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4106 Background: The WNT/beta catenin (CTNNB1) pathway plays an integral role in the development of HCC. CTNNB1 has been implicated in HCC progression, metastasis, and drug resistance. We examined associations between CTNNB1 mutations and mRNA expression and clinical outcomes in a real-world cohort of patients with HCC. Methods: 1652 HCC tumors were tested at Caris Life Sciences (Phoenix, AZ) and analyzed with Whole Transcriptome Sequencing (WTS; Illumina Novaseq), Whole Exome Sequencing (NovaSeq,WES) and NextGen DNA sequencing (NextSeq, 592 genes). mRNA expression (transcripts per million) was further stratified into top (Q4) and bottom quartiles (Q1). Kaplan Meier estimates were calculated for overall survival (OS) in the molecularly defined cohorts and estimated from time of tissue collection to last contact. Significance was determined to be p <0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q<0.05). Results: Pathogenic CTNNB1 mutations were present in 32% of HCC and mutation status was not associated with CTNNB1 expression level. Pts whose tumors had lower CTNNB1 expression had significantly improved OS, 17.9 vs 12.4 months, Q1 vs Q4, HR 0.72, CI: 0.58-0.89 p=0.002. This association remained significant in patients who received first-line IO (Q1 vs Q4: OS 16.7 vs 10.6 mo, HR 0.54, CI: 0.32-0.94, p=0.025) or TKI (Q1 vs Q4: OS 27.1 vs 17.6 mo, HR 0.60, CI: 0.38-0.94, p=0.025). Low CTNNB1-expressing tumors (Q1) had more frequent ARID1A mutations (15% vs 8%); less frequent TP53 mutations (31% vs 42%); lower VEGFA, EPHB4, EPHA2, HIF1A, TGFB1/2/3 expression, lower MAPK activation and lower T-cell inflamed scores vs Q4 tumors (all q < 0.05). All tumors were MSS. CTNNB1 mutation status (MT vs WT) did not impact survival (OS 17.6 vs 15.3 mo, CTNNB1-MT vs CTNNB1-WT, HR 1.05, CI: 0.91-1.20, p=0.55). Similarly, CTNNB1 mutation status (MT vs WT) did not impact OS in pts treated with IO (19.8 vs 19.6 mo, HR 0.99, p=0.94) or TKI (23.0 vs 22.0 mo, HR 0.86, p=0.33). Conclusions: CTNNB1 mRNA expression, but not CTNNB1 mutation status, is associated with survival in HCC. Patients whose tumors had lower CTNNB1 expression appeared to derive more benefit from immune checkpoint inhibitors and TKI therapy in first line. CTNNB1 expression is associated with DNA repair, immune, neuronal and angiogenic pathways which may pave the way for potential therapeutic opportunities. Further studies are needed to prospectively evaluate CTNNB1 as a biomarker for treatment selection in HCC.

AbstractBackground[177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL).MethodsPost hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong).ResultsIn the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms.ConclusionsIn this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.

Key Points Measuring blood potassium has always required access to blood. The surface electrocardiogram, analyzed using an artificial intelligence algorithm, can detect hyperkalemia bloodlessly. The artificial intelligence-analyzed electrocardiogram exhibited a high negative predictive value but substantially lower positive predictive value. Background Artificial intelligence (AI) electrocardiogram (ECG) analysis can enable detection of hyperkalemia. In this validation, we assessed the algorithm's performance in two high acuity settings. Methods An emergency department (ED) cohort (February to August 2021) and a mixed intensive care unit (ICU) cohort (August 2017 to February 2018) were identified and analyzed separately. For each group, pairs of laboratory-collected potassium and 12 lead ECGs obtained within 4 hours of each other were identified. The previously developed AI ECG algorithm was subsequently applied to leads 1 and 2 of the 12 lead ECGs to screen for hyperkalemia (potassium >6.0 mEq/L). Results The ED cohort ( N =40,128) had a mean age of 60 years, 48% were male, and 1% ( N =351) had hyperkalemia. The area under the curve (AUC) of the AI-enhanced ECG (AI-ECG) to detect hyperkalemia was 0.88, with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive likelihood ratio (LR+) of 80%, 80%, 3%, 99.8%, and 4.0, respectively, in the ED cohort. Low-eGFR (<30 ml/min) subanalysis yielded AUC, sensitivity, specificity, PPV, NPV, and LR+ of 0.83, 86%, 60%, 15%, 98%, and 2.2, respectively, in the ED cohort. The ICU cohort ( N =2636) had a mean age of 65 years, 60% were male, and 3% ( N =87) had hyperkalemia. The AUC for the AI-ECG was 0.88 and yielded sensitivity, specificity, PPV, NPV, and LR+ of 82%, 82%, 14%, 99%, and 4.6, respectively in the ICU cohort. Low-eGFR subanalysis yielded AUC, sensitivity, specificity, PPV, NPV, and LR+ of 0.85, 88%, 67%, 29%, 97%, and 2.7, respectively in the ICU cohort. Conclusions The AI-ECG algorithm demonstrated a high NPV, suggesting that it is useful for ruling out hyperkalemia, but a low PPV, suggesting that it is insufficient for treating hyperkalemia.

