Citations

Background: TITIN truncational variants (TTNtv) is the predominant genetic factor for dilated cardiomyopathy (DCM). Therapeutic development for TTNtv DCM has been confounded by allelic heterogeneity (AH), i.e. while truncations in the C-terminal A-domain (TTNtv-As) are pathogenic, truncations in the N-terminal Z-disc domain (TTNtv-Zs) are largely benign. Molecular mechanisms underlying AH remain elusive, partially because of the lack of an in vivo animal model. Objective: We enquire whether zebrafish is a faithful vertebrate model for deciphering AH in TTNtv DCM and for therapeutic development. Methods and Results: Through comparing phenotypes among a series of ttntv -As and ttntv -Zs in adult zebrafish, we detected DCM-like phenotypes only in ttntv -As but not ttntv -Zs. Similar to human TTNtv DCM and corresponding rodent models, zebrafish ttntv -As manifest decreased ejection fraction, enlarged heart size, myofibril dys-organization, compromised exercise capacity, and dysregulated autophagy. Moreover, we noted exaggerated cardiac senescence at the later stage of the pathogenesis of ttntv DCM. Because AH in autophagy dysregulation was also detected in homozygous ttntv-A zebrafish embryos, we screened autophagy genes and identified ulk1 inhibition that is able to repair the dysregulated autophagy. A similar repairing effect of ulk1 inhibition on dysregulated autophagy was noted in an adult heterozygous ttntv-A model, which is sufficient to attenuate the cardiac senescence and improve cardiac function. Conclusion: Our data suggested adult zebrafish as the first vertebrate model that is able to recapitulate AH in TTNtv DCM patients. Conserved phenotypes including autophagy dysregulation are recapitulated in this lower vertebrate model, while cardiac senescence has been suggested as a novel pathological event. Genetic studies in this animal strongly suggest that repairing autophagy dysregulation is a therapeutic avenue for TTNtv DCM, and identified ulk1 as a candidate therapeutic target gene.

6559 Background: Recent findings that Black and Hispanic patients were significantly underrepresented in industry-sponsored prostate cancer trials warrant a detailed investigation across cancer types to assess the association between funding source and enrollment disparities. Methods: Phase II/III clinical trials in prostate, breast, colorectal, and lung cancers reporting age, gender, race/ethnicity, and reporting NIH or industry as the funding source were considered eligible for inclusion. For age, and gender analysis, all trials were considered eligible. For race/ethnicity analysis, trials recruiting from the United States (US) were considered eligible. Enrollment-incidence ratios (EIR) comparing trial proportion from age/gender or racial/ethnic subgroups against global cancer incidence in the corresponding group (from Global Burden of Disease) or US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 22), were computed. Trial-level EIRs were pooled using a random-effects model and subsequently stratified by funding source. A univariate meta-regression was conducted to assess the temporal changes in EIR by each funding category. Results: Of 42,390 studies initially identified, 2234 trials (1989-2021) met the eligibility criteria. Regarding age, 361 (16%) trials reported age categories by 65 years threshold. Of 698 trials recruiting from the US, 498 (71%) reported race, and 198 (28%) reported ethnicity. Regarding representation, older adults were under-represented (EIR: 0.66; 95% CI: 0.62-0.70) in the industry but not in NIH-sponsored clinical trials (0.79; 0.62-1.00). Regarding gender, no significant disparity was observed regarding the enrollment of men and women in colorectal and lung cancer clinical trials. In terms of race, there was a greater under-representation of Black patients in industry sponsored trials (0.29; 0.26-0.32) as compared to NIH-sponsored clinical trials (0.65; 0.57-0.74) [Pint <0.01]. Asian patients were significantly overrepresented in industry sponsored trials (3.17; 2.69-3.74) but not in NIH sponsored clinical trials (1.43; 0.85-2.41) [Pint <0.01]. Hispanic patients were significantly under-represented in both, industry (0.27; 0.22-0.34) and NIH-sponsored clinical trials (0.35; 0.22-0.55) [Pint 0.32]. Secondary analyses including trials recruiting exclusively from the US, and analyses by specific cancer types showed consistent results. Recruitment of older adults, men, and Black patients is decreasing over time. Conclusions: There is a consistent under-representation of older adults in industry-sponsored, and of Black and Hispanic patients in both industry-sponsored and NIH-sponsored clinical trials. The under-representation of Black patients is likely to be greater in industry-sponsored trials, which has worsened over the last three decades.

