Citations

Introduction: Bicuspid Aortic Valve (BAV), the most common adult congenital heart defect, is a major cause of aortic insufficiency or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications to sporadic late onset disease. We determined the frequency and gene content of rare genomic copy number variants (CNVs) in isolated BAV cases. Methods: We performed genome-wide SNP microarray analysis of familial BAV cases with early onset complications in the UTHealth BAV Research Registry (EBAV, n=394) and elderly probands from the International BAV Consortium (BAVCON, n=4216). CNVs were detected in Illumina genotypes using the PennCNV, QuantiSNP and cnvPartition algorithms. BAV cases were compared to 16,576 controls without known cardiovascular disease from the Database of Genotypes and Phenotypes. Only CNV calls with >6 consecutive variants, >20 kb in length, identified by at least two algorithms and intersected with known genes were included. For comparison, we assessed a cohort with left ventricular outflow tract obstructive lesions including BAV (LVOTO, n=1561) using identical methods. CNV burden and associations were tested using PLINK. Results: We identified 84 large recurrent CNVs in BAV cases that are absent or rare (<0.1%) in controls. 34 rare CNVs overlap between BAV and LVOTO cases and involve candidate genes that interact with each other during heart development. The largest and most prevalent of the recurrent CNVs are 8p23 duplications involving GATA4 (OR 340, CI: 42-2700). CNVs of genes that cause BAV when mutated were significantly enriched in cases (n=135, P =1x10 -27 ). The overall burden of rare genic CNVs, specifically large deletions, was also increased in BAV cases (empiric P < 1x10 -5 ) and was higher in younger EBAV cases than in older BAVCON cases. Conclusion: We identified likely pathogenic CNVs in more than 10% of BAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

Background: Aesthetic soft-tissue filler injections for lip enhancement are popular and performed throughout the world. When injecting lips with a cannula, as the cannula is advanced, resistance is perceived in consistent locations, potentially indicating boundaries between intralabial compartments. Objective: We aimed to investigate whether intralabial compartments exist and, if so, to describe their volumes, location, boundaries, and dimensions. Methods: This cadaveric study investigated a total of 20 human body donors (13 male, seven female) with a mean (SD) age at death of 61.9 years (23.9) and body mass index of 24.3 kg/m2 (3.7). The investigated cohort included 11 White donors, eight Asian donors, and one Black donor. Dye injections simulating minimally invasive lip treatments were conducted. Results: Independent of sex or race, six anterior and six posterior compartments in the upper and lower lip were identified, for a total of 24 lip compartments. Compartment boundaries were formed by vertically oriented septations that were found in consistent locations. The anterior compartments had volumes ranging from 0.30 to 0.39 cc; the posterior compartment volume ranged from 0.44 to 0.52 cc. The compartment volumes were larger centrally and decreased gradually toward the oral commissure. Conclusions: The volume and size of each of 24 compartments contribute to the overall appearance and shape of the lips. To achieve a natural lip shape preserving aesthetic outcome it may be preferable to administer the volumizing product using a compartment-respecting injection approach.

e20005 Background: iAEs such as cytokine release syndrome (CRS) and neurotoxicity (NT) are common with CAR T cell therapies such as ide-cel; CRS and NT observed with ide-cel are generally low grade and manageable with tocilizumab (toci) and corticosteroids. Identifying iAE risk with sensitivity and specificity is challenging, suggesting multifactorial etiology and limitations evaluating dynamic processes at specific timepoints. Macrophage activation syndrome (MAS; per CTCAE) has a specific molecular profile representing a homogeneous subgroup within CRS, tending to be more severe/refractory to front-line management. Using longitudinal data on post-infusion soluble factors we aimed to develop a candidate post-infusion inflammatory risk score based on MAS molecular signature and determine associations with pt baseline characteristics. Methods: Statistical learning tools were applied to the longitudinal profile of 34 factors measured over 28 d after ide-cel infusion in 291 pts from KarMMa (NCT03361748) and KarMMa-2 (NCT03601078) to extract features describing the profiles. Unsupervised machine learning-based clustering was applied to these features and enrichment for MAS cases within each cluster was assessed. A metric describing membership in a cluster of interest was used as a candidate post-infusion inflammatory risk score for further correlative analyses. Results: Pts with MAS had cytokine profiles consistent with high levels of pro-inflammatory signalling across multiple inflammatory cell types. Cytokine profiles of MAS were qualitatively similar to those of CRS/NT; however, unsupervised clustering showed a distinct group of pts with MAS. A metric of similarity to the MAS-enriched cluster was defined as a candidate post-infusion inflammatory risk score, posited to identify pts more likely to have more severe/refractory iAEs. This inflammatory risk score positively correlated with CRS and NT grades and frequency of toci usage (Kruskal-Wallis test; all P < 0.001). A prototype predictive model based on baseline pt and clinical characteristics strongly correlated with post-infusion inflammatory risk score (Pearson; ρ = 0.88). Low blood counts, higher tumor burden, and elevated levels of inflammatory markers on the day of ide-cel infusion were associated with a higher inflammatory risk score. Conclusions: A molecular profile of severe/refractory iAEs was preliminarily identified in ide-cel treated pts with MM. This profile enabled derivation of a candidate post-infusion inflammatory risk score and a prototype predictive model of this risk score based on pt baseline characteristics was developed. These results may help identify pts at risk for severe/refractory iAEs, who may be potential candidates for closer monitoring or novel interventions, and warrant further study. Clinical trial information: NCT03361748 , NCT03601078 .

