Citations

Background: Many medications, electrolyte perturbations, and several diseases can prolong the QTc beyond its 99 th percentile value resulting in acquired QT prolongation (AQTP). In contrast, approximately 1 in 2,000 people have congenital long QT syndrome (LQTS) hallmarked by pathological QT prolongation. Recently, we developed an AI-ECG model to distinguish these two groups, however this model does not elucidate which ECG segments distinguish LQTS from AQTP. Methods: Using the cohort from our previous study, all patients with LQTS evaluated in the Mayo Clinic Genetic Heart Rhythm Clinic and controls were included. Next, every patient/control with ≥1 ECG above age- and sex-specific 99 th percentile for QTc was selected and matched at 1:100 ratio. Subsequently, 5 ML algorithms (logistic regression, Naïve Bayes, random forest, Gradient boosting and XGBoost) were trained using 52 features representing segments of the 12-lead ECG (e.g. wave peak times, amplitudes, areas under wave, duration; 52x12 features). Training and testing sets were spilt at 80:20 ratio and 5-fold cross validation was performed to prevent overfitting. Following analysis, the top 100 features were re-analyzed to refine results. Results: Among >1,600 patients with LQTS, 690 had ≥ 1 ECG with a QTc above the established threshold compared to 28,186 controls. Following age- and sex-matching and splitting, 22,410 (training), and 5,776 (testing) ECGs were used. Of the 5 ML algorithms, XGBoost demonstrated best performance (AUC 0.913, accuracy 0.836, sensitivity 0.857, specificity 0.835) to distinguish LQTS from AQTP. Following filtering for the top 100 features, performance of the algorithm remained high with AUC of 0.912 (accuracy 0.84, sensitivity 0.841, specificity 0.84). The features with the greatest impact on classification output included time from T wave onset to T wave peak (leads V1, V4, V4), QRS interval duration (leads V1, V3, V4, aVR), and amplitude at end of ST segment (aVF). Conclusions: Distinguishing monogenetically driven LQTS from multi-factorial AQTP is critical in clinical practice for proper management, mitigation of offending QT-prolonging factors, and treatment. Building on our previously developed AI-ECG-LQTS ‘mutation detector’, this model identifies some of the elements within the ‘black box’ that distinguish an ECG and QTc stemming from a patient with LQTS compared to a similar prolonged QTc value that is arising due to non-genetic, acquired QT-prolonging factors.

Background: Mavacamten was approved by the US Food and Drug Administration (FDA) in April 2022 for the treatment of adults with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (HCM). Few studies have reported on the long-term real-world effectiveness and safety of mavacamten. We evaluated clinical outcomes in patients on mavacamten in multiple health centers across the United States. Research Questions: This study assessed the real-world effectiveness and safety of mavacamten in patients with symptomatic obstructive HCM. Methods: In this multi-center observational study, we evaluated patient characteristics at baseline, NYHA class, left ventricular outflow tract gradients (LVOTg) at rest and Valsalva, and left ventricular ejection fraction (LVEF) in patients with symptomatic obstructive HCM treated with mavacamten for up to 72 weeks. Results: Mavacamten was initiated in 172 patients across 4 US centers (UCSF, Mayo Arizona, Stanford, and Atlantic Health System/Morristown Medical Center). Baseline characteristics included: 56% female, mean age 64 (standard deviation ±13) years, 47% NYHA class III, mean resting LVOTg of 47 mmHg and mean Valsalva LVOTg of 89 mmHg, and 23% non-White. Comorbidities included hypertension (56%) and atrial fibrillation (25%) at baseline (Table). Patients experienced a notable early response to mavacamten in resting and Valsalva gradients by week 4, which was sustained through week 72 (Figure A). No patients were NYHA class III at week 72, compared to 47% at baseline (Figure B). Mean LVEF did not change substantially between baseline and week 72. No patients experienced an LVEF of <40% and 2% experienced an LVEF of <50%. Conclusions: This is the largest observational study to date demonstrating the effectiveness and safety of mavacamten with substantial sustained reductions in resting and Valsalva LVOTg, and progressive improvements in NYHA class without considerable changes in mean LVEF up to 72 weeks.

Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy. Among women with LQT2, the post-partum period has been considered high risk for cardiac events. However, whether this risk persists after establishing their diagnosis and implementing their LQT2-directed treatment program remains to be determined. Objective: To describe the management and outcomes of LQT2 women during the 9 months post-partum period. Methods: A retrospective analysis of 1869 patients with LQTS treated and evaluated at a tertiary center specializing in Genetic Heart Disease from January 2000 to November 2023 was performed to identify women with diagnosed and treated LQT2 who had a pregnancy during follow-up. Data were abstracted for patient demographics, clinical characteristics, symptomatic status, and treatment plans before and after pregnancy. Results: Overall, 30 pregnancies occurred in 22 women with LQT2. Their average QTc was 489 ± 34 ms with 7 patients (32%) having a resting QTc > 500 ms. Prior to their first post-partum period, 5/22 (23%) were symptomatic with 2 (9%) experiencing a LQT2-triggered sudden cardiac arrest (SCA). Before their post-partum period, their LQT2-directed therapy comprised preventative measures only in 7 (23%), drug therapy in 16 (53%), combination therapy in 7 (23%), and 10 women (43%) had an implantable cardioverter defibrillator (ICD). Pre-emptive treatment intensification was done for 24/30 post-partum periods. Only a single VF-terminating ICD therapy occurred in 1 (3%) of the 30 post-partum periods involving a 21-year-old with p.Lys610Asn-KCNH2 variant, QTc = 490 ms, and a pre-diagnosis presentation of seizures. Conclusion: Although the post-partum period is regarded as a ‘high risk’ window of time for women with LQT2, the risk of a LQT2-triggered cardiac event after diagnosis and implementation of contemporary therapies is very low. This designation of “high risk” among correctly diagnosed and treated women is misleading and generates inappropriate and unnecessary anxiety.

