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Abstract Background In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI. Patients and methods This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy. The primary endpoint was relapse-free survival (RFS) from initiation of 2L adjuvant dab/tram (RFS-2), analyzed via Kaplan-Meier methods. Results Thirty-eight patients were included (median age 50 years, 63% male, 87% stage III, median follow-up 19 months from 2L dab/tram initiation). Median dab/tram duration was 10.1 months (range: 1 day–22.7 months), with half discontinuing due to progression or adverse events. Median (95% CI) RFS-2 was 18.9 (14.9–28.1) months, with 91%, 81%, and 58% remaining relapse-free at 6, 12, and 18 months, respectively. Most patients remained distant metastasis-free at 6, 12, and 18 months (97%, 85%, and 71%, respectively). Two patients were deceased at the last follow-up, with 97% alive at 18 months. Conclusions Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

Lymphedema is a frequent complication of breast cancer treatment. As the survival rates of breast cancer continue to increase, the number of women with lymphedema will also increase. Surgical treatment of lymphedema has made significant advances during the past 20 years, and our understanding of these procedures continues to evolve. Vascularized lymph node transfer is an increasingly popular option for surgical treatment of lymphedema; however, the mechanism behind symptomatic relief is not fully understood. A proposed theory for improvement in lymphedema symptoms is lymphangiogenesis and spontaneous regeneration of lymphatic vessels, the timing and degree of which are not well defined. We present the case of a 40-year-old woman with a 10-year history of right upper extremity lymphedema secondary to bilateral mastectomy and right axillary lymph node dissection, who subsequently underwent vascularized omental lymph node transfer and lymphovenous bypass with radiographic evidence of spontaneous lymphatic reconnection within 9 months. To our knowledge, this is the earliest reported radiographic evidence of lymphatic regeneration in a human subject to date, adding to the growing body of evidence to support the therapeutic benefits of vascularized lymph node transfers.

BACKGROUND: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46–0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47–0.88) and 0.53 (95% CI, 0.41–0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04988386.

Background: Active compression-decompression cardiopulmonary resuscitation (ACD-CPR) combined with an impedance threshold device (ITD) and controlled head-up positioning, collectively termed AHUP-CPR, is associated with improved outcomes compared with conventional CPR (C-CPR). Active decompression (AD) forcibly lifts the anterior chest wall with suction after each compression, while the ITD simultaneously impedes airflow into the lungs. AD and ITD synergistically lower intrathoracic pressure during decompression, improving venous return, ventricular refilling and cardiac output. Concurrently, head-up positioning lowers intracranial pressures and improves cardiac preload. This pig study focused on the physiological role of AD during AHUP-CPR, simulating real clinical scenarios. Methods: Ten male and female farm pigs (~40 kg) were anesthetized, intubated and ventilated. Hemodynamic parameters, end-tidal CO2 (ETCO2), and biventricular pressure-volume loops were recorded continuously. Ventricular fibrillation was induced and left untreated for 10 mins. Then, after 2 min of automated C-CPR in the flat position, AHUP-CPR with a 3 cm lift above the neutral position of the chest was performed for 13 min. AD was then abruptly discontinued, restarted 1 min later, and increased incrementally every min to up to 4 cm of active lift. Data were analyzed with a linear mixed-effects model, using random intercepts for individual pigs. Results: Upon cessation of AD, coronary and cerebral perfusion pressures, compression and decompression aortic pressures, compression right atrial pressure, ETCO2, right and left ventricular preload, compliance, stroke volume and cardiac output all decreased immediately and significantly (p<0.01), whereas decompression right atrial and biventricular pressures increased. With restoration of AD, physiological parameters returned to ≥ 90% of pre-AD discontinuation values (Figures 1 and 2). Conclusion: Full chest wall lift, achieved with > 3 cm of AD, was needed to maintain and optimize hemodynamics during AHUP-CPR in pigs. After pausing AD, incremental restoration of AD resulted in nearly complete restoration of peripheral and central hemodynamic measures. These observations support the benefit of and need for ≥3 cm of AD to optimize AHUP-CPR. Effective means to generate ≥3 cm of AD should be considered when implementing and developing AHUP-CPR devices to optimize outcomes.

