Citations

AbstractIntroductionPrior consensus meetings have addressed the relationship between phosphodiesterase type 5 (PDE5) inhibition and cardiac health. Given significant accumulation of new data in the past decade, a fourth consensus conference on this topic was convened in Pasadena, California, on March 10 and 11, 2023.ObjectivesOur meeting aimed to update existing knowledge, assess current guidelines, and make recommendations for future research and practice in this area.MethodsAn expert panel reviewed existing research and clinical practice guidelines.ResultsKey findings and clinical recommendations are the following: First, erectile dysfunction (ED) is a risk marker and enhancer for cardiovascular (CV) disease. For men with ED and intermediate levels of CV risk, coronary artery calcium (CAC) computed tomography should be considered in addition to previous management algorithms. Second, sexual activity is generally safe for men with ED, although stress testing should still be considered for men with reduced exercise tolerance or ischemia. Third, the safety of PDE5 inhibitor use with concomitant medications was reviewed in depth, particularly concomitant use with nitrates or alpha-blockers. With rare exceptions, PDE5 inhibitors can be safely used in men being treated for hypertension, lower urinary tract symptoms and other common male disorders. Fourth, for men unresponsive to oral therapy or with absolute contraindications for PDE5 inhibitor administration, multiple treatment options can be selected. These were reviewed in depth with clinical recommendations. Fifth, evidence from retrospective studies points strongly toward cardioprotective effects of chronic PDE5-inhibitor use in men. Decreased rates of adverse cardiac outcomes in men taking PDE-5 inhibitors has been consistently reported from multiple studies. Sixth, recommendations were made regarding over-the-counter access and potential risks of dietary supplement adulteration. Seventh, although limited data exist in women, PDE5 inhibitors are generally safe and are being tested for use in multiple new indications.ConclusionStudies support the overall cardiovascular safety of the PDE5 inhibitors. New indications and applications were reviewed in depth.

1564 Background: Physical function (PF) is a core outcome in cancer trials that can inform treatment tolerability. PF can be assessed across modalities including by patient (pt) report, clinician (clin) report, performance tests and digital sensors. The optimal approach for PF measurement has not been defined. Methods: In4M is a prospective observational study evaluating PF in pts initiating chemotherapy for breast cancer or lymphoma followed over 9 months. We used an electronic platform (Hugo) to aggregate serially assessed pt-reported PF, clin- and pt-reported ECOG performance status (PS), 6-minute walk test (6MWT) and wearable (Fitbit) data. We evaluated feasibility in all pts; associations among PF measures and the ability of PF measures to detect change were evaluated in pts with both baseline (BL) and 3-month (3M) data. We used Pearson correlations to assess the relationship of average daily steps with measures of PF. To assess change, we compared each PF measure from BL to 3M using a 2-sided α=.05 paired t-test. Results: Of the208 pts enrolled, 193 (93%) and 159 (76%) completed surveys, and 121 (58%) and 124 (60%) provided wearable data (evaluable: ≥1 day data) at BL and 3M, respectively. When requiring a stringent BL with 4+ days of data with ≥1 weekend day to be evaluable, 88 (42%) and 120 (58%) provided wearable data at BL and 3M. At both BL and 3M, pt-reported PF was generally more highly correlated with wearable-derived daily steps than clin-reported PF and 6MWT were (Table). Significant declines in PF were observed for pt- and clin-reported PF (all p<0.05), but not other modalities. Conclusions: Longitudinalassessment of multi-modal PF data including pragmatic wearable data collection was feasible in pts receiving chemotherapy. Pt-reported PF was the only modality that was both correlated with step count and able to detect change. Additional wearable metrics, correlations among PF measurements and outcomes, and clinically meaningful change scores will be reported. Optimal PF measurement may improve future reporting of treatment tolerability. Clinical trial information: NCT05214144 . [Table: see text]

