Citations

Abstract Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, counteracted the oncogenic effects of TP63 fusions in multiple preclinical models in vivo. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2. Citation Format: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla Heavican-Foral, Huiyun Liu, Geoffrey Nelson, Lu Yang, Renee Chen, Katherine Donovan, Marcus Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit Nirmal, Salvia Jain, Catharine Leahy, Kristen Jones, Kristen Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing Chan Chan, Shannan Ho Sui Ho Sui, Samuel Ng, Andrew Feldman, Steven M. Horwitz, Mathew Meyerson, Karen Adelman, Eric Fischer, Chun-Wei Chen, David Weinstock, Myles Brown. TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5755.

The WHO defines social determinants of health (SDoH) as the conditions in which we are born, grow, work, and live as well as other large systems that positively or negatively affect our health. Many healthcare systems currently lack the resources and strategies required to accurately assess and address SDoH. Action must be taken because studies have found that chronic diseases, including cancer, are affected by SDoH. The aim of this study is to identify the incidence of social needs in an inpatient gynecologic oncology population and its relation to patient demographics and clinical diagnostic data to guide and inform future intervention. Patients agreeing to participate in the study completed a needs assessment survey during their inpatient stay at the hospital between November 2020 to March 2021. The survey contained seven questions, six of which were questions screening for social needs including food and housing security, transportation means, financial stability, health literacy, and social support. Responses were considered positive if any degree of need was reported. Demographic and cancer diagnosis data were then collected and included zip code, race, cancer stage and age at diagnosis, treatment history, and number of hospital admissions and length of stay over the past 12 months. The most substantial reported needs across all gynecologic malignancies were social support (65%), health literacy (37%), and financial need (22%). Less need was reported in the categories of food (11%), housing (7%), and transportation (4%). SDoH have been studied in the outpatient gynecologic population and the needs seen in this study are similar to the needs of that population. However, there are likely different challenges and frequencies of unmet need in the different types of gynecologic cancers that may affect the stage at which their cancer is diagnosed as well as the number of hospital admissions related to their cancer care.

Abstract Objective Flares of autoimmune rheumatic diseases (AIRDs) following COVID-19 vaccination are a particular concern in vaccine-hesitant individuals. Therefore, we investigated the incidence, predictors and patterns of flares following vaccination in individuals living with AIRDs, using global COVID-19 Vaccination in Autoimmune Diseases (COVAD) surveys. Methods The COVAD surveys were used to extract data on flare demographics, comorbidities, COVID-19 history, and vaccination details for patients with AIRDs. Flares following vaccination were identified as patient-reported (a), increased immunosuppression (b), clinical exacerbations (c) and worsening of PROMIS scores (d). We studied flare characteristics and used regression models to differentiate flares among various AIRDs. Results Of 15 165 total responses, the incidence of flares in 3453 patients with AIRDs was 11.3%, 14.8%, 9.5% and 26.7% by definitions a–d, respectively. There was moderate agreement between patient-reported and immunosuppression-defined flares (K = 0.403, P = 0.022). Arthritis (61.6%) and fatigue (58.8%) were the most commonly reported symptoms. Self-reported flares were associated with higher comorbidities (P = 0.013), mental health disorders (MHDs) (P < 0.001) and autoimmune disease multimorbidity (AIDm) (P < 0.001). In regression analysis, the presence of AIDm [odds ratio (OR) = 1.4; 95% CI: 1.1, 1.7; P = 0.003), or a MHD (OR = 1.7; 95% CI: 1.1, 2.6; P = 0.007), or being a Moderna vaccine recipient (OR = 1.5; 95% CI: 1.09, 2.2; P = 0.014) were predictors of flares. Use of MMF (OR = 0.5; 95% CI: 0.3, 0.8; P = 0.009) and glucocorticoids (OR = 0.6; 95% CI: 0.5, 0.8; P = 0.003) were protective. A higher frequency of patients with AIRDs reported overall active disease post-vaccination compared with before vaccination (OR = 1.3; 95% CI: 1.1, 1.5; P < 0.001). Conclusion Flares occur in nearly 1 in 10 individuals with AIRDs after COVID vaccination; people with comorbidities (especially AIDm), MHDs and those receiving the Moderna vaccine are particularly vulnerable. Future avenues include exploring flare profiles and optimizing vaccine strategies for this group.