Abstract Introduction: Recurrence after tumor resection is a major cause of failure in HPV-negative head and neck squamous cell carcinoma (HNSCC), with up to 50% of patients recurring within 2 years. There is unmet need for an accurate diagnostic test that can predict risk of recurrence prior to adjuvant therapy selection. We previously demonstrated that ctDNA in lymphatic exudate collected via surgical drains (“lymph”) accurately identifies molecular residual disease (MRD) and outperforms plasma in HNSCC patients using a targeted sequencing (TS) approach. While TS assays are robust and sensitive, they have key limitations, namely limited ctDNA features, higher cost, longer turnaround times, and lower throughput. Here we evaluate whole genome sequencing (WGS) for detection of MRD in both lymph and plasma sampled 24 hours after surgery. Methods: Lymph, plasma, and whole blood were collected 24 hours postoperatively from 30 HPV-negative HNSCC patients (stages I – IV) along with resected tumor. To detect ctDNA, we utilized WGS analyses of patient matched tumor, germline (blood), and cfDNA from lymph or plasma samples at approximately 150x, 30x, and 30x depth, respectively. Tumor- specific single nucleotide variants were identified from tumor and germline datasets, from which a candidate variant set was used to determine the presence of ctDNA within lymph or plasma DNA through a random forest machine learning model. ctDNA status was determined based on the level of signal compared to a reference population of noncancerous donor plasma samples (n=80). 5 tumors and 1 lymph sample failed QC; in total, 24 patients remained, yielding 10 patients with disease recurrence and 14 with no evidence of disease with &gt;1 year of follow-up. The Kaplan-Meier (KM) estimator with log-rank test and Cox proportional-hazards model were used for survival analyses. Results: KM survival analyses indicated that WGS of lymph ctDNA accurately predicts recurrence (sensitivity (SN) = 50%, specificity (SP) = 93%; p = 0.003, Hazard ratio (HR) = 6.0), consistent with previously published results using a TS MRD approach in this cohort (SN = 80%, SP = 64%, p = 0.02, HR = 5.3). WGS of lymph ctDNA outperformed plasma at this timepoint (SN = 30%, SP = 93%, p = 0.03, HR = 4.2). WGS of lymph ctDNA also showed enhanced performance in locoregional relapse (n=21, SN = 57%, SP = 93%; p = 0.006, HR = 6.7). Finally, the ctDNA fraction of proximal lymph was higher than paired plasma in all locoregional recurrences (n=7), while peripheral plasma had a higher ctDNA fraction in 2 out of 3 distant recurrences. Conclusions: Tumor-informed WGS analysis of lymph ctDNA represents a robust MRD approach in HPV-negative HNSCC. Lymph outperforms time-matched plasma for prediction of recurrence, particularly in patients with locoregional relapse. Accurate MRD identification in the immediate post-surgical timeframe suggests that lymph analysis has potential to augment pathology and longitudinal plasma testing to provide more personalized adjuvant treatment decision-making in patients with HPV-negative HNSCC. Citation Format: Zhuosheng Gu, Seka Lazare, Noah Earland, Marra S Francis, Adam Harmon, Megan Long, Amy Greer, Ellen Verner, Andrew Georgiadis, Mark Sausen, Shakti Ramkissoon, Jose P Zevallos, Aadel A Chaudhuri, Taylor J Jensen, Wendy Winckler. Tumor-informed whole genome sequencing of ctDNA from lymph and plasma detects molecular residual disease in HPV-negative head and neck cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A043.

Objective To describe the immediate clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) in treating long COVID symptoms. Long COVID currently impacts approximately 5.3% of US adults, presenting with persistent fatigue, depression, anxiety, cognitive impairments, and social function decline. Repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex has improved these symptoms in some studies. Methods Five patients (ages 52–63 years, 3 female patients) underwent accelerated rTMS using intermittent theta burst stimulation (600 pulses over 3 minutes 20 seconds, 80%–120% of resting motor threshold) to the left dorsolateral prefrontal cortex. The treatment consisted of twice-daily sessions over 20–30 treatments. Outcomes were measured using the Patient-Reported Outcomes Measurement and Information System (PROMIS) questionnaires, assessing fatigue, depression, anxiety, cognitive function, and social function at baseline and immediately posttreatment. Results One patient discontinued immediately due to intolerable scalp pain. Posttreatment PROMIS scores showed the following: fatigue decreased from 74.5 to 61.8, depression from 60.3 to 51.5, and anxiety from 62.0 to 54.0. Scores increased for cognitive (26.8 to 32.3) and social (31.0 to 32.5) function. These changes, although not statistically significant, indicate a trend toward symptom reduction. Subjectively, 3 of 4 patients who completed the rTMS course reported improvements. Conclusion This case series suggests that rTMS may offer symptomatic relief in long COVID patients. Although the observed improvements in PROMIS were not statistically significant, even minimal improvements are clinically significant for patients enduring prolonged suffering. These preliminary findings are encouraging and underscore the need for further research with larger cohorts to validate the efficacy of rTMS in long COVID symptom relief.