Introduction: Remote monitoring using implantable cardioverter-defibrillators (ICDs) or cardiac resynchronization therapy defibrillator (CRT-D) can be used as an adjunctive diagnostic tool to traditional hospital and clinic visits to monitor the volume status of patients with heart failure (HF). Methods: We searched PubMed, Cochrane Library, and ClinicalTrials.gov (inception through February 4th, 2021) for randomized controlled trials (RCTs) evaluating ICDs/CRT-D remote monitoring versus standard of care in patients with HF. Of 642 articles retrieved after removing duplicate items, we included 11 RCTs encompassing 5,965 patients. Absolute risk difference (ARD) with 95% credible interval (CrI) was estimated. Pooled (posterior) risk difference was computed using Bayesian hierarchical methods, random effects model and weakly informative prior. Results: The ARD for mortality was centered at -0.01 (95%CrI: -0.03; 0.01, Tau: 0.02), with 82% probability of ARD of ICD/CRT-D remote monitoring with respect to control being less than 0. The ARD for cardiovascular mortality was centered at -0.03 (95%CrI: -0.11; 0.05, Tau: 0.10), with 84% probability of ARD of ICD/CRT-D remote monitoring with respect to control being less than 0. The ARD for HF admissions was centered at -0.00 (95%CrI: -0.07; 0.06, Tau: 0.08), with 57% probability of ARD of ICD/CRT-D remote monitoring with respect to control being less than 0 [Figure]. Conclusions: This meta-analysis suggests that ICD/CRT-D remote monitoring in patients with HF is associated with a higher probability of reduced all-cause mortality, and cardiovascular mortality compared with standard care. However, ICD-CRT/D remote monitoring was associated with minimal probability of difference in HF hospitalizations.

Abstract Cytokines mediate strong immunomodulatory effects in cancer. Elraglusib (9-ING-41), an inhibitor of GSK-3, is a potent antitumor and immune-modulatory agent in phase 2 clinical trials for the treatment of various cancers. Here, we examined the immune environment of elraglusib-treated cancer patients by measuring peripheral blood protein levels to explore whether the expression level of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) is correlated with clinical outcome. Using a customized Luminex platform, the expression of forty CCSG hypothesized to be linked to GSK-3 activity was assessed in pre-dose plasma samples obtained from 45 cancer patients with relapsed/refractory metastatic disease (NCT03678883; the 1801 trial). All patients in the 1801 trial were treated with elraglusib (dose range: 1-15 mg/kg) either as a single agent (Part 1; n=21) or in combination with chemotherapy (Part 2; n=24). Pre-dose peripheral blood protein levels were examined as binary predictors of clinical outcome using optimal cutoff points determined by maximally selected rank statistics. In the aggregate Part 1 and 2 populations (n=45), we identified 13 CCSG that significantly stratified the cohort by overall survival (OS). High pre-dose levels of CD95 and TNFRSF10C were associated with better OS. CD95 was a better prognostic of OS than TNFRSF10C (HR: 2.27, 95% CI: 1.10-4.67, p-value: 0.023). Low pre-dose levels of 11 CCSG were also significantly associated with favorable OS, with IL-8 being the most predictive (HR: 0.137, 95% CI: 0.0545-0.346, p-value: &lt;0.0001). Part 1 and 2 predose samples were also analyzed separately, and many of the biomarkers identified in the aggregate analysis retained significance in the separated analysis. In Part 1, CXCL5, IFN-alpha, and IL-18 emerged as unique markers, and in Part 2, CCL22 was the single unique marker.The results of our exploratory study identified several putative biomarkers of elraglusib clinical benefit and demonstrated potential immunomodulatory mechanisms of elraglusib that will be used to inform the further clinical development of elraglusib for the treatment of metastatic cancer. Citation Format: Taylor Weiskittel, Kelsey Huntington, Leiqing Zhang, Austin Koukol, Benedito A. Carneiro, Hu Li, Andrey Ugolkov, Wafik El-Deiry, Andrew Mazar. Identification of potential immune biomarkers for GSK-3 inhibitor elraglusib (9-ING-41) in patients with relapsed/refractory metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6426.