6557 Background: Trials that inadequately include underrepresented minority (URM) populations widen inequities in cancer care. We assessed reporting patterns, representation, and trends of URM representation in breast cancer (BC) trials. Methods: We analyzed all phase 2/3 trials for age disparity and trials recruiting from the US for racial/ethnic disparity amongst BC RCTs (1990-2021). Enrollment-incidence ratios (EIR), which compare trial proportions (TP) from age subgroups against global estimates of incidence in the corresponding age group (from Global Burden of Disease) and racial/ethnic subgroups against US-population-based incidence in the corresponding racial/ethnic group (from SEER 22), were calculated. Individual-trial EIRs were pooled using random-effects meta-analyses. EIRs of <0.80 indicated meaningful underrepresentation, while EIRs >1.20 indicated meaningful overrepresentation. Meta-regression was used to explore associations between key trial characteristics and EIR, and trends in EIR over the last three decades. Results: Of 842 global trials with 490,657 participants, 232 (27.6%) reported the number of participants in specific age strata and 144 (17.1%) reported outcomes by age. Only 60 trials recruited exclusively from the US. Of these, 41 (68.3%) reported race and 24 (40.0%) reported ethnicity, and 2 (3.3%) analyzed outcomes by race. Older adults aged ≥65 years (TP: 24.3%; EIR: 0.53 [95% CI: 0.47-0.60]) and Hispanic women (TP: 5.3%; 0.54; 0.40-0.75) were underrepresented across global trials and US-only trials respectively. Black women were significantly underrepresented in trials that led to FDA approval (0.38; 0.25-0.58) but not in US-only trials. Stratified analysis by BC subtype (with subtype-specific population incidence) showed underrepresentation of Black women in US-only trials for HER2+ BC (0.66; 0.47-0.93), Hispanic women in ER+ BC (0.42; 0.20-0.90), Asians in triple-negative BC (0.24; 0.11-0.53), and older women in HER2+ BC (0.35; 0.31-0.40) and triple-negative BC (0.36; 0.29-0.45). From 1990-2021, the representation of older women declined significantly (meta-regression coefficient for EIR: -0.4 per 10 years), while Black and Hispanic representation showed no significant change. Black (p = 0.02) and Hispanic representation (p = 0.05) worsened significantly in larger trials. Conclusions: Published reports of BC trials do not consistently report the inclusion of URM. Older and Hispanic women were consistently underrepresented, whereas Black women were underrepresented in large, practice-changing trials. [Table: see text]

(1) Background: COVID-19 caused the worst international public health crisis, accompanied by major global economic downturns and mass-scale job losses, which impacted the psychosocial wellbeing of the worldwide population, including Saudi Arabia. Evidence of the high-risk groups impacted by the pandemic has been non-existent in Saudi Arabia. Therefore, this study examined factors associated with psychosocial distress, fear of COVID-19 and coping strategies among the general population in Saudi Arabia. (2) Methods: A cross-sectional study was conducted in healthcare and community settings in the Saudi Arabia using an anonymous online questionnaire. The Kessler Psychological Distress Scale (K-10), Fear of COVID-19 Scale (FCV-19S) and Brief Resilient Coping Scale (BRCS) were used to assess psychological distress, fear and coping strategies, respectively. Multivariate logistic regressions were used, and an Adjusted Odds Ratio (AOR) with 95% Confidence Intervals (CIs) was reported. (3) Results: Among 803 participants, 70% (n = 556) were females, and the median age was 27 years; 35% (n = 278) were frontline or essential service workers; and 24% (n = 195) reported comorbid conditions including mental health illness. Of the respondents, 175 (21.8%) and 207 (25.8%) reported high and very high psychological distress, respectively. Factors associated with moderate to high levels of psychological distress were: youth, females, non-Saudi nationals, those experiencing a change in employment or a negative financial impact, having comorbidities, and current smoking. A high level of fear was reported by 89 participants (11.1%), and this was associated with being ex-smokers (3.72, 1.14–12.14, 0.029) and changes in employment (3.42, 1.91–6.11, 0.000). A high resilience was reported by 115 participants (14.3%), and 333 participants (41.5%) had medium resilience. Financial impact and contact with known/suspected cases (1.63, 1.12–2.38, 0.011) were associated with low, medium, to high resilient coping. (4) Conclusions: People in Saudi Arabia were at a higher risk of psychosocial distress along with medium-high resilience during the COVID-19 pandemic, warranting urgent attention from healthcare providers and policymakers to provide specific mental health support strategies for their current wellbeing and to avoid a post-pandemic mental health crisis.