Importance The modified Japanese Orthopaedic Association (mJOA) scale is the most common scale used to represent outcomes of degenerative cervical myelopathy (DCM); however, it lacks consideration for neck pain scores and neglects the multidimensional aspect of recovery after surgery. Objective To use a global statistical approach that incorporates assessments of multiple outcomes to reassess the efficacy of riluzole in patients undergoing spinal surgery for DCM. Design, Setting, and Participants This was a secondary analysis of prespecified secondary end points within the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial, a multicenter, double-blind, phase 3 randomized clinical trial conducted from January 2012 to May 2017. Adult surgical patients with DCM with moderate to severe myelopathy (mJOA scale score of 8-14) were randomized to receive either riluzole or placebo. The present study was conducted from July to December 2023. Intervention Riluzole (50 mg twice daily) or placebo for a total of 6 weeks, including 2 weeks prior to surgery and 4 weeks following surgery. Main Outcomes and Measures The primary outcome measure was a difference in clinical improvement from baseline to 1-year follow-up, assessed using a global statistical test (GST). The 36-Item Short Form Health Survey Physical Component Score (SF-36 PCS), arm and neck pain numeric rating scale (NRS) scores, American Spinal Injury Association (ASIA) motor score, and Nurick grade were combined into a single summary statistic known as the global treatment effect (GTE). Results Overall, 290 patients (riluzole group, 141; placebo group, 149; mean [SD] age, 59 [10.1] years; 161 [56%] male) were included. Riluzole showed a significantly higher probability of global improvement compared with placebo at 1-year follow-up (GTE, 0.08; 95% CI, 0.00-0.16; P = .02). A similar favorable global response was seen at 35 days and 6 months (GTE for both, 0.07; 95% CI, −0.01 to 0.15; P = .04), although the results were not statistically significant. Riluzole-treated patients had at least a 54% likelihood of achieving better outcomes at 1 year compared with the placebo group. The ASIA motor score and neck and arm pain NRS combination at 1 year provided the best-fit parsimonious model for detecting a benefit of riluzole (GTE, 0.11; 95% CI, 0.02-0.16; P = .007). Conclusions and Relevance In this secondary analysis of the CSM-PROTECT trial using a global outcome technique, riluzole was associated with improved clinical outcomes in patients with DCM. The GST offered probability-based results capable of representing diverse outcome scales and should be considered in future studies assessing spine surgery outcomes.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults, but it can also cause childhood-onset complications. The presentation and clinical course of young adults who present due to BAV complications are relatively uncharacterized. In a multicenter study, we found that young people who experience significant complications related to BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early-onset BAV complications.

Background The epidemiology and pathophysiology of heart failure (HF) differ in women and men. Whether these differences extend to the subgroup of patients with advanced HF is not well defined. Methods and Results This is a retrospective cohort study of all adult Olmsted County, Minnesota residents with advanced HF (European Society of Cardiology criteria) from 2007 to 2017. Differences in survival and hospitalization risks in women and men following advanced HF development were examined using Cox proportional hazard regression and Andersen‐Gill models, respectively. Of 936 individuals with advanced HF, 417 (44.6%) were women and 519 (55.4%) were men (self‐reported sex). Time from development of HF to advanced HF was similar in women and men (median 3.2 versus 3.6 years). Women were older at diagnosis (mean age 79 versus 75 years), less often had coronary disease and hyperlipidemia, but more often had hypertension and depression ( P <0.05 for each). Advanced HF with preserved ejection fraction was more prevalent in women than men (60% versus 30%, p<0.001). There were no differences in adjusted risks of all‐cause mortality (hazard ratio [HR], 0.89 [95% CI, 0.77–1.03]), cardiovascular mortality (HR, 0.85 [95% CI, 0.70–1.02]), all‐cause hospitalizations (HR, 1.04 [95% CI, 0.90–1.20]), or HF hospitalizations (HR, 0.91 [95% CI, 0.75–1.11]) between women and men. However, adjusted cardiovascular mortality was lower in women versus men with advanced HF with reduced ejection fraction (HR, 0.72 [95% CI, 0.56–0.93]). Conclusions Women more often present with advanced HF with preserved ejection fraction and men with atherosclerotic disease and advanced HF with reduced ejection fraction. Despite these differences, survival and hospitalization risks are largely comparable in women and men with advanced HF.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

BACKGROUND AND OBJECTIVE: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. METHODS: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. RESULTS: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm 3 vs 0.49 ± 1.17 cm 3 , P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. CONCLUSION: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.

Objective: To characterize our single institutional experience with robotic and open uretero-enteric stricture (UES) repair. Materials and Methods: We queried our ureteral reconstructive database for UES repair between 01/2017 and 10/2023. Patients with <3 months follow-up were excluded. Prior to surgery, patients underwent ureteral rest (4 weeks) with conversion to nephrostomy tube. Clinical characteristics, complications, reconstructive success (uretero-enteric patency), need for repeat intervention, and renal function were assessed in patients undergoing open and robotic UES reconstruction. Results: Of 50 patients undergoing UES repair during the study period, 45 were included for analysis due to complete follow-up (34 [76%] robotic and 11 [24%] open repair). UES repair was performed in 50 renal units a median of 13 months (interquartile range 7–30) from index surgery, and most often involved the left renal unit (34/50; 68%). Compared with robotic, open cases were significantly more likely to have undergone open cystectomy (100% vs 68%, p = 0.04), have longer strictures (median 4 vs 1 cm, p < 0.001), require tissue substitution (27% vs 3%, p = 0.04), and have lengthier postoperative hospitalization (5 vs 2 days, p < 0.001). There was no significant difference in total operative time (410 vs 322 minutes) or 30d major complications (18% vs 21%). At a follow-up of 13 months, per patient reconstructive success was 100% (11/11) for open and 97% (33/34) for robotic, respectively. Conclusion: In select patients with short UES unlikely to require advanced reconstructive techniques, a robotic-assisted approach can be considered. Careful patient selection is associated with limited morbidity and high reconstructive success.