Citations

Abstract There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder with oftentimes an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in bipolar disorder (BD). We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association with a subset of BD-I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement (response- emergent mania).

Introduction: Genome-wide association studies have identified common genetic variants associated with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and left ventricular (LV) characteristics. However, the association of these variants with myocardial fibrosis (MF), an important pathophysiological mediator of cardiomyopathy, is unknown. Hypothesis: We used the Multi-Ethnic Study of Atherosclerosis (MESA), to evaluate the association of these loci with interstitial MF measured by cardiac MRI (CMR). Methods: Unrelated MESA participants with T1-mapping CMR and no history of MI or heart failure were included (n=1,235). We used the extracellular volume (ECV) fraction as a well-established surrogate of interstitial MF. Genotyping was performed by Affymetrix Human SNP array 6.0, and imputation was performed using the TOPMED reference panel. Log ECV(%) was regressed on 50 candidate SNPs, in each ethnicity/race group, adjusting for age, sex, and population stratification principal component. The race-specific results were pooled by fixed-effect meta-analyses using METASOFT. Results: The SMARCB1 rs2186370 intronic variant, previously identified as a risk variant for DCM and HCM, was associated with ECV (p=0.0004). The rs2186370 A allele (frequency: 0.18 in Whites, and 0.50 in African Americans) was associated with a 1.6% increase in ECV. The rs2070458 A allele (another SMARCB1 intronic variant), in complete linkage disequilibrium with rs2186370, was known previously to be associated with increased LV wall thickness, mass, and concentricity. The direction of effect was similar in all four ancestry groups, but the effect was strongest in African Americans. These variants are strong expression quantitative loci (eQTLs) in human LV tissue and are associated with genotype-dependent expression of SMARCB1 ( p =7.3х10 -22 ) and MMP11 ( p =2.5х10 -24 ). Conclusions: In conclusion, variants in two linked SMARCB1 loci previously associated with HCM, DCM and LV traits, are associated with CMR-based interstitial MF. These loci are eQTL not only for SMARCB1 but also for MMP11 an important mediator of MF . These findings underscore the important link between MF and CM, and potentially provide novel mechanistic targets in understanding the development of CM.

Abstract Background: The genotoxin colibactin, produced by Escherichia coli containing the pks island, is associated with a tumor single base substitution (SBS) mutational signature SBS88. It is unknown whether lifestyle and environmental factors related to gut dysbiosis impact colorectal cancer (CRC) risk and survival differently by colibactin signature status. Methods: Utilizing the resources of the Genetic Epidemiology of Colorectal cancer Consortium and Colon Cancer Family Registry (GECCO-CCFR), a consortium including both case-control and cohort study designs, SBS88 tumor mutational signature was measured in 4308 CRC cases who were microsatellite stable (MSS) and had at least five somatic single nucleotide variants for signature decomposition. Associations of 13 lifestyle and environmental factors with CRC risk by colibactin signature status were assessed using logistic and multinomial regression; associations with CRC survival were assessed using Cox proportional hazards regression. Results: 392 (9%) of the 4308 MSS tumors were positive for SBS88. Having a BMI ≥30 kg/m2 (versus a BMI 18.5-24.9 kg/m2) was strongly associated with worse CRC-specific survival among those with the SBS88 signature, but not among those with SBS88 negative CRC [further adjusted hazard ratio (HR) = 3.40 95% confidence interval (CI) 1.47, 7.84, and HR = 0.97 95% CI 0.78, 1.21, respectively, P for heterogeneity = 0.066]. Associations of fruit intake with CRC risk may be differential by SBS88 status. In minimally adjusted models, those in the highest quartile of fruit intake (versus the first quartile) had 0.53 (95% CI 0.37, 0.76) times the risk of SBS88 positive CRC, as opposed to 0.75 (95% CI 0.66, 0.85) times the risk of SBS88 negative CRC (P for heterogeneity = 0.047). Among cohort studies specifically, associations between CRC risk and BMI, alcohol, and fruit intake also differed by SBS88 status (P for heterogeneity ranging 0.02-0.05). Conclusions: Higher BMI may be associated with worse CRC-specific survival among those with SBS88 positive tumors. BMI, alcohol, and dietary factors may be differentially associated with CRC risk based on SBS88 status. Citation Format: Claire Elizabeth Thomas, Peter Georgeson, Conghui Qu, Robert S. Steinfelder, Daniel D. Buchanan, Mark A. Jenkins, Andrea Gsur, Jane C. Figueiredo, Polly A. Newcomb, Peter T. Campbell, Christina Newton, Caroline Y. Um, Lisa Boardman, Victor Moreno, Jenny Chang-Claude, Michael Hoffmeister, Marc J. Gunter, Andrew T. Chan, Shuji Ogino, Ellen L. Goode, Brigid Lynch, Yohannes A. Melaku, Steven Gallinger, Sonja I. Berndt, Wen-Yi Huang, Ulrike Peters, Amanda I. Phipps. Lifestyle and environmental factors in relation to colorectal cancer risk and survival by colibactin tumor mutational signature status [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 6453.