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.

Abstract Lymphopenia following chemoradiation for high grade gliomas (HGG) is common and is associated with decreased survival. NT-I7 (efineptakin alfa) is a long-acting analog of the lymphocyte pro-survival cytokine, interleukin-7. Our Phase I dose-escalation study of 19 patients with HGG demonstrated early elevations in CD4+ and CD8+ T cells in the first 4 weeks after administration of NT-I7. In this study, we explored the diversity and potential functionality of the NT-I7-expanded T cell population. A subset of 4 subjects with glioblastoma multiforme (GBM) treated at 720 µg/kg of NT-I7 during adjuvant temozolomide in our study (NCT03687957) underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) of peripheral blood. CITE-seq with TCR clonotype sequencing (10x Genomics 5’) permitted simultaneous tracking of the T cell phenotype at the protein level, individual T cell clones, and gene expression dynamics between 4 timepoints: pre-treatment, and post-treatment weeks 1, 2, and 13. Here, we report the results of differential expression analyses between timepoints and patient-specific differences in T cell clonotype expansions. Both CD4+ and CD8+ T cells in our study patients had increased expression of T cell activation markers LTB, CISH, and CD74. CD8+ T cell subsets demonstrated additional elevations in genes important in cytotoxic function (granzymes (GZMA, GZMB) and perforin (PRF1)), MHC Class II expression (HLA-DRA, HLA-DRB1), and AP-1 transcription factor subunits (JUND, JUN, JUNB, FOS, FOSB). After excluding known viral antigen clonotypes, 2 of 4 patients demonstrated TCR clonotype expansion. Notably, nearly all the expanded TCR clonotypes were found within CD8+ T cells, but not CD4+ T cells. NT-I7 promotes activation, cytotoxic function, and selective clonotype expansion of CD8+ T cells in patients with HGG. This, combined with its role in increased CD4+ T cell counts, suggests NT-I7 may be a powerful tool to restore immune function after treatment-associated lymphopenia in HGG.

Introduction: Long QT syndrome (LQTS) is a potentially life-threatening genetic heart disease. Patients with LQTS may also have co-existent mental health illnesses that may benefit from psychiatric medications. However, because many of these medications have QT-prolonging potential (www.crediblemeds.org), many of these patients receive suboptimal mental health care. Objective: To evaluate the frequency, management, and incidence of breakthrough cardiac events (BCEs) in patients with LQTS and concomitant mental health issues treated with psychiatric medications. Methods: A retrospective review was conducted on patients cared for in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic between 2000 and 2024 focusing on patients with LQTS and a concomitant psychiatric diagnosis requiring medication with known, possible or conditional risk of torsades de pointes (TdP). Electronic medical records were reviewed for data. BCEs were defined as LQTS-triggered syncope, seizures, appropriate ICD therapy, sudden cardiac arrest (SCA), or sudden cardiac death (SCD). Patients with missing information were excluded. Results: Overall, 195 /1899 LQTS patients [10%, 86 (43%) with LQT1, 83 (42%) with LQT2, and 16 (8%) with LQT3] had a concomitant psychiatric diagnosis requiring medication [150 female (76%), mean age at diagnosis 27 ± 18 years, median follow-up time 6.6 years (IQR 2.9-13)]. The most common psychiatric conditions were depression (71%), anxiety (62%), and ADHD (9%). The mean duration of therapy was 3.36 +/- 3.48 years and the most common medications used were fluoxetine (26%), sertraline (14%), and escitalopram (11%). There was no significant difference in QTc after starting the first psychiatric medication when compared to baseline (473 ± 33 vs 474 ± 35 ms, p=0.6). Prior to their LQTS diagnosis and while therefore untreated, 61/195 (31%) had at least 1 LQTS-associated cardiac event. This occurred in the setting of a psychiatric drug in 7 patients (11%). Following LQTS diagnosis and treatment, 14/195 patients (7%) have experienced a non-lethal BCE of which only 3/14 (21%) while on psychiatric medications. Conclusions: Although avoidance of medications with known QT-prolonging potential is prudent, attention to patient’s overall well-being besides just their LQTS must be given. After correct diagnosis and treatment, LQTS patients with concomitant mental health issues may be safely and effectively treated with medications known to prolong QTc.

AbstractBackgroundIsolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.MethodsRetrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.ResultsA total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.ConclusionsTVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.