Citations

Background: Recognition of the causes of early mortality after ventricular tachycardia (VT) ablation in patients with reduced left ventricular ejection fraction is an essential step toward improving post-procedural outcomes. Objective: This study sought to determine the causes of early mortality (≤30-days) after VT ablation in patients with reduced left ventricular ejection fraction and to understand further the circumstances surrounding death after the procedure. Methods: We performed a retrospective analysis of all patients undergoing VT ablation in patients with reduced left ventricular ejection fraction from January 1, 2013, to November 10, 2021, at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a detailed chart review of the electronic health record within the Mayo Clinic system and outside records. Results: A total of 503 patients (mean age 63 ± 13 years, 11.2% female) with EF <50% were included in the study. The 30-day all-cause mortality rate was 5% (n=25), and the mortality rate due to a procedural complication was 0.4%. Among all 30-day deaths, recurrent VT was the most common primary cause of death (44%). This was followed by decompensated heart failure (28%), procedure-related death (8%), cerebrovascular accident (CVA) (4%), and infection (4%). Most patients (91%) who died from VT had the VT recurrence within three days of the ablation. 76% of patients with early mortality had delayed referral for VT ablation, and 72% opted for comfort care before death. Conclusions: The overall early mortality (≤30-days) rate after catheter ablation of VT in patients with reduced left ventricular ejection fraction was 5%, but the death rate directly due to a procedural complication was only 0.4%. The most common cause of death was recurrent VT, followed by heart failure. Further research into ablation strategies is vital to improving the safety, efficacy, and durability of VT ablation.

Background: Recognition of the infectious characteristics among the sepsis-related early mortality after transvenous lead removal (TLR) is an essential step to improving patient outcomes. Objective: This study sought to understand the infectious characteristic and circumstances among the sepsis-related early mortality after TLR. Methods: We performed a retrospective analysis of all patients undergoing TLR from January 1, 2001, to January 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Patient details were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system and outside records when available. Results: A total of 2,319 patients were included in the study. The overall 30-day sepsis-related mortality rate was 1.25% (n=29). Among the sepsis-related deaths, 24 patients (83%) had systemic cardiac implantable electronic device (CIED) infection, and 4 patients (14%) initially had isolated pocket infection. The average time from admission to TLR was 11 days. MSSA was the most common organism (n=8, 28%), and this was followed by MRSA (n=4, 14%) and Candida (n=3, 10%). Twenty of these patients (69%) had vegetation on the echocardiogram: vegetation on lead only in 9 patients, vegetation on both valve and lead in 8 patients, and vegetation on valve only in 3 patients. Among valvular vegetations, 5 patients had tricuspid valve vegetations, 3 patients had aortic valve vegetations, 2 patients had mitral valve vegetations, and 1 patient had both mitral and aortic valve vegetation. The average size of vegetation was 1.3±0.8 x 1.1±0.6 cm. Conclusions: The 30-day sepsis-related mortality rate was 1.25%. Among the sepsis-related early deaths, MSSA was the most common organism, and more than two-thirds (69%) of the patients had vegetations on cardiac imaging. This highlights the importance of further research to improve the infection outcome in TLR patients.

Background: Recognition of the causes of early mortality after transvenous lead removal (TLR) is an essential step for the development of quality improvement programs. Objective: This study sought to determine the causes of early mortality after TLR and to further understand the circumstances surrounding death after TLR. Methods: We performed a retrospective analysis of all patients undergoing TLR from January 1, 2001, to January 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system and outside records when available. The causes of death were further characterized based on whether it was related to the TLR procedure. Results: A total of 2,319 patients were included in the study. The overall 30-day all-cause mortality rate was 3%. Among all 30-day deaths, infection was the most common primary cause of death (42%). This was followed by decompensated heart failure (17%), procedure-related death (10%), sudden cardiac arrest (7%), and respiratory failure (6%). The 30-day mortality rate directly due to complications associated with the TLR procedure was 0.3% due to vascular tear and cardiac perforation. A third of deaths (33%) occurred after discharge from index hospitalization, among which 43% were readmitted before their death, 35% died at home or a nursing facility, and 22% were discharged on comfort care and died in hospice. The main reasons for readmission prior to death were sepsis and decompensated heart failure. Conclusions: The majority (90%) of 30-day mortality after TLR was not due to complications associated with TLR procedures. The primary causes were infection and decompensated heart failure. This highlights the importance of further research to reduce postoperative mortality from these factors, including deaths after hospital discharge.