9538 Background: Uveal melanoma has a poor prognosis following metastasis to the liver. Immune checkpoint inhibitors (ICIs) are often utilized in patients with metastatic uveal melanoma (MUM); however, ICIs in MUM have low response rates. We studied the association of immune infiltrates in MUM liver metastases with survival outcomes for all patients, in addition to evaluating if immune infiltrates improve survival for patients treated with ICIs. Methods: We included MUM patients with liver metastases who had pre-treatment liver biopsies available at Mayo Clinic Rochester. Demographics, disease characteristics, treatments, and clinical outcomes were obtained from the electronic medical record. Core biopsies of liver metastases were reviewed for the presence of lymphocytes at interface of the tumor and liver parenchyma, and for tumor-infiltrating lymphocytes (TILs). If TILs were present, then additional immunohistochemistry (IHC) staining was performed for CD3, CD4, CD8, PD1, CD25, and FoxP3. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with Cox proportional hazards regression. Median OS and hazard ratios (HR) were calculated and p-values (p) <0.05 were considered statistically significant. Results: 140 patients with MUM who had pre-treatment liver biopsies were identified. 122 biopsies were evaluable for the presence of lymphocytes, either at the tumor-liver interface, or for TILs. 80/122 (65.6%) biopsies showed presence of any lymphocyte and 27/80 had TILs. 27 biopsies had sufficient tissue for further IHC classification. CD8+ T cells were identified in 27/27 samples, T cell PD1 positivity ≥1% in 4/27 samples, and regulatory T cell markers (CD25 and/or FoxP3) in 18/27 samples. Median OS for the entire cohort was 16 months (mo). Patients still alive at the time of data analysis had at least one year of follow-up available (range 13-124 mo). Univariate analyses (UVA) showed no significant improvement in OS based on the presence of any lymphocytes (HR 1.01, p 0.98), lymphocytes at the tumor-liver interface (HR 1.10, p 0.64), TILs (HR 0.78, p 0.27), >50% CD8+ T cells (HR 0.88, p 0.77), or absence of FoxP3+ T cells (HR 0.68, p 0.40). In the 69 patients treated with ICIs (pembrolizumab, nivolumab, or ipilimumab plus nivolumab), neither the presence of any lymphocytes (HR 1.19, p 0.56) nor TILs (HR 0.68, p 0.24) were associated with an OS benefit. Conclusions: We present a large cohort of patients with MUM where we characterized immune infiltrates in liver metastases and evaluated clinical outcomes. OS did not significantly improve with the presence of any lymphocytes, TILs, CD8+ T cells, or with the absence of FoxP3+ T cells. These results were consistent across all patients whether they were treated with ICIs or not. Our findings suggest that lymphocytes in MUM are functionally dormant and highlights the need for novel immune-activating treatment strategies.

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.

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 Introduction Inflatable penile prosthesis (IPP) placement is associated with high postoperative patient satisfaction. Patients often express concerns about postoperative penile length. There is scant evidence in the literature of clinical and surgical factors that predict IPP length. Objective To evaluate predictors of cylinder length for men undergoing primary IPP placement in a large multicenter cohort. Methods Patients undergoing primary IPP placement for treatment of erectile dysfunction at 16 high-volume implant centers were included. All patients had preoperative demographics, surgical characteristics, and device length retrospectively collected at their respective institutions and combined for analysis. Descriptive statistics were reported for the full group. Univariate analysis was utilized to isolate variables significantly associated with device length and all variables reaching p&lt;0.1 were included in linear regression modeling. Results 3,953 men underwent primary IPP placement. The mean age was 61.8±10.4 years and BMI was 29.8±4.2 kg/m2. The mean total device length was 20.6±2.1cm. 1291 (32.7%) had diabetes mellitus, 641 (16.2%) were smokers, 705 (17.8%) had a prior radical prostatectomy, 195 (4.9%) had prior radiation, 549 (13.9%) had Peyronie’s disease, and 884 (22.4%) had a history of intracavernosal injections. In univariate analysis, BMI (B=0.05, 95%CI 0.04 to 0.07, p&lt;0.001), a history of Peyronie’s disease (20.4 vs 20.6cm, p=0.02), and use of intracavernosal injection (20.7 v 20.9cm, p=0.02) were predictors of shorter total device length. Use of rear tip extenders (20.7 v 20.0cm, p&lt;0.001), penoscrotal approach (21.0 v 20.3, p&lt;0.001), and single corporal dilation (20.8 v 20.4cm, p&lt;0.001) were associated with longer length. In multivariable analysis, a history of Peyronie’s disease (B=-0.29, 95%CI -0.47 to -0.11, p=0.002) and greater BMI (B=0.05, 95%CI 0.03 to 0.07, p&lt;0.001) were predictors of shorter total device length. Independent predictors of longer device length were penoscrotal approach (B=-0.85, 95%CI -1.03 to -0.65, p&lt;0.001), rear tip extender use (B=1.00, 95%CI 0.84 to 1.17, p&lt;0.001), and single corporal dilation (B=-0.5, 95%CI -0.67 to -0.34, p&lt;0.001). Conclusions In this series, Peyronie’s disease and greater BMI are independent predictors of shorter IPP device length, while use of rear tip extenders, single corporal dilation, and penoscrotal approach are independent predictors of longer device length. These results are important in counseling patients regarding expectations of postoperative length. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Endo Pharma, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma

