Citations

Abstract While the launch of the da Vinci Surgical System catalyzed the expansion of robotic surgery across disciplines, adoption in plastic surgery remains modest. To explore this disconnect, this study surveys plastic surgeons to gauge interest, utilization, and perceived barriers to robotic surgery adoption. A 15-question survey on training, access, interest, and barriers to robotic procedures was developed on Qualtrics and distributed via email to members of the American Society of Plastic Surgeons (ASPS) in May 2024. Descriptive statistics were used to summarize responses. About 123 responses were collected among 3,512 survey recipients. Among respondents, 84.6% reported having access to a surgical robot; however, only 13.8% had training on robotic systems during residency, and only 12.2% utilized the technology for plastic surgery procedures. Interest in robotics was noted among 47.9% of respondents, particularly for deep inferior epigastric perforator (DIEP) flap procedures (65.5%), rectus/Vertical Rectus Abdominis Myocutaneous (VRAM) flap (58.2%), and hernia repairs (27.3%). Key barriers to adoption included training requirements (63.9%), lack of demand (60.2%), increased operative time (54.6%), and financial concerns (26.9%). Additional obstacles cited were credentialing difficulties and skepticism about the necessity of robotics in plastic surgery. The present survey identified inadequate training, high costs, and limited demand as key barriers to the adoption of robotics in plastic surgery, reflecting the current lack of robotic integration into residency curricula, as well as the substantial investment and maintenance costs associated with robotic systems. Nevertheless, the strong interest in robotics highlights the need for expanded training programs, promotion of clinical benefits, and research quantifying potential downstream savings to overcome these barriers.

Abstract Gangliosides are structurally complex glycosphingolipids that regulate cellular signaling via interactions with extracellular binding partners and by influencing protein function within the membrane. Their comprehensive analysis remains analytically challenging, in part due to low endogenous abundance, extensive structural diversity, and the frequent occurrence of isomeric species arising from both glycan and ceramide moieties. Here, we present a hydrophilic interaction liquid chromatography (HILIC) nanoelectrospray ionization tandem mass spectrometry (nanoESI-MS/MS) method specifically designed to achieve isomer-resolved analysis and molecular species-level quantification of gangliosides. To improve characterization of low-abundance fatty acyl fragments, the workflow was extended by combining nanoESI with online fraction collection and subsequent direct infusion. The method demonstrated stable chromatographic performance, high sensitivity, and reproducible quantitative results across ten mouse tissues. Application of the workflow enabled quantification of 80 ganglioside molecular species belonging to 18 subclasses and revealed pronounced tissue-specific differences in subclass distribution and ceramide composition. Overall, this study establishes a robust and sensitive platform for comprehensive ganglioside analysis, providing new opportunities to investigate ganglioside diversity, regulation, and function in complex biological systems.

Abstract Background Arrhythmogenic mitral valve prolapse (AMVP) is increasingly recognized as a cause of sustained ventricular arrhythmias (VA) and sudden cardiac death. Although prior studies have identified clinical and imaging risk markers in AMVP, it remains unclear whether the arrhythmogenic phenotype differs between women and men. Purpose To investigate sex-specific differences in clinical profiles, structural substrates, and arrhythmia presentations in patients with AMVP who experienced sustained VA. Methods We conducted a sex-based sub-analysis of a multicenter cohort (35 centers from 15 countries) of patients with AMVP and sustained VA. Participants were grouped by sex and by initial arrhythmia type (sustained monomorphic ventricular tachycardia [SMVT] vs ventricular fibrillation [VF]). Data collected included clinical history, ECG findings, echocardiographic measurements, and cardiac MRI (CMR) markers, such as late gadolinium enhancement (LGE) patterns and mitral annular disjunction (MAD). These factors were compared across groups. Results The study comprised 129 women (57%) and 96 men (43%). Women were diagnosed at younger ages (39±16 years vs. 49±16 years, p<0.03) and had more frequently a family history of MVP (22% vs 10%, p=0.027). MAD was significantly more common in women (66% vs 48%, p=0.015) while LGE was more frequently observed in men than women (N=39 (72%) vs N=41 (53%), p=0.028), with no significant regional patterns (myocardial and/or papillary muscle). ECG T-wave inversion (p=0.627), PVC burden (p>0.03) and arrhythmia types were similar in men and women. However, stress was a more often commonly recognized as the initiating trigger for VA in men than in women (38% [N=24] vs. 18% [N=18], p<0.05). The overwhelming majority of VA were initiated by PVCs in both sexes with no differences in the initiating mechanisms. Conclusion In patients with AMVP presenting with sustained VA, the arrhythmic phenotype and initiating mechanisms are similar between sexes, although stress was a significantly stronger trigger for VA in men. Women more often exhibited MAD, whereas LGE was more frequent in men. These findings suggest that structural and tissue-based markers, rather than sex alone, contribute to the development of malignant arrhythmias in AMVP.

