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Abstract Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although lipoprotein(a) [Lp(a)] is known to be a well-established risk factor for atherosclerotic cardiovascular disease, its role in the development of AF, independent of this association, remains unclear. Methods and results Adult patients from the three Mayo Clinic sites with a baseline Lp(a) and without AF history were included. Patients were categorized into two groups based on their Lp(a) levels: high Lp(a) (≥50 mg/dL) and low Lp(a) (<50 mg/dL). Survival probabilities free from incident AF were compared between Lp(a) groups, during a follow-up period up to 15 years, using the Kaplan–Meier curve and the log-rank test. Multivariable Cox regression analysis was also conducted. A total of 75 376 patients were included (median age: 55 years, 59% males), with a median follow-up duration of 8.8 (inter-quartile range: 3.4, 14.8) years. Incident AF was detected in 5738 (7.6%) patients. Survival probability free from incident AF was significantly lower in patients with elevated Lp(a) (86%) compared with those with low Lp(a) (88%, log-rank P < 0.001). Multivariable analysis adjusted for potential risk factors of AF showed a statistically significant association of elevated Lp(a) with an 11% increase in AF risk (adjusted hazard ratio: 1.11, 95% confidence interval: 1.05–1.18). Conclusion Our study suggests that elevated Lp(a) (≥50 mg/dL) is an independent risk factor for incident AF. Future prospective studies are warranted to validate our results and to test if reducing Lp(a) could mitigate the burden of AF.

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of 12%. It has two major molecular subtypes: classical and basal, regulated by the master transcription factors (MTFs) GATA6 and ΔNp63, respectively. Objective This study sought to uncover the transcriptional regulatory mechanisms controlling PDAC subtype identity. Design We integrated primary tumour single-cell RNA-seq, patient-derived xenograft RNA-seq and multispectral imaging to identify MTF-dependent, subtype-specific markers. We created subtype-specific fluorescent reporter systems and conducted drug screenings to find actionable targets. We analysed chromatin accessibility (ATAC-seq), genome-wide occupancy (ChIP-seq) for epigenetic status (H3K27ac), MTFs (GATA6, ΔNp63), RNA polymerase II (Pol II), H3K4me3-anchored chromatin topology (HiChIP) and nascent RNA capture sequencing (PRO-seq). Additionally, we used nuclease-dead Cas9 (dCas9) to manipulate transcriptional regulatory mechanisms. Results Our approach identified glucocorticoid receptor (GR) agonists as agents that suppress the classical transcriptional programme by interacting with GATA6. GATA6 regulates classical-specific transcription through promoter-proximal pause release. Depletion of GATA6 increased Pol II occupancy at GATA6-bound enhancers and transcriptional start sites, stabilising enhancer–promoter interactions. Artificially inducing pausing at GATA6-bound enhancers with dCas9 abrogated target gene expression and induced pausing at both the enhancer and target gene promoter. Conversely, in basal PDAC ΔNp63 promotes Pol II recruitment and stabilises enhancer–promoter interactions. Conclusion This study provides new insights into the transcriptional control and role of GR agonists in controlling PDAC molecular subtype identity.

Background: It has been demonstrated that an athlete’s psychological readiness contributes to one’s ability to successfully return to sport (RTS) after anterior cruciate ligament (ACL) reconstruction. However, the effect of graft choice on psychological readiness is not yet understood. Purpose/Hypothesis: The purpose of this study was to evaluate the association between graft choice and an athlete’s psychological readiness to RTS. It was hypothesized that similar ACL-Return to Sport after Injury (ACL-RSI) scores would be achieved among patients who underwent ACL reconstruction with quadriceps autograft (QA), hamstring tendon autograft (HA), and bone–patellar tendon–bone (BTB) autograft. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who underwent primary ACL reconstruction at a single institution between January 2017 and December 2018 were placed into separate cohorts depending on graft type (HA, BTB, or QA; n = 30 patients in each group), and the ACL-RSI, International Knee Documentation Committee subjective form, and Lysholm scores were compared between the different graft cohorts at 6 months postoperatively, at RTS, and at 2 years postoperatively. Also, the rate of patients who achieved an ACL-RSI score of ≥65 (predictive of return to preinjury sport at 2 years postoperatively) was calculated, as was the RTS rate and time. Results: The QA group demonstrated significantly higher ACL-RSI scores than both the HA and BTB groups at 6 months postoperatively ( P < .0001) and RTS ( P = .011). The QA group also had a higher rate of achieving ≥65 on ACL-RSI than the other groups at 6 months postoperatively ( P = .002) and RTS ( P = .024). There was no significant difference in the RTS rate between the 3 groups, although the QA group demonstrated a significantly quicker return (QA, 8.1 months; BTB, 9.6 months; HA, 10.5 months; P < .001). Conclusion: Athletes undergoing primary ACL reconstruction with QA achieved a higher mean ACL-RSI score and more often achieved a score of ≥65 at the 6-month and RTS time points compared with the HA and BTB groups. QA may afford an advantage over other grafts in terms of improved psychological readiness to RTS.

