Citations

The current recommendation for bioprosthetic valve replacement in severe aortic stenosis (AS) is either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). We evaluated the performance of a machine learning-based predictive model using existing periprocedural variables for valve replacement modality selection. We analyzed 415 patients in a retrospective longitudinal cohort of adult patients undergoing aortic valve replacement for aortic stenosis. A total of 72 clinical variables including demographic data, patient comorbidities, and preoperative investigation characteristics were collected on each patient. We fit models using LASSO (least absolute shrinkage and selection operator) and decision tree techniques. The accuracy of the prediction on confusion matrix was used to assess model performance. The most predictive independent variable for valve selection by LASSO regression was frailty score. Variables that predict SAVR consisted of low frailty score (value at or below 2) and complex coronary artery diseases (DVD/TVD). Variables that predicted TAVR consisted of high frailty score (at or greater than 6), history of coronary artery bypass surgery (CABG), calcified aorta, and chronic kidney disease (CKD). The LASSO-generated predictive model achieved 98% accuracy on valve replacement modality selection from testing data. The decision tree model consisted of fewer important parameters, namely frailty score, CKD, STS score, age, and history of PCI. The most predictive factor for valve replacement selection was frailty score. The predictive models using different statistical learning methods achieved an excellent concordance predictive accuracy rate of between 93% and 98%.

In modern eye care, the adoption of ophthalmology chatbots stands out as a pivotal technological progression. These digital assistants present numerous benefits, such as better access to vital information, heightened patient interaction, and streamlined triaging. Recent evaluations have highlighted their performance in both the triage of ophthalmology conditions and ophthalmology knowledge assessment, underscoring their potential and areas for improvement. However, assimilating these chatbots into the prevailing healthcare infrastructures brings challenges. These encompass ethical dilemmas, legal compliance, seamless integration with electronic health records (EHR), and fostering effective dialogue with medical professionals. Addressing these challenges necessitates the creation of bespoke standards and protocols for ophthalmology chatbots. The horizon for these chatbots is illuminated by advancements and anticipated innovations, poised to redefine the delivery of eye care. The synergy of artificial intelligence (AI) and machine learning (ML) with chatbots amplifies their diagnostic prowess. Additionally, their capability to adapt linguistically and culturally ensures they can cater to a global patient demographic. In this article, we explore in detail the utilization of chatbots in ophthalmology, examining their accuracy, reliability, data protection, security, transparency, potential algorithmic biases, and ethical considerations. We provide a comprehensive review of their roles in the triage of ophthalmology conditions and knowledge assessment, emphasizing their significance and future potential in the field.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

AbstractOn May 27, 2022, the Asia Pacific Heart Rhythm Society and the Heart Rhythm Society convened a meeting of leaders from different professional societies of healthcare providers committed to arrhythmia care from the Asia Pacific region. The overriding goals of the meeting were to discuss clinical and health policy issues that face each country for providing care for patients with electrophysiologic issues, share experiences and best practices, and discuss potential future solutions. Participants were asked to address a series of questions in preparation for the meeting. The format of the meeting was a series of individual country reports presented by the leaders from each of the professional societies followed by open discussion. The recorded presentations from the Asia Summit can be accessed at https://www.heartrhythm365.org/URL/asiasummit‐22. Three major themes arose from the discussion. First, the major clinical problems faced by different countries vary. Although atrial fibrillation is common throughout the region, the most important issues also include more general issues such as hypertension, rheumatic heart disease, tobacco abuse, and management of potentially life‐threatening problems such as sudden cardiac arrest or profound bradycardia. Second, there is significant variability in the access to advanced arrhythmia care throughout the region because of differences in workforce availability, resources, drug availability, and national health policies. Third, collaboration in the area already occurs between individual countries, but no systematic regional method for working together is present.

Abstract Cancer Associated Macrophage Like cells (CAMLs) are antigen presenting circulating stromal cells found in the blood of cancer patients (pts). Recently, PD-L1 expression on CAMLs was described in breast (BC), lung (LC) and renal cell carcinomas (RCC), appearing to parallel the inflammatory PD-L1 state of the tumor microenvironment, and acting as a possible predictive biomarker for PD-L1/PD-1 immunotherapeutics (IMTs). We monitored CAML PD-L1 from 48 pts in an array of solid tumors, prior PD-L1/PD-1 IMTs induction, to evaluate CAML’s ability to predict response by progression free survival (PFS) and overall survival (OS). Three single blind multi-year prospective studies were run to test PD-L1 CAML expression against PFS & OS, prior to induction of therapy in metastatic (m) LC (n=24), mBC (n=16) or mRCC (n=8). We recruited pts with pathologically confirmed progressing disease after at least one failed prior line of therapy. Blood samples (7.5 mL) were taken prior to start of new therapeutic regimes, i.e. pembrolizumab (n=36) or nivolumab (n=12). Whole blood was filtered by CellSieve microfilters to collect CAMLs, stain for PD-L1, and then scored as a binary high or low, to evaluate PFS & OS hazard ratios (HRs) by censored univariate & multivariate analysis at 24 months. CAMLs were found in 98% of all tested samples. Overall, pts with high CAML PD-L1 expression treated with IMT had significantly better PFS (HR=2.9, 95%CI=1.4–6.1, p=0.0067) and better OS (HR=2.7, 95%CI=1.2–6.1, p=0.0317) vs patients with low CAML PD-L1. These data suggests that PD-L1 expression in circulating CAMLs appears to predict pts with increased benefit to PD-L1/PD-1 IMTs in an array of tumor subtypes, though larger studies are needed to validate these findings. Private Funding by Creatv MicroTech, Inc. and supported grants by NCI-NIH (R43CA206840), and the Defense Advanced Research Projects Agency (DARPA)(W911NF-14-C-0098).

