Citations

Introduction: Heart failure with preserved ejection fraction(HFpEF) is a syndromemwith limited treatment modalities. Our control over 30 day readmissions and readmission outcomes is limited. Methods: HCUP’s Nationwide Readmissions Database (NRD) from 2013-14 was used for HFpEF related hospitalizations using ICD-9- CM diagnostic code:428.3x in primary diagnosis field. 30-day readmissions were identified and classified into two groups: same-hospital readmissions and different-hospital readmissions. A comparative analysis was conducted focused on three metrics - mortality, length of stay (LOS) and cost of hospitalization. We used hierarchical two-level modeling and propensity score matching to adjust for confounders. Results: Of the 94,988 readmitted patients (age >65 years: 79%, Females: 61.45%) - 76,665 (80.70%) to the same hospital and rest to different hospitals. After adjusting extensive list of confounders, same hospital readmission was associated with better outcomes including in hospital mortality (OR: 0.73, 95% CI: 0.66 - 0.80, p<0.001), LOS (Days: -1.14, 95% CI: -1.31 - -0.97, p<0.001), Cost of care ($: -4208, 95% CI: - 4681 - -3734, p<0.001). For validation of our results, we ran propensity score matching, showed similar results - in hospital mortality (6.23% vs 8.07%), LOS (6.30 ± 0.08 vs 7.47 ± 0.095), Cost of care (14042.7 ± 215.7 vs 18685.4 ± 279.2). Post hoc high-risk subgroup analysis were conducted and showed similar results (Figure). Number needed to treat (for mortality) was 74 patients. Up to ~ 100 million dollars could have been saved over 2 years. Conclusions: Considering scale of problem and limited option to prevent worse outcomes, Simple interventions such as redirecting patient to same hospital as previous admission would be beneficial.

We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Abstract Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

260 Background: dysphagia (dys) palliation in non-operable esophageal cancer (EC) continues to be a challenge. While chemotherapy and radiation help with dys, many patients require endoscopic interventions during their illness. Self-expanding metal stents have been the mainstay of endoscopic interventions but have a significant risk of severe adverse events and prevent the patient from being able to lie flat without severe reflux. Cryotherapy (cryo) is an emerging technique that can be used while the patient is receiving systemic therapy (ST). Previous retrospective studies showed improvement in dys with a favorable adverse event profile but did not report on quality of life (QOL) or reflux symptoms in patients receiving ST. Prospective studies have shown modest improvement in dys and QOL in patients not receiving ST. This prospective study reports the outcomes of cryo including dys, QOL, reflux symptoms and adverse events (AE) in patients receiving ST. Methods: A prospective multicenter cohort study of 35 adult inoperable EC patients undergoing cryo from Sep 2017 to Aug 2021. QoL was assessed using a modified EORTC QLQ-OES18 questionnaire (score 18 to 72, higher scores indicating worse QoL) while dys was measured using a 4-point Likert scale (0, no Dys; 1, Dys to solids; 2, Dys to semi-solids; 3, Dys to liquids; 4, Dys to saliva) at the start of cyro and 1-2 weeks post cryo. Paired t-test was used to evaluate changes in QoL and Dys between pre- and post-cryo. Results: There were 29 males and 6 females (30 stage IV and 5 stage III at diagnosis). Among 35 patients, a total of 104 cryo procedures were performed, with a mean of 3 per patient. The median number of tumor sites treated per cryo was 2 while the median number of cryo cycles delivered per tumor site was 3. The median total freeze time per tumor site was 60 seconds. The mean QoL score improved significantly from 31.8 pre-cryo to 28.2 with one cryo session (improvement of 3.6 points; p < 0.001). The mean dysphagia score improved significantly from 1.42 to 1.05 per cryo session (improvement of 0.37 points; p = 0.002). The mean After a mean of 3 cryo sessions, QoL score improved significantly from 35.9 pre-cryo to 29.8 post-cryo (improvement of 6 points; p = 0.001) and the mean dysphagia score improved significantly from 1.97 pre-cryo to 1.25 post-cryo (improvement of 0.72 points; p = 0.004). 86.5% of patient were able to sleep lying flat without heartburn or regurgitation. 6 patients received another intervention (1 stenting, 3 radiation and 2 dilation) for Dys palliation. 8 patients underwent feeding tube placement. Cryotherapy related grade 3 or higher adverse events occurred after 3 cryo sessions. Conclusions: Cryotherapy for palliation in non operable esophageal cancer improved dysphagia and quality of life without causing reflux and had a favorable adverse event profile with most patients not needing another intervention for dysphagia palliation.

Abstract Background Glycemic traits—such as hyperinsulinemia, hyperglycemia, and type 2 diabetes—have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. Methods Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). Results In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. Conclusions Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

AbstractBackgroundThe incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants.MethodsRelying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.ResultsIncreasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores.ConclusionsPersonal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.

AbstractBackgroundMultiple myeloma (MM) measurable residual disease (MRD) evaluated by flow cytometry is a surrogate for progression‐free and overall survival in clinical trials. However, analysis and reporting between centers lack uniformity. We designed and evaluated a consensus protocol for MM MRD analysis to reduce inter‐laboratory variation in MM MRD reporting.MethodsSeventeen participants from 13 countries performed blinded analysis of the same eight de‐identified flow cytometry files from patients with/without MRD using their own method (Stage 1). A consensus gating protocol was then designed following survey and discussions, and the data re‐analyzed for MRD and other bone marrow cells (Stage 2). Inter‐laboratory variation using the consensus strategy was reassessed for another 10 cases and compared with earlier results (Stage 3).ResultsIn Stage 1, participants agreed on MRD+/MRD− status 89% and 68% of the time respectively. Inter‐observer variation was high for total numbers of analyzed cells, total and normal plasma cells (PCs), limit of detection, lower limit of quantification, and enumeration of cell populations that determine sample adequacy. The identification of abnormal PCs remained relatively consistent. By consensus method, average agreement on MRD− status improved to 74%. Better consistency enumerating all parameters among operators resulted in near‐unanimous agreement on sample adequacy.ConclusionUniform flow cytometry data analysis substantially reduced inter‐laboratory variation in reporting multiple components of the MM MRD assay. Adoption of a harmonized approach would meet an important need for conformity in reporting MM MRD for clinical trials, and wider acceptance of MM MRD as a surrogate clinical endpoint.