Study Design. Retrospective observational study. Objective. To evaluate whether the combined American Spine Registry and Medicare (ASR/CMS) data yield substantially different findings versus ASR data alone with regard to key parameters such as risk stratification, complication rates, and readmission rates in lumbar surgery investigated through an analysis of 8755 spondylolisthesis cases. Summary of Background Data. Medicare data correlation has been effective for determining revision rates for other procedures, such as total hip replacement. Our aim is to determine whether these findings are translatable in the realm of lumbar spinal surgery investigated through an analysis of 8755 spondylolisthesis cases. Materials and Methods. The American Spine Registry (ASR) was queried for Medicare-eligible patients who underwent lumbar spinal fusion for lumbar spondylolisthesis. This cohort was analyzed based on ASR data alone in comparison to the same patients in the combined ASR/Medicare (ASR/CMS) data set. The primary outcome of interest was readmission at 30 and 90 days postoperatively. Results. There were 8755 Medicare-eligible cases with a diagnosis of spondylolisthesis within the ASR. The mean age was 72.7 years and 60.8% were female. Medical comorbidities were more frequently detected in the combined ASR/CMS data set, reflected by a higher mean Charlson Comorbidity Index score (3.49 vs. 3.27, P<0.001). Hospital readmission rates were significantly higher in the combined ASR/CMS data set at both 30 days (4.89% vs. 1.83%, P<0.001) and 90 days (7.68% vs. 2.66%, P<0.001), with notable increases in readmissions for infections and medical complications. Discharge disposition remained comparable across data sets, with most patients discharged to home or home health care. Conclusion. This study demonstrates that integrating patient-identified Medicare data with the ASR provides a more comprehensive assessment of outcomes for lumbar spinal fusion surgery as demonstrated through an analysis of 8755 spondylolisthesis cases. These findings, establish the importance of multisource data linkage to overcome the limitations of single-source registries, thereby enhancing data quality for clinical decision-making and quality improvement in spinal surgery.

Abstract Rhabdomyolysis following revascularization of the ischemic upper extremity can lead to life- & limb- threatening sequelae. In the context of replantations and vascularized composite allografting, a reconstructive procedure usually reserved for upper limb amputees, prolonged tissue ischemia is detrimental to extremity functional recovery. Currently, validated survival small animal models of extremity reperfusion injury that permit longitudinal assessment of limb function are lacking. To date, studies that evaluated reperfusion injury-induced neuromuscular impairment rely on terminal ex vivo procedures and do not provide clinically translatable measurements. Furthermore, it is unclear if upper extremity musculature exhibits a different ischemic threshold compared to the lower limb given the relatively rare incidence of upper limb ischemia. Here, we present a reliable rat model of extremity post-reperfusion syndrome (PRS) that comprehensively recapitulates the biochemical hallmarks of rhabdomyolysis secondary to upper extremity reperfusion injury and allows for monitoring in vivo upper limb function using clinically relevant electrodiagnostic and kinematic metrics. In addition to inducing severe metabolic derangements, our forelimb PRS provided insights on gross motor and electrophysiological alterations upper extremity reperfusion injury. We identify gait coordination parameters such as stride frequency and forelimb-hindlimb coordination index and electrophysiological metrics including compound muscle action potential amplitude as objective, non-invasive outcome measures for limb function assessment in small animal models of extremity PRS. This comprehensive, validated functional model can serve as an invaluable tool to evaluate therapeutics or preconditioning regimens to attenuate PRS and mitigate resulting neuromuscular dysfunction.