Despite advancements in the early-stage detection and expansion of treatments for prostate cancer (PCa), patient mortality rates remain high in patients with aggressive disease and the overtreatment of indolent disease remains a major issue. Prostate-specific antigen (PSA), a standard PCa blood biomarker, is limited in its ability to differentiate disease subtypes resulting in the overtreatment of non-aggressive indolent disease. Here we assess engorged cancer-associated macrophage-like cells (CAMLs), a ≥50 µm, cancer-specific, polynucleated circulating cell type found in the blood of patients with PCa as a potential companion biomarker to PSA for patient risk stratification. We found that rising PSA is positively correlated with increasing CAML size (r = 0.307, p = 0.004) and number of CAMLs in circulation (r = 0.399, p < 0.001). Over a 2-year period, the presence of a single engorged CAML was associated with 20.9 times increased likelihood of progression (p = 0.016) in non-metastatic PCa, and 2.4 times likelihood of progression (p = 0.031) with 5.4 times likelihood of death (p < 0.001) in metastatic PCa. These preliminary data suggest that CAML cell monitoring, in combination with PSA, may aid in differentiating non-aggressive from aggressive PCas by adding biological information that complements traditional clinical biomarkers, thereby helping guide treatment strategies.

Histone‐lysine N‐methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial‐to‐mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor‐beta‐independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA‐seq and assay for transposase‐accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild‐type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell‐intrinsic and cell‐extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.

12051 Background: The combination of ipilimumab and nivolumab (Ipi-Nivo) is a standard of care regimen in many malignancies. However, immune-related adverse events (irAE) are common and are of great concern, especially when treating the elderly population. This subgroup of patients may be at greater risk for serious irAEs and be less able to tolerate the potential treatment side effects. We sought to retrospectively evaluate our experience treating elderly patients ≥ 80 years with Ipi-Nivo to characterize adverse events. Methods: A retrospective chart review of the electronic medical records of all patients treated with Ipi-Nivo at the Mayo Clinic Health System was performed. Patients with any solid tumor who received their first dose of Ipi-Nivo at the age of ≥ 80 were included. Records were analyzed for baseline characteristics, cancer type, toxicity, and response to therapy. Differences between continuous and categorical variables were assessed using the students’ t-test and the chi-squared test, respectively. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazard models assessed the relative contribution of factors to survival after treatment. P values < 0.05 were considered statistically significant. All analyses were performed using SAS V.9.4. Results: Forty-six patients met inclusion criteria, 13 females and 33 males. Median age of first dose was 83 (Range: 80 - 94). Sixty-seven percent had an ECOG performance status (PS) 0-1 and 33% had an ECOG PS 2-3. Thirteen (28.3%) patients received 4 cycles of Ipi-Nivo. Cancers included: 18 (40%) melanomas, 10 (21%) mesothelioma, 9 (19.5%) lung cancers, and 9 (19.5%) other types. Thirty-one patients (67%) developed at least one irAE. Of the irAEs, 8 (17.4%) were grade 1, 20 (43.5%) were grade 2, 14 (30.4%) were grade 3, and 3 (6.5%) were grade 4. Systemic steroids were used in 29 (63%) patients. Twenty-six (56.5%) patients were hospitalized for any cause, and 12 (26.1%) were hospitalized due to an irAE. Of the 26 patients hospitalized during treatment, 19 (73%) died within 1 year of discharge; 11 (42%) died within < 1 month of discharge and 3 (12%) died within 1-3 months of discharge. Median OS from the date of first Ipi-Nivo dose was 14.6 months in the ECOG PS 0-1 and 6.5 months in the ECOG PS 2-3. ECOG PS of 0-1 was associated with a significantly decreased risk of mortality (HR [hazard ratio] 0.33, 95 % CI [confidence interval]: 0.15-0.70; p=0.0025) compared to ECOG PS of 2-3. Conclusions: This is the first analysis to evaluate the outcomes of Ipi-Nivo in patients ≥ 80 years. Approximately 60% of the patients required systemic steroids and a quarter were hospitalized with grade 3-4 irAEs. As expected, patients with ECOG PS 2-3 did significantly worse than ECOG PS 0-1. Ipi-Nivo should be used with caution in patients ≥ 80 years.