Abstract Purpose: VV1 is designed to induce selective oncolysis of tumor cells and amplify cellular antitumor immune responses. This open-label, phase I, multicenter clinical trial assessed the safety and tolerability of VV1 monotherapy administered intratumorally or intravenously or administered intravenously in combination with avelumab. Patients and Methods: Patients with advanced solid tumors received intratumoral (n = 27) or intravenous VV1 monotherapy (n = 33) or intravenous VV1 plus avelumab (n = 16). Infusion durations (15–180 minutes) and viral dose (1.7 × 1010 or 1 × 1011 TCID50) were also evaluated. Study objectives included VV1 safety and tolerability, pharmacokinetics, pharmacodynamics, preliminary efficacy, and immune responses. Results: Intratumoral and intravenous VV1 were well tolerated, and injection reactions were infrequent. The most common adverse events of any grade related to VV1 were cytokine release syndrome (58%), fatigue (33%), and decreased lymphocyte count (32%). Virus infection of tumors was confirmed by NIS imaging and increases in serum levels of virally encoded interferon-β (IFNβ). Histologic tumor analysis at 28 days after intratumoral VV1 administration indicated increases in tumor-infiltrating immune cells. Two durable partial responses were recorded: a patient with pheochromocytoma after one intravenous dose of VV1 and a patient with thymic cancer in the combination arm. Stable disease was observed in 17 of 49 patients (34.7%) who received intravenous VV1. Conclusions: This first-in-human study demonstrates that intratumoral or intravenous VV1 administration had an acceptable safety profile as monotherapy and intravenously in combination with avelumab. There is preliminary antitumor activity. Intratumoral VV1 plus cemiplimab is now showing promise in the neoadjuvant setting. Significance: VV1 is a tumor-selective oncolytic vesicular stomatitis virus engineered to express IFNβ and the thyroidal NIS reporter gene. In this phase I study, we have demonstrated that a single administration of VV1, as a monotherapy or with an immune checkpoint inhibitor is safe, infects tumor lesions resulting in intratumoral infiltration of immune cells, and exhibits early signs of antitumor activity in patients with advanced unresectable and metastatic solid tumors.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. 1 The NCCN Guidelines Panel for AML convenes annually to update recommendations for the diagnosis and treatment of AML in adults. These recommendations are based on a review of recently published clinical trials that have led to significant improvements in treatment or have yielded new information regarding biologic factors that may have prognostic importance. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding the monitoring and management of measurable (minimal) residual disease.

Pharmacological plasminogen reduction enhanced liver regeneration experimentally and clinically. siRNA-induced plasminogen deficiency promoted hepatocyte proliferation after partial hepatectomy in mice, contrasting genetic deficiency models. In the HeLiX trial, tranexamic acid reduced post-hepatectomy liver failure odds, suggesting a novel therapeutic strategy.

e18026 Background: Immune checkpoint inhibitor (ICI) therapy is part of standard of care first-line therapy for recurrent or metastatic (R/M) HNSCC. However, less than 20% of patients (CPS ≥1) have an objective response to ICI monotherapy, and most tumors progress within ~3 months. We sought to improve the proportion of patients who benefit from a chemotherapy-free regimen by combining intratumoral (IT) VV1 oncolytic virus (VSV-IFNβ-NIS) injections with the anti-PD-1 antibody, cemiplimab. We report a pre-planned analysis of Simon's stage 1 results. Methods: We activated a phase 2 study testing the efficacy of first line IT VV1 plus cemiplimab in 1 st line patients with R/M HNSCC. A Simon's two-stage design was employed whereby 10 patients would be accrued in stage 1, and if 3 or more responses were observed, 12 additional patients would be accrued for stage 2. The primary endpoint was objective response rate (ORR) per investigator (RECIST 1.1). Eligible patients had untreated R/M HNSCC from primary oropharynx, oral cavity, hypopharynx, or larynx sites with CPS ≥1. Patients had to have at least one measurable lesion amenable to IT injection. Treatment comprised of IT injections to 1-5 lesions of oncolytic VV-1 virus and IV cemiplimab 350 mg on day 1, repeated every 21 days. Each lesion could be injected 3 times; a 4th injection was allowed if a partial response (PR) was achieved after 3 injections. Cemiplimab could be continued for up to 2 years until progression or unacceptable toxicity. Results: Patient and tumor characteristics, as well as efficacy and toxicity are summarized in the table below. Ten patients were treated at the time of Stage 1 analysis, with 3 showing a confirmed PR for ORR of 30%. Responder CPS scores were 45, 12 and 20%. Two of the responders subsequently showed progression after 6.2 and 9.9 months, the third has maintained PR at 7.7 months to date. Eight of 10 patients showed decrease in the sum of target lesion size (mean decrease of 16%; range -57 to 77%). One grade 2 event of ICI nephritis resolved with corticosteroid treatment. Conclusions: Three patients showed confirmed PR by RECIST 1.1 in Simon's stage 1, meeting criteria to proceed to Simon's stage 2. A total of 22 patients in the HNSCC will be enrolled. VV1 plus cemiplimab shows promise in first line R/M HNSCC based on these initial results. Clinical trial information: NCT04291105 . Patient demographics. N (treated) 10 Sex 20% female Median age (y) 60 (54 – 76) Oropharynx 7 HPV+ 7 Oral cavity 3 PD-L1 CPS median (range) 7.5 (1-45%) Locoregional injection 3 Distant injection 6 Local and distant injection 1 Best response (RECIST 1.1) PR 3 SD 5 PD 2 Adverse Events #pts any VV1/cemiplimab-related G3 AE 4 Lymphopenia 3 Elevated ALK 1

