Citations

Abstract Atypical Teratoid/Rhabdoid Tumors (ATRTs) are malignant tumors of the central nervous system in children. They are almost universally characterized by genetic loss of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin Subfamily member B1 (SMARCB1) - a core subunit of the ATP-dependent SWI/SNF chromatin remodeling complex, and dysregulation of lineage restricted enhancers. Here, we show that tumor subgroup-specific upregulation of a distant member of the transforming growth factor-β (TGF-β), bone morphogenic factor (BMF) family of proteins drives insensitivity to NK-mediated cytolysis in vitro and in vivo. Mechanistically, subgroup-specific loss of chromatin occupancy by the RE1 Silencing Transcription Factor (REST) to its consensus RE1 motif, allowed deposition of enhancer-specific histone H3 lysine4 (K4) mono-methylation and histone H3K27 acetylation marks to activate an enhancer-promoter interaction. Restoration of REST binding or BET-domain inhibition resulted in a significant reduction in the enhancer marks and enhancer-promoter interaction and involved histone H3K27me3 deposition at the REST binding site, to facilitate gene silencing and sensitization of ATRTs to NK-mediated cytolysis. Thus, our study has identified a novel function for REST as a modulator of tumor-intrinsic enhancer activity and tumor-extrinsic immune microenvironment. Of equal significance, we highlight a role of REST in recruiting the polycomb repressive complex-2 (PRC2) in gene silencing in ATRTs.

Abstract Oncolytic viruses (OV) are live viruses that can selectively replicate in cancer cells. We have engineered an OV (CF33) to make it cancer-selective through the deletion of its J2R (thymidine kinase) gene. In addition, this virus has been armed with a reporter gene, human sodium iodide symporter (hNIS), to facilitate noninvasive imaging of tumors using PET. In this study, we evaluated the oncolytic properties of the virus (CF33-hNIS) in liver cancer model, and its usefulness in tumor imaging. The virus was found to efficiently kill liver cancer cells and the virus-mediated cell death exhibited characteristics of immunogenic death based on the analysis of 3 damage-associated molecular patterns: calreticulin, ATP, and high mobility group box-1. Furthermore, local or systemic administration of a single dose of the virus showed antitumor efficacy against a liver cancer xenograft model in mice and significantly increased survival of treated mice. Finally, PET scanning was performed following injection of the radioisotope I-124, for imaging of tumors, and a single dose of virus as low as 1E03 pfu, administered intra-tumorally or intravenously, allowed for PET imaging of tumors. In conclusion, CF33-hNIS is safe and effective in controlling human tumor xenografts in nude mice, and it also facilitates noninvasive imaging of tumors.

AbstractIntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research.HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.

Aim: Stent-retriever (SR) thrombectomy has demonstrated superior outcomes in patients with acute ischemic stroke compared with medical management alone, but differences among SRs remain unexplored. We conducted a Systematic Review/Meta-Analysis to compare outcomes between three SRs: EmboTrap ® , Solitaire™, and Trevo ® . Methods: We conducted a PRISMA-compliant Systematic Review among English-language studies published after 2014 in PubMed/MEDLINE that reported SRs in ≥25 patients. Functional and safety outcomes included 90-day modified Rankin scale (mRS 0-2), mortality, symptomatic intracranial hemorrhage (sICH), and embolization to new territory (ENT). Recanalization outcomes included modified thrombolysis in cerebral infarction (mTICI) and first-pass recanalization (FPR). We used a random effects Meta-Analysis to compare outcomes; subgroup and outlier-influencer analysis were performed to explore heterogeneity. Results: Fifty-one articles comprising 9,804 patients were included. EmboTrap had statistically significantly higher rates of mRS 0-2 (57.4%) compared with Trevo (50.0%, p = 0.013) and Solitaire (45.3%, p < 0.001). Compared with Solitaire (20.4%), EmboTrap (11.2%, p < 0.001) and Trevo (14.5%, p = 0.018) had statistically significantly lower mortality. Compared with Solitaire (7.7%), EmboTrap (3.9%, p = 0.028) and Trevo (4.6%, p = 0.049) had statistically significantly lower rates of sICH. There were no significant differences in ENT rates across all three devices (6.0% for EmboTrap, 5.3% for Trevo, and 7.7% for Solitaire, p = 0.518). EmboTrap had numerically higher rates of recanalization; however, no statistically significant differences were found. Conclusion: The results of our Systematic Review/Meta-Analysis suggest that EmboTrap may be associated with significantly improved functional outcomes compared with Solitaire and Trevo. EmboTrap and Trevo may be associated with significantly lower rates of sICH and mortality compared with Solitaire. No significant differences in recanalization and ENT rates were found. These conclusions are tempered by limitations of the analysis including variations in thrombectomy techniques in the field, highlighting the need for multi-arm RCT studies comparing different SR devices to confirm our findings.