Abstract Background Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. Methods This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. Results Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P &lt; .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P &lt; .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P &lt; .001). Conclusions Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

694 Background: The treatment landscape of localized renal cell carcinoma (RCC) is rapidly evolving. Recent trials have demonstrated contrasting efficacy with adjuvant immunotherapy. Therefore, we sought to assess the mixed treatment comparisons among different adjuvant treatment options using updated data from trials and quantified the absolute effect with these treatments stratified by risk categories. Methods: This living network meta-analysis was conducted using the living interactive evidence (LIvE) synthesis framework. We used stratified baseline risks of disease progression from observational data and at 5, 10, 15 years from the Leibovich risk stratification system (based on risk scores ranging from 0 to ≥15). Corresponding intervention risks were then approximated using relative effect estimates (from NMA) and baseline risks. The difference between CIRs and baseline risks were calculated to present absolute risk differences in each risk category. Results: This NMA included eight RCTs with 8480 participants and seven unique treatment options. Pembrolizumab (pembro; rank 1) was associated with improved disease-free survival (DFS) when compared to atezolizumab (atezo; rank 6; hazard ratio: 0.68; 0.49;0.93), and nivolumab-ipilimumab (nivoipi; rank 5; 0.68; 0.48-0.97). However, no statistically significant difference was observed between pembro and atezo for overall survival (0.53; 0.28-1.01). Survival data for nivoIpi was not reported. No new statistically significant differences were observed since last update. The absolute benefit of atezo and nivoipi was minimal with higher T and N patients (Table). The results were similar with increasing Leibovich risk scores. Conclusions: Current evidence favors the use of a risk adapted approach when offering adjuvant immunotherapy. Adjuvant pembrolizumab remains a preferred treatment in patients with RCC who underwent nephrectomy. [Table: see text]