Background: Patients with Fontan palliation have reduced aerobic capacity because of impaired cardiac, pulmonary, and skeletal muscle function. However, the assessment of aerobic capacity in this population still relies on comparisons with people without cardiovascular disease, rather than comparison with the expected aerobic capacity of other Fontan patients. The purpose of this study was to determine the expected aerobic capacity of adults with Fontan palliation. Method: Adults with Fontan palliation who underwent cardiopulmonary exercise test at Mayo Clinic (2003-2023) were stratified into quartiles based on the predicted peak VO 2 . We assessed the correlates of predicted peak VO 2 , and the relationship between predicted peak VO 2 quartiles and cardiovascular outcomes (death/transplant). Results: Of 323 patients (age 29±9 years; 177 [55%] men), the median peak VO2 was 19.1 (15.2 - 23.9) ml/kg/min, and this corresponds to a predicted peak VO 2 of 51% (range 19 -88; interquartile range 41 - 62). The correlates of higher predicted peak VO 2 were smaller body mass index, higher systemic saturation, and lower Fontan pressures. The top, 2 nd ,3 rd , and bottom quartile of predicted peak VO 2 corresponds to predicted peak VO 2 of 63-88%, 51-62%, 41-50%, and 19-40%, respectively. Using the top quartile as the reference, the 3 rd quartile (HR 1.13, 95% CI 1.03-1.28, p=0.02), and 4 th quartile were associated with a higher risk of death/transplant (HR 1.32, 95% CI 1.16-1.69, p<0.001). Conclusions: The results of the current study would help calibrate the interpretation of exercise test data in adults with Fontan palliation and improve risk stratification in this population.

Background: Artificial intelligence (AI) can be used to predict a person’s age from the electrocardiogram (ECG) (AI-ECG age) and has been proposed as a measurement of biological age. The difference between AI-ECG age and chronological age (defined as delta-age) is an independent predictor of mortality in the general population. This study assessed the relationship between AI ECG estimated age and mortality among adults living with congenital heart disease (CHD). Methods: A previously validated neural network to estimate AI-ECG age was used to analyze standard digital 12-lead ECGs in a cohort of subjects aged >18 years seen in the adult CHD (ACHD) clinic between 1992 to 2023. A single ECG, collected during the year of the first visit to the ACHD clinic was analyzed to compute the delta-age.. A positive delta-age indicates an AI ECG estimated age higher than the subject’s chronological age. The relationship between the delta-age and mortality was evaluated using Cox proportional hazard models adjusting for influential clinical factors including chronologic age, sex, ACHD severity, NYHA class and history of arrhythmia. Results: Of 5,780 subjects tested (50% females), the mean chronological age was 39.1 ± 15.0 years. AI ECG estimated age was 52.3 ± 16.6 years. Complexity of CHD was classified as mild, moderate, and severe in 7.4%, 73.9% and 18.7% of patients respectively. Patients with severe CHD had the highest delta-age of 17.1 (±18.2) years followed by moderate 12.7 (±13.6) y and simple 7.7 (±11.5) y. Patients with single ventricle had the highest deviation in AI estimated age [median delta-age 21.0 (IQR 28.6) y] followed by those with a systemic right ventricle [median delta-age of 16.3 (IQR 29.3) y]. During a median follow-up of 6.4 y (25th – 75th centile 1.58 – 13.7 y), mortality occurred in 839 (14.5%) patients. After adjusting for chronological age, CHD severity, and other clinical variables, delta-age gap was associated with increased mortality risk (HR 1.06 (1.03 – 1.09) per 5-year increment in delta-age, p<0.005), Table 1. Conclusion: The difference between AI ECG and chronological age is an independent predictor of all-cause mortality in ACHD patients.

Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.

Introduction: The incidence and risk factors for atrial arrhythmia (AA) [atrial fibrillation (AF) and atrial flutter (AFL)] in adults with systemic right ventricle (SRV), specifically congenitally corrected-TGA (cc-TGA) and D-TGA palliated with atrial switch procedures, is not well understood. This study aims to better define these risks. Methods: Adults with SRV presenting to the Mayo Clinic between 1971 and 2022 were identified. Clinical characteristics, ECG and echocardiographic parameters were recorded at first evaluation. Sustained AA (> 30s) incidence at follow-up was documented using ECG. Cox regression analysis identified associations of incident AA. Results: Among 447 patients with SRV (mean age 34.7±14.8, 55.9% male, cc-TGA n=247; D-TGA post-atrial baffle n=200), AA was documented in 231 (51.6%) at a mean age of 37.5±18.8y. Isolated AF was observed in 88 (38.1%), isolated AFL in 71 (30.7%), and both AF and AFL in 72 (31.2%) patients. Univariate analysis showed significant predictors of AA as: age (HR:1.03, p<0.001), male sex (HR:1.49, p=0.026), NYHA class≥2 (HR:1.98, p<0.001), ventricular pacing (HR:1.64, p=0.019), QRS duration (HR:1.008, p<0.001), SRV enlargement (HR:1.73, p=0.01), SRV ejection fraction (HR:0.979,p=0.012), left atrial enlargement (HR:1.947, p=0.006), hypertension (HR:1.57, p=0.047), CKD (HR:0.991, p=0.021), and obesity (HR:1.66, p=0.023). In multivariable analysis, age (HR:1.032, p<0.001) and QRS duration (HR:1.007, p=0.013) were significant predictors of AA. Kaplan Meier analysis of time from first evaluation to incidence of AA is shown in the figure. AA was associated with heart failure in 56 (26.7%) patients. During 11.2±10.5 years of follow-up, mortality occurred in 50 (21.6%) with AA and 19 (8.8%) without AA. Conclusion: Atrial arrhythmia occurred in more than half of patients with SRV, predominantly in the third decade of life. Significant associations of AA included advancing age, longer QRS duration, enlargement of pulmonary venous atrium, reduced SRV function, hypertension and obesity. AA was associated with heart failure in one-fourth of patients and higher mortality. Close monitoring and early intervention in patients with risk factors may help mitigate the development of AA.