AbstractObjectiveTo compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.MethodsGenotypes from the National Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers.ResultsPRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 [1.53–1.91]) compared with APOE‐ε4 carriers (1.53 [1.4–1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older.InterpretationPRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4.

AbstractBackgroundThe Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system has become the gold standard for outcomes reporting in endoscopic orbital surgery for orbital cavernous hemangiomas (OCHs). A recent systematic review demonstrated similar outcomes between OCHs and other primary benign orbital tumors (PBOTs). Therefore, we hypothesized that a simplified and more comprehensive classification system could be developed to predict surgical outcomes of other PBOTs.MethodsPatient and tumor characteristics as well as surgical outcomes from 11 international centers were recorded. All tumors were retrospectively assigned an Orbital Resection by Intranasal Technique (ORBIT) class and stratified based on surgical approach as either exclusively endoscopic or combined (endoscopic and open). Outcomes based on approach were compared using chi‐squared or Fisher's exact tests. The Cochrane‐Armitage test for trend was used to analyze outcomes by class.ResultsFindings from 110 PBOTs from 110 patients (age 49.0 ± 15.0 years, 51.9% female) were included in the analysis. Higher ORBIT class was associated with a lower likelihood of gross total resection (GTR). GTR was more likely to be achieved when an exclusively endoscopic approach was utilized (p < 0.05). Tumors resected using a combined approach tended to be larger, to present with diplopia, and to have an immediate postoperative cranial nerve palsy (p < 0.05).ConclusionEndoscopic treatment of PBOTs is an effective approach, with favorable short‐term and long‐term postoperative outcomes as well as low rate of adverse events. The ORBIT classification system is an anatomic‐based framework that effectively facilitates high‐quality outcomes reporting for all PBOTs.

Evaluate the quantitative, subjective (Deauville score [DS]) and reader agreement differences between standard ordered subset expectation maximization (OSEM) and Bayesian penalized likelihood (BPL) positron emission tomography (PET) reconstruction methods. A retrospective review of 104 F-18 fluorodeoxyglucose PET/computed tomography (CT) exams among 52 patients with diffuse large B-cell lymphoma. An unblinded radiologist moderator reviewed both BPL and OSEM PET/CT exams. Four blinded radiologists then reviewed the annotated cases to provide a visual DS for each annotated lesion. Significant (P < .001) differences in BPL and OSEM PET methods were identified with greater standard uptake value (SUV) maximum and SUV mean for BPL. The DS was altered in 25% of cases when BPL and OSEM were reviewed by the same radiologist. Interobserver DS agreement was higher for OSEM (>1 cm lesion = 0.89 and ≤1 cm lesion = 0.84) compared to BPL (>1 cm lesion = 0.85 and ≤1 cm lesion = 0.81). Among the 4 readers, average intraobserver visual DS agreement between OSEM and BPL was 0.67 for lesions >1cm and 0.4 for lesions ≤1 cm. F-18 Fluorodeoxyglucose PET/CT of diffuse large B-cell lymphoma reconstructed with BPL has higher SUV values, altered DSs and reader agreement when compared to OSEM. This report finds volumetric PET measurements such as metabolic tumor volume to be similar between BPL and OSEM PET reconstructions. Efforts such as adoption of European Association Research Ltd accreditation should be made to harmonize PET data with an aim at balancing the need for harmonization and sensitivity for lesion detection.