Abstract Introduction Climacturia has been reported in up to 64% of patients following radical prostatectomy (RP). In 2017, a prospective multicenter, multinational, investigational pilot study was conducted examining outcomes using a novel surgical technique, the Mini-Jupette sling, for the management of men with post-RP erectile dysfunction (ED) and climacturia and/or minimal stress urinary incontinence (SUI). We sought to report the 5-year outcomes from this original cohort. Objective To assess long-term safety and efficacy of the mini-jupette sling in the treatment of ED and concomitant mild SUI and/or climacturia Methods We identified patients who were enrolled in the previous multicenter study with post-RP ED and climacturia and/or mild SUI (2 ppd) and underwent IPP insertion with simultaneous placement of a Mini-Jupette sling. Data including current ppd, improvement in climacturia, complications, need for revision of IPP or additional urinary incontinence surgery, and date of most recent follow-up were collected. Results Of the original 38 patients, 5 have since died and 10 were lost to follow-up with 23/38 (61%) patients available for evaluation of long-term outcomes. The average follow-up time was 59 months (SD= 8.8) with a mean age of 69 years (SD= 6.8). Most patients (n=21, 91%) had subjective improvement of SUI and climacturia. One patient with persistent bothersome incontinence underwent artificial urinary sphincter (AUS) placement in 2018 with no complications, while the other is still considering a repeat procedure due to minor but persistent SUI. The mean ppd decreased from 1.4 preoperatively to 0.3 at a mean 5 years of follow-up. Most patients reported satisfaction in their urinary symptoms with 91% and 73% reporting improvement in SUI and climacturia respectively, compared to 86% and 93% respectively in the original series. One (4.3%) patient had an IPP revision for pump malfunction. There were no device infections reported. Conclusions The Mini-Jupette sling appears to be a safe and effective procedure with durable improvements in SUI and climacturia at 5 years of follow-up. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus, Intuitive Surgical, Fidalis, Hims & Hers Health Inc

The global burden of paediatric and congenital heart disease (PCHD) is substantial. We propose a novel public health framework with recommendations for developing effective and safe PCHD services in low-income and middle-income countries (LMICs). This framework was created by the Global Initiative for Children’s Surgery Cardiac Surgery working group in collaboration with a group of international rexperts in providing paediatric and congenital cardiac care to patients with CHD and rheumatic heart disease (RHD) in LMICs. Effective and safe PCHD care is inaccessible to many, and there is no consensus on the best approaches to provide meaningful access in resource-limited settings, where it is often needed the most. Considering the high inequity in access to care for CHD and RHD, we aimed to create an actionable framework for health practitioners, policy makers and patients that supports treatment and prevention. It was formulated based on rigorous evaluation of available guidelines and standards of care and builds on a consensus process about the competencies needed at each step of the care continuum. We recommend a tier-based framework for PCHD care integrated within existing health systems. Each level of care is expected to meet minimum benchmarks and ensure high-quality and family centred care. We propose that cardiac surgery capabilities should only be developed at the more advanced levels on hospitals that have an established foundation of cardiology and cardiac surgery services, including screening, diagnostics, inpatient and outpatient care, postoperative care and cardiac catheterisation. This approach requires a quality control system and close collaboration between the different levels of care to facilitate the journey and care of every child with heart disease. This effort was designed to guide readers and leaders in taking action, strengthening capacity, evaluating impact, advancing policy and engaging in partnerships to guide facilities providing PCHD care in LMICs.