapy in recurrent GBM (rGBM). The EF-19 study evaluated efficacy of TTFields vs BSC in rGBM in post-approval real-life setting. METHODS This registry trial (192 rGBM patients, &amp;gt;21 yrs, KPS &amp;gt; 70) were treated with TTFields (200 kHz, &amp;gt;18h/day). Primary endpoint was overall survival (OS); secondary endpoints were OS in the per protocol (PP) population, time to treatment failure and adverse events (AEs). The registry data were compared to OS of all 117 patients in EF-11 BSC group (Stupp EJC 2012). The sample size (N=192) was based on non-inferiority log-rank test with two-sided alpha (0.05), 80% power, HR of 1.0 comparing TTFields to control with an upper one-sided 95% CI of HR &amp;lt; 1.375. RESULTS Median OS with TTFields versus EF-11 BSC was 7.4 versus 6.4 months, p=0.053; HR = 0.64 (95%CI 0.46–0.91, Cox-test P=0.012). Median OS (PP) with TTFields versus EF-11 BSC was 8.1 months versus 6.5 months; p=0.045; HR 0.65. OS was significantly higher TTFields as the 95% CI upper limit of HR was lower than the pre-defined threshold of 1.375. The overall incidence of AEs was lower with TTFields than EF-11 BSC (67% vs. 95%). The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9) versus BSC arm (1.6 months; 95% CI 1.1, 1.9); HR=0.53 (95% CI 0.41, 0.68, p&amp;lt; 0.0001). Skin AE was the most common AE in the TTFields arm. CONCLUSION The results of the EF-19 registry study confirm the effectiveness and safety of TTFields monotherapy in rGBM.