Abstract Background In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug–drug interactions, but also a potential cardioprotective effect of these drugs. Aim In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. Method A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. Outcomes Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. Results An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug–drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non–PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non–PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. Clinical Implications Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. Strengths and Limitations Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. Conclusion The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

Introduction: Influenza infection is associated with increased cardiovascular morbidity and mortality. Many observational and clinical trials suggested that influenza vaccine can reduce cardiovascular outcomes. Methods: We searched EMBASE, PubMed, and Cochrane Library (inception through May 24th, 2022) for randomized controlled trials (RCTs) evaluating influenza vaccine and its association with cardiovascular outcomes. We used Mantel-Haenszel method with Paule-Mandel estimator of tau2 and Hartung-Knapp-Sidik-Jonkman adjustment (due to the small number of the included studies) to calculate the risk ratio (RR) and 95% confidence interval (CI). Results: Eight RCTs with a total of 14,420 patients were included in our analysis. Influenza vaccine as compared with control/placebo was associated with significantly lower risk of major adverse cardiovascular events (MACE) at follow-up [RR: 0.75; 95%CI: 0.57; 0.97; I2:56%] [Figure]. There was no significant difference between influenza vaccine and placebo/control in terms of all-cause mortality [RR: 0.84; 95%CI: 0.54; 1.33; I2:50%], cardiovascular mortality [RR: 0.77; 95%CI: 0.39; 1.50; I2:57%], or myocardial infarction [RR: 0.75; 95%CI: 0.52; 1.10; I2:0%]. Conclusion: Our meta-analysis suggests that influenza vaccine compared with control/placebo was associated with lower rates of MACE without a significant difference in the mortality or myocardial infarction rates.

e14555 Background: 9-ING-41 (elraglusib) is a novel inhibitor of GSK-3β that has shown early signs of clinical benefit in a phase 1/2 clinical trial (ACT1801; NCT03678883). Early data support a multi-modal mechanism of action for elraglusib that targets both the tumor and immune system. Thus, the discovery and validation of biomarkers of drug sensitivity to elraglusib is a high priority. Here, we take inspiration from the literature on checkpoint inhibitor therapy and explore the potential of cytokines to predict elraglusib clinical response. Methods: Peripheral plasma samples from 59 patients enrolled in the 1801 phase 1/2 trial of elraglusib were assayed for 40 circulating cytokine levels. Patients advanced solid tumors refractory to standard treatments and received either elraglusib (1.0-15.0 mg/kg) as a single agent or in combination with other chemotherapies. Samples were taken from time points prior to elraglusib administration (pre-dose), after cycle 1, or after cycle 2. Each cytokine time point combination was used to stratify patients into high and low categories using an optimal cut-point determined using maximally selected rank statistics. Kaplan Meier and Cox Proportional Hazards analysis was used to determine the efficacy of each cytokine as a biomarker. The change in cytokine values between pre-dose and cycle 1 or pre-dose and cycle 2 was evaluated in a similar manner. Results: A total of 142 samples spanning eight different tumor histologies were collected and analyzed. A total of 240 cytokine-timepoint combinations were evaluated, and 53 significantly stratified patients by overall survival (p-value < 0.05). Of those, 35 showed that higher levels of the given cytokine correlated with a survival benefit and 18 a survival decrease. Notable among the cytokines demonstrating survival benefits were Granzyme B at Cycle 1 Day 4 (HR: 9.54, p-value:0.015) and TGF β at Cycle 1 Day 4 (HR: 8.48, p-value:0.0063). Strong hazard ratios were also observed for cytokines that correlated with survival decreases including TRAIL-R2 at Cycle 1 Day 2 (HR: 9.56e-02, p-value:0.0001), and IL-10 at Cycle 1 Day 4 (HR: 8.77e-02, p-value:0.007). Delta between timepoints was also able to stratifying patients by overall survival. Conclusions: Plasma cytokine profiling is a promising approach for discovery and validation of biomarkers prognostic for elraglusib clinical benefit. Numerous cytokines measured pre-dose stratified patients into significant survival groups suggesting a potential strategy for patient enrichment in clinical trials of elraglusib. These initial findings are being expanded by 1) increasing the cohort to accommodate histology specific investigations; 2) examining which cytokines are elraglusib response-specific versus drug-agnostic; and 3) combining cytokines in multivariate and machine learning models for optimal predictive capacity. Clinical trial information: NCT03678883 .