Background: As machine learning becomes increasingly utilized in orthopaedic clinical research, the application of machine learning methodology to cohort data from the Multicenter ACL Revision Study (MARS) presents a valuable opportunity to translate data into patient-specific insights. Purpose: To apply novel machine learning methodology to MARS cohort data to determine a predictive model of revision anterior cruciate ligament reconstruction (rACLR) graft failure and features most predictive of failure. Study Design: Cohort study; Level of evidence, 3. Methods: The authors prospectively recruited patients undergoing rACLR from the MARS cohort and obtained preoperative radiographs, surgeon-reported intraoperative findings, and 2- and 6-year follow-up data on patient-reported outcomes, additional surgeries, and graft failure. Machine learning models including logistic regression (LR), XGBoost, gradient boosting (GB), random forest (RF), and a validated ensemble algorithm (AutoPrognosis) were built to predict graft failure by 6 years postoperatively. Validated performance metrics and feature importance measures were used to evaluate model performance. Results: The cohort included 960 patients who completed 6-year follow-up, with 5.7% (n = 55) experiencing graft failure. AutoPrognosis demonstrated the highest discriminative power (model area under the receiver operating characteristic curve: AutoPrognosis, 0.703; RF, 0.618; GB, 0.660; XGBoost, 0.680; LR, 0.592), with well-calibrated scores (model Brier score: AutoPrognosis, 0.053; RF, 0.054; GB, 0.057; XGBoost, 0.058; LR, 0.111). The most important features for AutoPrognosis model performance were prior compromised femoral and tibial tunnels (placement and size) and allograft graft type used in current rACLR. Conclusion: The present study demonstrated the ability of the novel AutoPrognosis machine learning model to best predict the risk of graft failure in patients undergoing rACLR at 6 years postoperatively with moderate predictive ability. Femoral and tibial tunnel size and position in prior ACLR and allograft use in current rACLR were all risk factors for rACLR failure in the context of the AutoPrognosis model. This study describes a unique model that can be externally validated with larger data sets and contribute toward the creation of a robust rACLR bedside risk calculator in future studies. Registration: NCT00625885 (ClinicalTrials.gov identifier).

Introduction: Ebstein's anomaly (EA) is associated with ECG signature of right bundle branch block (RBBB). Patients with EA also have high incidence of accessory pathways (AP) and it has been hypothesized that the absence of RBBB on ECG may be associated with a higher prevalence of AP. This study aims to assess the prevalence of RBBB in patients with EA and examine the correlation between its absence and the presence of AP. Methods: Adults (age>18 years) with EA, identified using the Mayo Adult Congenital Heart Disease registry, were divided into 3 groups based on the QRS morphology of their first ECG. Those with prior AP ablation were excluded. The demographic characteristics, baseline ECG data, echocardiographic parameters and EP study data were retrospectively collected and compared between the three groups using Chi-square or ANOVA test as appropriate. Results: Of 596 patients with EA, 358(60.06%) patients had a RBBB, bifascicular block or an incomplete RBBB (group1) ; 18 (3.02%) patients had either a LBBB , ventricular pre-excitation, isolated left anterior or posterior fascicular block (group 2); and 220 (36.92%) patients had normal QRS (group 3). The characteristics of these groups are compared in the table. Patients with RBBB had larger RV size, reduced RV systolic function and higher likelihood of tricuspid valve surgery. EP study was performed in 51 (14%), 3 (17%) and 51 (23%) patients in groups 1, 2,and 3 respectively. One or more APs were noted in 11/51 (22%) and 14/51 (30%) patients with RBBB and normal QRS respectively (p=0.18). Additionally, in patients who did not undergo an EP study, supraventricular tachycardia was documented in 39/307 (13%), 2/15(13%) and 13/169 patients (8%) in group 1,2 and 3 respectively during followup . Conclusion: In a large cohort of adults with EA in a tertiary referral center, greater than one-third of patients had a normal QRS complex without RBBB. However, EP study did not reveal a significant difference in the prevalence of accessory pathways between patients with and without RBBB. In EA, the absence of RBBB may not increase the risk of an underlying accessory pathway.