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BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Background: We aimed to evaluate the outcomes of patients with confirmed and possible cardiac sarcoidosis who had an ICD implant and identify predictors of ventricular arrhythmias and mortality in this patient population. Methods: We performed a retrospective study patients with a diagnosis of cardiac sarcoidosis (CS) at Mayo Clinic and had an ICD implanted for primary or secondary prevention indication. Adult patients (≥18 years) with a diagnosis of possible or confirmed (biopsy-proven) CS with an ICD implanted between 1993 and 2022 were included. Primary outcomes included sustained ventricular arrhythmia (VT) resulting in a documented appropriate ICD shock and death from any cause. Secondary outcomes included ICD-related complications. Results: We identified 148 patients, in which 23 patients (15.5%) experienced VT events with a total of 160 treated episodes. 4 patients (2.7%) experienced inappropriate ICD shocks (11 episodes). During a median follow up of 3.1 years, 26 patients deceased, and the overall survival was 98% and 77% at 1 and 5 year. Older age, CAD, CKD, paced rhythm and QRS duration were associated with worse survival (Figure 1 – 4) . Device related complications were rare, except for the higher percentage of CHF in patients with VT after implant, however this was not statistically significant. Patients with ICD therapies were younger (53 vs 58 years, p=0.029), had higher LGE burden (26.9 vs 16.3%, p=0.01), and higher percentage of LV mass (26.9 vs 16.3, p=0.011). Multivariate logistic regression model which showed that patients with biopsy proven sarcoidosis had significantly higher odds of VT events (OR: 3.04, 95% CI: 1.02 to 9.08, p = 0.046). In patients with increased LV mass (every 10 g increase), the odds of developing VT increased by 1.49 (95% CI: 1.02 to 2.19, p = 0.041). LV mass and LGE percentage showed fair ability of predicting the outcome by ROC analysis. Youden’s index showed 26 for LV mass and 16% for LGE percent as the optimal cut-off points for predicting VT outcomes (Figure 5) . The sensitivity, specificity, positive predictive value, negative predictive value were 81.8%, 74.1%, 37.5%, 95.6% and 75.4% respectively for an LV mass of 26 grams and 81.8%, 63.8%, 30.0%, 94.9% and 66.7% respectively for an LGE percentage of 16%. Conclusion: LGE burden continues to be a major predictor for VT events in patients with CS. Myocardial tissue burden and electrical abnormalities from CS predict mortality than myocardial function loss.

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.

Abstract Background Resident Doctors (RDs) in the UK must balance clinical training with non-clinical administrative tasks. Concerns increase over how these tasks impact their professional development, job satisfaction and patient care. The shift toward consultant-delivered care has led to a redistribution of responsibilities, increasing administrative burden on RDs. Aims This study aims to quantify how RDs allocate time between patient-facing and non-patient-facing tasks and assess impact on job satisfaction. Design National multicentre observational cohort study. Methodology The Time Allocation in Clinical Training study is a multicentre, observational cohort study conducted over seven months (January–July 2024) at secondary NHS centres. 137 RDs, from Foundation Year 1 to Specialty Training Year 8, were observed for 4-hour periods, with time tracked using stopwatches for five task categories. An optional survey assessed job satisfaction, rated on a five-point Likert scale. Results RDs spent 73.0% of their time on non-patient-facing tasks, and 17.9% on patient-facing activities. Women spent more time on non-patient-facing tasks compared to men (75.0% vs. 69.9%, P = 0.03). Junior RDs (Foundation years and Core trainees) spent significantly less time on patient-facing tasks compared to senior RDs (ST6-8) (38.4% vs. 17.8%; P = 0.004). Most RDs (62%) reported dissatisfaction with the administrative burden. Electronic health record users spent significantly more time on administrative tasks than paper-based record users (44.1% vs. 37.3%; P = 0.02). Conclusions The study reveals a significant imbalance between clinical and administrative tasks, with excessive administrative workload contributing to RD dissatisfaction. Streamlining administrative duties and integrating digital solutions is crucial for improving job satisfaction, clinical development and healthcare delivery in the NHS.