40 Background: Previously we have reported enrollment disparities in PCa clinical trials. Funding source can influence minority representation in clinical trials. Hence, we aimed to evaluate the impact of source of funding on enrollment disparities in PCa clinical trials. Methods: MEDLINE and EMBASE were searched to identify phase II/III PCa trials. All relevant trials reporting age by 65 years were considered eligible for inclusion. Trials recruiting from the United States (US) were considered eligible for analysis by race and ethnicity. The trial proportions of age, or racial/ethnic subgroup category and the global incidence in the corresponding age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database) were used to compute enrollment incidence ratio (EIR) at each trial. EIRs with corresponding 95% confidence intervals (CI) were then meta-analyzed using a random-effects model and stratified by sources of funding (industry, US-government, and others [academic and non-US govt]). A univariate meta-regression was conducted to assess the temporal changes in EIR by each funding category. Results: Of 127 trials recruiting from the US, 89 (70%) reported race, and 35 (27%) reported ethnicity. Among those, 57 (64%), 14 (16%), and 18 (20%) trials reported industry, US-government, and other sources of funding, respectively. Of those reporting ethnicity, 23 (66%), 4 (11%), and 8 (23%) trials reported industry, US-government, and other sources of funding, respectively. Among the 287 eligible trials, 49 trials (17%) reported age by 65 years. Of those, 36 (73%), 6 (12%), and 7 (13%) reported industry, US-government, and other sources of funding, respectively. In terms of racial/ethnic enrollment, Black patients were significantly under-represented in industry funded trials (0.33; 0.27-0.41). No significant disparity was observed in US-government funded trials (0.75: 0.57-1.00). The P-value of interaction was <0.0001. Hispanics were significantly under-represented in industry funded clinical trials (0.56; 0.43-0.74). The number of US-government funded trials reporting Hispanics were small (<10) which precluded any meaningful statistics. No significant disparity was observed in terms of older adults (EIR: 1.00; 95% CI: 0.95; 1.05) overall and by funding sources. Black patients’ representation in industry funded PCa trials has significantly decreased over the last three decades. No significant change was observed in US-government funded PCa trials over the last three decades (P:0.004). Conclusions: Black and Hispanic men with PCa are likely to be under-represented in industry sponsored clinical trials. Black patients’ representation in industry sponsored trials has declined over time, thus widening the cancer-care inequities in these patients.

116 Background: The impact of socioeconomic status on genitourinary (GU) cancer mortality in the United States (US) is unclear. Hence, we evaluated the association of the socioeconomic status with GU cancer mortality across the US counties. Methods: County-level age-adjusted mortality rates (AAMR) per 100,000 person-years (PY) for populations diagnosed with GU cancers were abstracted from the wide-ranging online data for epidemiological research (WONDER) database. The agency for toxic substances and disease registry (ATSDR) was queried to obtain county-level social vulnerability indices from 2014-2018. Percentile ranking scores (PRS: ranging from 0-1) were computed for each US county and further categorized into quartiles (Q: 1st: 0-0.25 [least vulnerable]; 4th: 0.75-1.00 [most vulnerable]). AAMRs were then linked with quartile rankings. A population-weighted, Poisson regression analysis was conducted to compute rate ratios (RR) of AAMRs between 4th and 1st Q with the corresponding 95% confidence intervals (CI). Results: A total 3142 US counties were included in this analysis. The AAMR for GU cancers was 22.6 overall deaths (OD) and 4.20 premature deaths (PD; defined as death at age <65 years) per 100,000 PY. GU cancer-related mortality increased in a stepwise fashion from the 1st Q to the 4th Q (OD: 21.6 vs 24.1; PD: 3.48 vs 5.19). In terms of OD by specific GU cancers, significantly higher AAMRs were observed in the 4th Q compared to the 1st Q for patients with prostate cancer (RR; 1.19 [95% CI;1.14-1.24]), and renal cell carcinoma (RCC; 1.12 [1.04-1.21]) but not for those with lower urothelial tract cancers (0.92 [0.87-0.96]). Among subgroups, non-Hispanic Blacks (1.19 [1.07-1.33]), and Hispanics (1.28 [1.08-1.51]) with prostate cancer and men with RCC (1.11; 1.03-1.19) in the 4th Q experienced significantly higher overall mortality when compared to those in the 1st Q. With regards to PD, significantly higher AAMRs were observed in the 4th Q vs 1st Q for patients with prostate cancer (1.54 [1.34-1.77]), and RCC (1.28 [1.12-1.45]). Consistently, men with RCC in the 4th Q also experienced higher premature mortality when compared to the 1st Q. Sparsity of mortality data among different ethnic/racial subgroups across the US counties precluded any formal assessment of disparity by specific GU cancers. A sensitivity analysis, conducted using the weighted linear regression approach, showed consistent results. Conclusions: Population level data suggest that socially vulnerable populations, especially Non-Hispanic Black and Hispanic men with prostate cancer, and men with renal cell carcinoma may be at an increased risk of cancer-related mortality. Hence, there is a dire need to address this mortality gap across different socioeconomic subgroups to ensure health-care equity. Investigations at the patient level are required to further ascertain these findings.