Background: Residual fragments (RFs) after percutaneous nephrolithotomy (PCNL) have a significant impact on patients' quality of life and clinical course. There is a paucity of studies that evaluate the natural history of RFs after PCNL. The objective of this study is to compare rates of reintervention, complications, stone growth, and passage in patients with RFs >4, ≤4, and ≤2 mm after PCNL. Methods: Sites from the Endourologic Disease Group for Excellence (EDGE) research consortium examined data of PCNL patients from 2015 to 2019 with at least 1-year follow-up. RF passage, regrowth, reintervention, and complications were recorded and RFs were stratified into >4 and ≤4 mm groups, as well as >2 and ≤2 mm groups. Potential predictors for stone-related events after PCNL were determined using multivariable logistic regression analysis. It was hypothesized that larger RF thresholds would result in lower passage rates, faster regrowth, and greater clinically significant events (complications and reinterventions) than smaller RF thresholds. Results: A total of 439 patients with RFs >1 mm on CT postoperative day 1 were included in this study. For RFs >4 mm, rates of reintervention were found to be significantly higher and Kaplan–Meier curve analysis showed significantly higher rates of stone-related events. Passage and RF regrowth were not found to be significantly different compared with RFs ≤4 mm. However, RFs ≤2 mm had significantly higher rates of passage, and significantly lower rates of fragment regrowth (>1 mm), complications, and reintervention compared with RFs >2 mm. On multivariable analysis, older age, body mass index, and RF size were found to be predictive of stone-related events. Conclusions: With the largest cohort to date, this study by the EDGE research consortium further confirms that clinically insignificant residual fragment is problematic for patients after PCNL, particularly in older more obese patients with larger RFs. Our study underscores the importance of complete stone clearance post-PCNL and challenges the use of Clinically insignificant residual fragment (CIFR).

Objective: The purpose of this feasibility pilot study was to evaluate safety and adherence of a wearable brain sensing wellness device designed to reduce stress among healthcare professionals (HCP). Methods: A total of 40 HCP were invited to participate in an open-label pilot study. Participants were asked to use a brain sensing wearable device (MUSE-S™) on a daily basis to reduce their stress, for a total of 90 days. Total study participation duration was 180 days. Study enrollment began in August 2021 and ended December 2021. The exploratory outcomes included stress, depression, sleep, burn-out, resilience, quality of life, and cognition. Results: Among the 40 HCP in study, the majority were female (85%), white (87.5%) and with an average age of 41.3 ± 11.0 years (SD). Participants used the wearable device an average of 23.8 times over a 30-day period with a mean duration of 5.8 min with each use. Study results demonstrate the positive impact of guided mindfulness using the wearable device MUSE-S™ and its accompanying application (APP). A statistically significant improvement was found for a reduction in stress ( P < .001) and improvement in resilience ( P = .02), quality of life ( P = .003), and cognition ( P < .001). The majority (91.9%) of the participants indicated they felt more relaxed after using the device, and 73% indicated they would continue to use this device at end-of-study. No adverse effects were reported. Conclusion: Study results show that 3 to 10 min of guided meditation during work hours through the use of a brain sensing wearable device is safe and acceptable, with associated health benefits for HCP.

AbstractObjectivesIn this study we aimed to describe and compare groups formed by a rules‐based algorithm to prospectively identify clients at risk of poor outcomes in order to guide tailored public health nursing (PHN) intervention approaches.DesignData‐driven methods using standardized Omaha System PHN documentation.SampleClients ages 13–40 who received PHN home visiting services for both the Caretaking/parenting and Mental health problems (N = 4109).MeasurementWe applied a theory‐based algorithm consisting of six rules using existing Omaha System data. We examined the groups formed by the algorithm using standard descriptive, inferential statistics, and Latent Class Analysis.ResultsClients (N = 4109) were 25.1 (SD = 5.9) years old and had an average of 7.3 (SD = 3.2) problems, 250 (SD = 319) total interventions, and 32 (SD = 44) Mental health interventions. Overall outcomes improved after PHN interventions (p < .001 for all) and having more Mental health signs/symptoms was negatively associated with outcome scores (p < .001 for all).ConclusionsThis algorithm may be helpful in identifying high‐risk clients during a baseline assessment who may benefit from more intensive mental health interventions. Findings show there is value using the Omaha System for PHN documentation and algorithm clinical decision support development. Future research should focus on algorithm implementation in PHN clinical practice.

Introduction/Objectives: A culture of joy in the workplace supports well-being, but less is known about the effect of a shared experience on well-being and burnout in a health care setting. This pilot study investigated personal well-being and occupational burnout among primary care staff who participated in a 3-month virtual book club. Methods: In December 2021, health care workers from a primary care practice were invited to participate in a 3-month virtual book club. Participants were emailed a preintervention survey with questions regarding well-being and burnout, the pandemic’s influence on emotional health, and demographic information. The book club met virtually every month from January 2022 through March 2022. After the March 2022 book club meeting, a paired postintervention survey was sent to participants with additional questions regarding their participation in the book club. Well-being and burnout were measured with the 11-point Well-Being Index, and the pandemic’s influence on emotional health was assessed with the 64-point Pandemic Emotional Impact Scale. Results: Of 12 book club participants, 9 participants (6 physicians and 3 nurses) completed surveys before and after the intervention. Postintervention improvement in the median score of the Pandemic Emotional Impact Scale was significant (7 points, P = .04). Although Well-Being Index results uniformly favored improved well-being after book club participation, the median improvement of 1 point was not significant ( P = .69). Conclusions: Social connection through a virtual workplace activity such as a book club may contribute to well-being and may decrease occupational burnout.