AbstractThe American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the US. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the US. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: Must and must not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. While must is the term to be used in the guidelines, if an entity that adopts the guideline has shall as the preferred term, the AAPM considers that must and shall have the same meaning. Should and should not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances.

BACKGROUND: Promotions in academic medicine are frequently based on number of publications and leadership positions held. While prior study has established women publish less than men, many evaluations are limited to individual specialties and do not evaluate involvement with educational activities. OBJECTIVE: To compare gender differences in academic output, intramural leadership positions, and educational leadership positions of academic physicians. METHODS: The curriculum vitae and de-identified demographic data of all permanent physicians employed at a multi-site academic medical center were reviewed from April to May 2020. Multivariable logistic and Poisson regressions evaluated leadership positions and number of publications. RESULTS: Of 3,359 physicians in the demographic database, 32.3% (n = 1,087) were women and 72.5% were white (n = 2,510). Of the 3,015 physicians in the curriculum vitae database, 32% (n = 962) were women. Women were more likely (p < 0.001) to be assistant professor (54% vs. 42.7%) and less likely to be associate (18.1% vs. 20.3%) or full professor (14.6% vs. 29.1%). Women assistant professors published 22% fewer articles (ratio estimate = 0.78, p < 0.001), associate professors 18% less (coefficient = 0.82, p < 0.001), and full professors 23% less (coefficient = 0.77, p < 0.001). Fewer women were program directors for residencies (1.6% vs. 2.9%, p = 0.02) or fellowships (5.4% vs. 7.4%, p = 0.04), and held fewer division or department leadership positions (OR 0.8, 95% CI as [0.6, 1.0], p = 0.03). CONCLUSION: Women physicians do not outperform men across any education, leadership, or publication category. A cultural shift is needed to redefine traditional metrics for leadership appointments if academic medicine hopes to achieve equity.

AbstractBackgroundMotor disturbances are common in patients with a variety of neurodegenerative and neurological syndromes, such as Parkinson’s disease and Frontotemporal Dementia (FTD). Accurately quantifying motoric changes could enable earlier detection and monitoring of these syndromes, and remote quantification may allow for more frequent assessments and may improve access to research for underrepresented and geographically dispersed participants. With these benefits in mind, investigators from the ALLFTD consortium developed smartphone tests of balance and finger tapping speed. Here we present preliminary test‐retest reliability and associations with gold standard tests.MethodThe tasks were analyzed in two independent samples. The first was an in‐person cohort of healthy older adults (n = 7), mild cognitive impairment (MCI, n = 1) and FTD (n = 3) who completed the smartphone standing/balance and finger tapping tests (FTT) twice in person. The second sample included 31 ALLFTD participants with a range of clinical presentations (healthy older adults [n = 11], FTD [n = 5], MCI [n = 2], unknown [n = 13]) who were asked to complete the balance test three times over two weeks at home. The primary outcomes were total taps for the FTT and root mean squared acceleration for the balance test. Test‐retest reliability was calculated using an intraclass correlation coefficient (ICC); given the small sample size, outliers (n = 6) were removed from the balance test. We tested the association of smartphone FTT with the gold standard mechanical FTT and the balance task with the CDR®+NACC‐FTLD‐SB (disease severity) using Spearman’s correlations. A Wilcoxon‐sign rank test compared participants with motor features on the Progressive Supranuclear Palsy Rating Scale (PSPRS>0) to those without (PSPRS = 0).ResultThe smartphone FTT showed good test‐retest reliability (ICC = 0.78) and a strong correlation (r = 0.8,p<0.05) with mechanical FTT. The test‐retest reliability for the balance task was excellent for the remote sample (ICC = 0.97) and in‐person (ICC = 0.89) samples. In the remote sample, greater acceleration was correlated with higher CDR®+NACC‐FTLD‐SB (r = 0.7,p = 0.003), and participants with motor features on the PSPRS had higher acceleration than those without (W = 11,p = 0.04).ConclusionThese findings provide preliminary support for the reliability and validity of the ALLFTD Mobile App tests of motor function. Replication in a larger sample is required.