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and accounts for majority of the deaths from renal cancer. SETD2, the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is frequently mutated in ccRCC. Studies have shown that SETD2 mutations are often subclonal and the mutation rate dramatically increases from 25% in primary ccRCC to more than 60% in metastatic ccRCC, suggesting SETD2 loss plays an important role in renal cancer metastasis. However, mechanisms underpinning how SETD2 mutation drives invasion and metastasis in ccRCC is largely unknown. Here, by performing RNA-seq and ATAC-seq in a non-tumorigenic renal epithelial cell line isogenic for SETD2 loss-of-function, we found that SETD2 inactivation induces dramatic changes in the transcriptome and drastically enhances chromatin accessibility, which allows binding of a variety of transcription factors. We also discovered that SETD2 loss induces a TGFβ-independent EMT program, which is a major pathway linked to metastasis. Correlation of RNA-seq with ATAC-seq identifies SOX2, OCT2 and PRRX1 as key transcription factors promoting the SETD2 loss-driven EMT program. Furthermore, we found that this distinct EMT program is in part triggered by secreted factors, which suggests that SETD2 mutation promotes a metastasis-permissive tumor microenvironment through paracrine signaling. In summary, our findings reveal that SETD2 is a key regulator of EMT phenotypes that may explain the role of SETD2 mutations in ccRCC metastasis and further uncover potential therapeutic targets for SETD2-mutant ccRCC patients. Citation Format: Tianchu Wang, Ryan Wagner, Ryan Hlady, Sungho Kim, Xiaoyu Pan, Thai Ho, Keith Robertson. SETD2 loss in renal epithelial cells induces epithelial to mesenchymal transition in a TGFβ-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1226.

695 Background: Recent results from COSMIC 313 trial and updated findings from other contemporary trials have added to the existing body of evidence for 1L mRCC. Therefore, we present the most up-to-date results from our living, interactive systematic review (LISR) to facilitate the choice of optimal therapy in 1L mRCC setting. Methods: This LISR and network meta-analysis is maintained using a novel living evidence synthesis (LIvE) framework. The framework facilitates the identification of new or updated studies using an automated ‘living’ search which is followed by screening and extraction in a semi-automated fashion within a machine learning assisted graphical user interface. Relevant data is parsed and analyzed to compute mixed treatment comparisons and certainty of evidence is adjudicated using a rule-based algorithm. Detailed methods have been published before (PMID: 33824031). Results: As of October 1st 2022, this LISR includes 16 clinical trials (30 references). Mixed treatment comparisons showed statistically significant PFS benefit with lenvatinib-pembrolizumab (LenPem; rank 1) when compared to cabozantinib-nivolumab (CabNivo; rank 3; hazard ratio [HR]: 0.69, 95% confidence interval: 0.52-0.93), CaboNivo-ipilimumab (CaboNivoIpi; rank 4; HR: 0.62; 0.43-0.89), avelumab-axitinib (AveAxi; rank 5; HR: 0.56; 0.43-0.75), PemAxi (rank 6; HR: 0.55; 0.42-0.72), atezolizumab-bevacizumab (AteBev; rank 7; HR: 0.46; 0.35-0.59), and NivoIpi (rank 8; HR: 0.45; 0.35-0.59). No significant differences were observed between CaboNivoIpi and other combination therapies for PFS improvement. Similarly, for OS, LenPem (rank 1), PemAxi (rank 2) and CaboNivo (rank 3) were ranked as potentially more efficacious treatment options than other counterparts. However, no statistically significant difference was observed for OS benefit with mixed treatment comparisons. The odds of achieving an ORR were higher with LenPem (rank 1; odds ratio [OR]: 2.44; 1.43-4.17), and CaboNivo (rank 2; OR: 1.77; 1.04-3.03) when compared to CaboNivoIpi (rank 6). NivoIpi (rank 1), LenPem (rank 2), CaboNivoIpi (rank 3) were ranked potentially as more efficacious treatments for achieving a CR. In terms of grade 3 or higher treatment related adverse events, NivoIpi (rank 3) was ranked as potentially the safest option among other combinations while CaboNivoIpi (rank 12), LenPem (rank 11), and CaboNivo (rank 10) were more likely to increase the risk of toxicity compared to most other treatments. Conclusions: Triplet combination of CaboNivoIpi may not provide additional survival benefit compared to other immunotherapy combinations and may increase toxicity. Patient-level considerations such as treatment toxicity, and quality of life should be factored in when opting intensified 1L therapies in mRCC patients.