Abstract Evaluation of basal cell carcinoma (BCC) involves tangential biopsies of a suspicious lesion that is sent for frozen sections and evaluated by a Mohs micrographic surgeon. Advances in artificial intelligence (AI) have made possible the development of sophisticated clinical decision support systems to provide real-time feedback to clinicians that could have a role in optimizing the diagnostic workup of BCC. There were 287 annotated whole-slide images of frozen sections from tangential biopsies, of which 121 contained BCC, that were used to train and test an AI pipeline to recognize BCC. Regions of interest were annotated by a senior dermatology resident, an experienced dermatopathologist and an experienced Mohs surgeon, with concordance of annotations noted on final review. Final performance metrics included a sensitivity and specificity of 0.73 and 0.88, respectively. Our results on a relatively small dataset suggest the feasibility of developing an AI system to aid in the workup and management of BCC.

Abstract Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.

AbstractBackgroundAbsolute dosimetry measurement is an integral part of Treatment Planning System (TPS) commissioning and it involves measuring the integrated absorbed dose to water for all energies in a pencil beam scanning delivery system. During the commissioning of Singapore's first proton therapy center, a uniform scanned field with an Advanced Markus chamber method was employed for this measurement, and a large dose fluctuation of at least 5% was observed for 10% of the energy layers during repeated measurements.PurposeThis study aims to understand the root cause of this fluctuation by relating the actual delivered spot information in the log file with the charge measurement by the ion chambers.MethodsA dedicated pencil beam dose algorithm was developed, taking into account the log file parameters, to calculate the dose for a single energy layer in a homogeneous water phantom. Three energies, 70.2, 182.7, and 228.7 MeV were used in this study, with the 182.7 MeV energy exhibiting large dose fluctuation. The dose fluctuation was investigated as a function of detector's sizes (pinpoint 3D, Advanced Markus, PTW 34070, and PTW 34089) and water depth (2 , 6, and 20 cm). Twelve ion chambers measurements were performed for each chamber and depth. The comparison of the theoretically predicted integrated dose and the charge measurement served as a validation of the algorithm.ResultsAbout 5.9% and 9.6% dose fluctuation were observed in Advanced Markus and pinpoint 3D measurements at 2 cm depth for 182.7 MeV, while fluctuation of 1.6% and 1.1% were observed in Advanced Markus with 228.7 and 70.2 MeV at similar depth. Fluctuation of less than 0.1% was observed for PTW34070 and PTW 34089 for all energies. The fluctuation was found to diminish with larger spot size at 20 cm depth to 1.3% for 182.7 MeV. The theoretical and measured charge comparison showed a high linear correlation of for all datasets, indicating the fluctuation originated from the delivered spot characteristics. The cause of fluctuation was identified to be due to the spill change occurring close to the detector, and since the spot positional deviation profiles were different between two spills, this resulted in local hot spots between columns of spots. The actual position of spill change varies randomly during measurement, which led to a random occurrence of hot spot within the detector's sensitive volume and a fluctuating dose measurement.ConclusionThis is the first report of a dose fluctuation greater than 5% in absolute dosimetry measurement with a uniform scanned field and the cause of the fluctuation has been conclusively determined. It is important to choose the MU and scanning pattern carefully to avoid spill change happening when the spot delivery is near the detector.

4028 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n = 27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP < 5% (n = 28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Spatially resolved sequencing technologies help us dissect how cells are organized in space. Several available computational approaches focus on the identification of spatially variable genes (SVGs), genes whose expression patterns vary in space. The detection of SVGs is analogous to the identification of differentially expressed genes and permits us to understand how genes and associated molecular processes are spatially distributed within cellular niches. However, the expression activities of SVGs fail to encode all information inherent in the spatial distribution of cells. Here, we devised a deep learning model, Spatially Informed Artificial Intelligence (SPIN-AI), to identify spatially predictive genes (SPGs), whose expression can predict how cells are organized in space. We used SPIN-AI on spatial transcriptomic data from squamous cell carcinoma (SCC) as a proof of concept. Our results demonstrate that SPGs not only recapitulate the biology of SCC but also identify genes distinct from SVGs. Moreover, we found a substantial number of ribosomal genes that were SPGs but not SVGs. Since SPGs possess the capability to predict spatial cellular organization, we reason that SPGs capture more biologically relevant information for a given cellular niche than SVGs. Thus, SPIN-AI has broad applications for detecting SPGs and uncovering which biological processes play important roles in governing cellular organization.

Abstract Aims To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA). Methods and results We analyzed mild stenosis (25–49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02–3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09–2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07–2.22; P = 0.020). Conclusion In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs. Clinical trial registration ClinicalTrials.gov NCT02803411