3099 Background: Immune checkpoint inhibitors (ICI) are effective in melanoma, but many patients experience progression on or after approved ICI +/- MAPK inhibitor therapy. Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy (RPT) and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted RPT that can be radiolabeled with either 203 Pb (patient selection and dosimetry assessments) or 212 Pb (alpha particle therapy). Here, we present data on the first in-human evaluation of [ 203 Pb/ 212 Pb]VMT01 in patients with metastatic melanoma. FDA granted Fast Track Designation to the product on the bases of preclinical experiments combining [ 212 Pb]VMT01 with immunotherapy. Methods: This is a first-in-human dose-finding study to determine the safety, pharmacokinetics, dosimetry and preliminary efficacy of [ 212 Pb]VMT01 in subjects with MC1R-positive metastatic melanoma who progressed on at least 1 approved first-line therapy (NCT05655312). Phase 1 of the trial includes escalating dose cohorts. The first two cohorts incorporate dosimetry evaluations (reported separately) with the imaging surrogate [ 203 Pb]VMT01 prior to receiving up to 3 treatment cycles of [ 212 Pb]VMT01 therapy (injected activity of 111 MBq (3 mCi) or 185 MBq (5 mCi) for Cohort 1 and 2, respectively). Participants are evaluated for any DLT for the first 6 weeks after cycle one. Efficacy is assessed by RECIST 1.1 criteria by the investigator. Following the start of the study the anticipated combination arm with nivolumab was opened as an amendment. Results: Cohort 1 (DCO 04Sep24) was completed with 3 enrolled participants who received 3 treatment cycles without any DLTs or SAEs. Cohort 1 participants showed prolonged stabilization of disease from start of treatment (mean: 11.1 months); one participant developed a confirmed objective response (PR) after completion of all three [ 212 Pb]VMT01 administrations and is still on trial after 13.1 months from start of treatment. Cohort 2 has completed with 7 enrolled participants. No DLTs or related SAEs have been observed. All participants in this Cohort progressed after either the first cycle (3 participants) or the second cycle (4 participants).Based on these preliminary results showing anti-tumor effect at the lower dose, additional cohorts for both monotherapy and in combination with nivolumab were introduced at a de-escalated dose of 55.5 MBq (1.5 mCi). Both cohorts are now open for enrollment. Updated safety and efficacy data will be analyzed and presented at ASCO. Conclusions: At 111 MBq and 185 MBq activity levels, [ 212 Pb]VMT01 was safe and well-tolerated. An objective response and prolonged stabilization of disease were observed at the 111 MBq activity level while no effect was seen at 185 MBq. The study will continue to explore potentially immunostimulating lower doses of administered activity of [ 212 Pb]VMT01 either as a monotherapy or in combination with nivolumab. Clinical trial information: NCT05655312 .

ABSTRACT Background Although Percutaneous Coronary Intervention (PCI) is the cornerstone treatment acute myocardial infarction (AMI), its use in the elderly, specifically nonagenarians patients, is not well studied. This study sought to compare the outcomes and complications of nonagenarian patients who experienced AMI between those who underwent PCI and those who underwent medical treatment only. Methods We evaluated 301,440 nonagenarian (ages 90−99) patients who presented to the hospital with AMI who were listed in the National Inpatient Sample from 2016 to 2021. AMI was defined according to the ICD‐10 Diagnostic Codes. Multivariable logistic regression analysis was used to examine the association of PCI with primary outcomes of mortality and secondary outcomes. The temporal trend of both the incidence of PCI in nonagenarian patients as well as the mortality rate between 2016 and 2021 were expressed as percentages over time. Results Of the total ( n = 301,440) nonagenarian patients with AMI, 33,035 patients underwent PCI while 268,406 did not undergo PCI and rather, just utilized optimized medical therapy (OMT). Of these, 3290 (9.96%) died in the PCI group, and 43580 (16.24%) died in the OMT group. All of the secondary outcomes were significantly different between the PCI and OMT groups. Comparing the two groups, the PCI group was associated with decreased mortality (OR 0.63 [95% CI, 0.58−0.69]; p < 0.001), acute heart failure (OR 0.88 [95% CI, 0.82−0.95] p < 0.001), and AKI (OR 0.75 [95% CI, 0.70−0.79]; p < 0.001), and increased cardiogenic shock (OR 3.06 [95% CI, 2.77−3.38]. The temporal of PCI in nonagenarian patients showed an increase in frequency from about 8.3 in 2016 to about 13.7% in 2021. Furthermore, comparing the mortality between the PCI and OMT groups showed a significant difference with a decreased mortality in the PCI group. Conclusions Nonagenarian patients experiencing AMI who underwent PCI is associated with a significant mortality decrease compared to those who underwent OMT only. The PCI group was also associated with a significant decrease in multiple secondary complications including acute heart failure, AKI, acute stroke, and an increase in cardiogenic shock. Temporally, we have seen an increase in PCI being used in nonagenarian patients over the interval.

Myocardial Bridging (MB) is typically a benign congenital coronary anomaly. MB can infrequently result in complications such as myocardial ischemia, arrhythmias, and sudden cardiac death. Recent studies suggest an underlying genetic component for MB involving DES, FBN1, SCN2B, or NOTCH1. The role of percutaneous coronary intervention (PCI) in managing MB, compared to optimal medical therapy (OMT), remains uncertain. Our study used the National Inpatient Sample (NIS) Database to identify patients aged 18 or older with myocardial bridging who were managed with PCI versus medical therapy. We compared the outcomes between both groups including in-hospital mortality, the trend of management of MB and other in-hospital outcomes or complications. Our results showed no statistically significant difference between both subgroups when comparing in-hospital mortality and secondary outcomes of cardiac arrest and the development of an acute kidney injury (AKI). Patients with myocardial bridging treated with PCI had a higher risk of developing cardiogenic shock, requiring LVAD, and requiring the use of intra-aortic balloon pump (IABP) compared to the medical therapy subgroup. Our study suggests the decision to perform PCI in myocardial bridging patients should be individualized such as in patients with refractory symptoms despite medical therapy or those with known high-risk features.