9557 Background: High-dose interleukin-2 (IL-2) is administered following tumor-infiltrating lymphocyte (TIL) therapy, yet cardiotoxicity frequently limits dose delivery. The clinical significance of peri-dose troponin elevations during IL-2 remains poorly defined. We evaluated troponin kinetics during IL-2 dosing and their association with significant cardiac events and IL-2 interruption. Methods: We retrospectively analyzed patients with metastatic melanoma treated with TIL therapy followed by inpatient high-dose IL-2 at Mayo Clinic Rochester (N = 24; 87 IL-2 doses). High-sensitivity troponin and ECGs were obtained before and after each IL-2 dose. Clinically significant cardiac events were defined as QTc prolongation > 480 ms, arrhythmias (excluding isolated sinus tachycardia), new ECG abnormalities, vasopressor requirement, or cardiology consultation. Dose-level outcomes included cardiac events and subsequent IL-2 dose interruption. Paired troponin changes were assessed using Wilcoxon signed-rank testing. Dose-level associations were evaluated using clustered logistic regression to account for repeated IL-2 doses within patients. Results: 24 patients received 87 IL-2 doses (median 3 [IQR 2 - 5]). Median age was 63 years (IQR 54 - 70), and 58% were male. Baseline troponin median was 11 ng/L (IQR 6 - 21); 38% had baseline troponin > 14 ng/L. Post-dose troponin exceeded 14 ng/L in 16/24 patients (67%) and 48/87 doses (52%). Median delta troponin was 0 ng/L (IQR −1 to 6; range −24 to 133), with post-dose levels higher than pre-dose values ( p = 0.02). Clinically significant cardiac events occurred in 33% of patients; no post-IL-2 reductions in left ventricular ejection fraction were observed. At the dose level, cardiac events occurred only when post-dose troponin exceeded 14 ng/L (15/48 [31%] vs 0/39 doses; p < 0.001). In clustered logistic regression, post-dose troponin ≥15 ng/L was independently associated with cardiac events (OR 9.6, 95% CI 1.5 - 60.6; p = 0.02) and subsequent IL-2 dose interruption (OR 3.4, 95% CI 1.1 - 10.7; p = 0.04). When modeled continuously, each 1-unit increase in log-transformed post-dose troponin was associated with higher odds of cardiac events (OR 3.3, 95% CI 1.6 - 6.7; p = 0.001) and IL-2 interruption (OR 2.8, 95% CI 1.6 - 4.9; p < 0.001). Baseline troponin correlated with peak post-dose troponin (ρ = 0.44, p = 0.04). Conclusions: Peri-dose troponin elevations are common during post-TIL high-dose IL-2; however, higher post-dose troponin independently identifies clinically significant cardiac toxicity and predicts IL-2 interruption after accounting for repeated dosing within patients. Baseline troponin modestly predicts peak elevations, supporting standardized, risk-stratified troponin monitoring and prospective evaluation of toxicity-adaptive IL-2 delivery strategies in TIL therapy.

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract Background For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Methods Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Results Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes ( BRCA1, BRCA2, PALB2, ATM, CHEK2 ). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). Conclusion This flexible, variant-level methodology combines nationally-collected ‘enriched’ datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.