e20646 Background: Thymic carcinomas tend to be aggressive malignancies with variable patterns of immunostaining. We aimed to assess whether the outcome of patients with thymic carcinomas was associated with immunoreactivity for conventional and emerging immunohistochemical markers of thymic carcinoma versus thymoma. Methods: Scoring of CD5, CD117, EZH2, POU2F3, BAP1, and MTAP immunohistochemistry on whole slide sections was compared to overall survival (OS) and progression free survival (PFS) for 36 thymic carcinoma patients, 28 of whom had complete tumor resection and 8 of whom had incomplete tumor resection. Results: Positive CD5 staining (defined as staining in ≥50% of tumor cells) was present in 13/36 cases (36%) and was significantly associated with longer OS (P = 0.005, hazard ratio = 0.18, CI 0.03-0.63) but not PFS (P = 0.14, hazard ratio = 0.48, CI 0.16-1.26), whereas the other markers were not significantly associated with OS or PFS. Positive CD5 staining remained significantly associated with OS in squamous cell carcinoma subgroup analysis (n = 23, HR = 0.17, CI 0.03-0.65, P = 0.009), patients who did not receive neo-adjuvant treatment (n = 24, HR = 0.21, CI 0.03-0.85, P = 0.03) and after adjusting for incomplete resection (HR = 0.20, CI0.03-0.73, P = 0.01), M1 stage (HR = 0.19, CI 0.03-0.71, P = 0.01) or neoadjuvant treatment (HR = 0.19, CI 0.03-0.71, P = 0.01) in bivariate models. Positive CD5 staining was also significantly associated with age ≥60 years, absence of neoadjuvant treatment, and positive POU2F3 staining. Conclusions: CD5 staining in ≥50% of tumor cells was significantly associated with longer OS for thymic carcinoma patients. Our study supports the notion that CD5 immunohistochemistry may have utility as a prognostic marker for thymic carcinomas.

6520 Background: Increased patient engagement in decision making may mitigate disparities in breast cancer surgical care. Socioeconomically disadvantaged patients disproportionately experience barriers to engagement. Decision aids (DA) increase engagement by providing information, establishing role expectations during the consult, and increasing confidence in surgeon interactions. The objective was to test the effectiveness of a surgical web-based DA in increasing engagement among breast cancer patients in clinics that care for a high proportion of socioeconomically disadvantaged patients. Methods: A stepped wedge trial was conducted with 10 NCI Community Oncology Research Program clinics (Alliance for Clinical Trials in Oncology Research Base, 6/19-12/21). Clinics were randomized to time of transition from usual care (UC) to delivery of a web-based DA. Patients with stage 0-3 breast cancer eligible for surgery provided consent prior to a surgical consult. Socioeconomic disadvantage was assessed with the Area Deprivation Index measured at the zip+4 level and dichotomized. Patient engagement was measured by Patient’s Self-Efficacy in Patient-Physician Interactions (PEPPI-5, follow-up survey) and count of Active Patient Behaviors (Street protocol, audio recorded consult). Intervention effects were tested with linear mixed-effects models, accounting for surgeon and clinic-level clustering, time, and enrollment post-COVID. Heterogeneity of treatment effect by socioeconomic disadvantage was assessed with an interaction term. Results: 573 patients enrolled. 44% (136/309) reviewed the DA. No significant difference in engagement was observed comparing DA and UC for PEPPI-5 (-0.80 [95% CI -2.13, 0.54], p = 0.24) or Active Patient Behaviors (2.52 [CI -4.11, 9.15], p = 0.46). Enrollment post-COVID was associated with increased Active Patient Behaviors (9.59 [CI 1.76, 17.43], p = 0.02) but no change in PEPPI-5 (-1.31 [CI -2.88, 0.26], p = 0.10). No heterogeneity of treatment effect was observed. Conclusions: In this trial conducted in clinics that serve diverse populations, no significant relationship was observed between a web-based DA and patient engagement. Conducting this stepped wedge trial during the pandemic was challenging. Future analyses will explore the impact of COVID on outcomes and effect of the decision aid for patients who reviewed it. UG1 CA189823; AHRQ R01HS025194; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03766009 . [Table: see text]

Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Abstract Background Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. Methods Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. Results Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. Conclusions BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Abstract Introduction Epilepsy is frequently encountered in the pediatric population and some patients are treated by stimulation of the vagus nerve to reduce their seizure frequency. Vagus nerve stimulation (VNS) may induce central sleep apnea. Adaptive servo ventilation is a known treatment option for central sleep apnea in certain adult patients with heart failure and Cheyne-Stokes respiration but is infrequently utilized in the pediatric population. Report of case(s) A 17-year-old male with a history of intractable generalized epilepsy, VNS placement, obstructive sleep apnea (OSA) and central sleep apnea (CSA) presented to our tertiary care center for management of his sleep disordered breathing. Initial management of sleep disordered breathing included CPAP for OSA. After VNS placement, the patient began to have a high residual apnea-hypopnea index on data card download of his CPAP. Polysomnography (PSG) was performed on CPAP and CSA events were noted that correlated with VNS firing. BiPAP was titrated and was unsuccessful in treating the CSA. VNS adjustment did not impact the sleep disordered breathing. Repeat titration with adaptive servo ventilation successfully treated the OSA and CSA. In follow up, the patient is tolerating ASV with improvement in his nocturnal sleep disordered breathing events and his daytime functioning. Conclusion Central sleep apnea can be induced by vagus nerve stimulation. This unique case documents successful treatment of vagus nerve stimulation induced central sleep apnea by adaptive servo ventilation in an adolescent patient. Support (if any)