826 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct, when combined they inhibit a broad spectrum of secondary KIT mutations. Herein we report extended experience of patients treated with 2 nd line combination bezuclastinib and sunitinib, including response assessment and safety. Methods: Peak (NCT05208047), a global randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in GIST pts with imatinib intolerance or resistance. In Part 1a of the 3-part study, the dose of an optimized formulation of bezuclastinib was escalated in serial cohorts to achieve a target exposure comparable to that achieved at the RP2D established in the prior Phase 1b/2a study. Part 1b evaluated the interaction between bezuclastinib + sunitinib. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Part 1 completed enrollment in Apr 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was selected for Part 2. All Part 1 data reported herein are as of Aug 2023; updated safety and efficacy will be presented. Results: Part 1 has completed enrollment with 19 pts in Part 1a and 23 in 1b. In Part 1a, Cohort 1 included 5 pts starting at bezuclastinib 300 mg QD + sunitinib 37.5 mg QD; Cohort 2 included 14 pts at bezuclastinib 600 mg QD + sunitinib 37.5 mg QD. Pt characteristics in Part 1a+1b: median age - 60 yrs (range: 33-77); 81% men; 98% ECOG PS 0-1; 98% metastatic and 2% locally advanced. The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events. There were limited (24%) dose reductions and infrequent (n=2) discontinuations due to TEAEs. Three pts experienced serious AEs possibly associated with study medications. In pts evaluable for response (received ≥1 cycle of study treatment and had assessments at baseline and post-baseline [n=40]), the objective response rate (ORR) was 20% (6 confirmed PRs, 2 unconfirmed PRs). Data remain immature to estimate median PFS for Part 1 pts. In a subset of pts with prior imatinib only (n=6), the closest approximation for pts enrolling in Part 2, the ORR was 33% (2 confirmed PRs). The majority of 2nd-line pts remain on treatment past 12 months. Conclusions: Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2 nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD. Clinical trial information: NCT05208047 .

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

AbstractBackgroundInflammatory bowel disease (IBD) affects more than 10 million people worldwide. Men and women are equally affected by Crohn's disease (CD). It has been shown that patients with CD are at an increased risk of a colorectal cancer (CRC) diagnosis and CRC‐related mortality. During the last two decades, biological therapies have revolutionized the treatment of CD. There are no current studies investigating the prevalence of CRC in patients with CD in the era of biological therapy and the possible features of patients with CD who are at high risk of developing CRC.AimWe aim to assess the prevalence of CRC, risk factors and profile of CRC in patients with CD receiving biological treatment compared with those who are not under biological therapy and the impact of CD‐associated colorectal strictures on CRC development. The study hypothesis is that the use of biological therapy in the control of CD activity may decrease the risk of developing CRC.Study design and settingAn international, retrospective, snapshot of the prevalence of CRC in patients with CD, reported according to the SPIRIT guidelines. The study will involve centres that hold regular IBD multidisciplinary team meetings and have both IBD colorectal surgeons and gastroenterologists. Each participating centre will provide a local consultant lead and a local trainee lead. Data will be collected within a 2‐year recruitment period (January 2017–January 2019).Study populationAdult patients who presented with CD during the study period. Patients with an incidental diagnosis of CD during evaluation for CRC will be excluded.Statistical planBaseline patient characteristics will be summarized using the appropriate descriptive statistics. Univariable, multivariable and Cox regression models will be used to identify factors significantly associated with CRC. For noncontinuous variables a comparison between the subgroups will be carried out using the chi‐square test corrected by Fisher's exact test if appropriate. A p‐value of <0.05 will be considered statistically significant.Data storageData will be stored on a secured server, pin‐code protected according to the local data management agreement.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment’s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.