Baicalin enhances the chemotherapy sensitivity of oxaliplatin-resistant gastric cancer cells by activating p53-mediated ferroptosis.

Gastric cancer is one of the most common malignant tumors, and chemotherapy is the main treatment for advanced gastric cancer. However, chemotherapy resistance leads to treatment failure and poor prognosis in patients with gastric cancer. Multidrug resistance (MDR) is a major challenge that needs to be overcome in chemotherapy. According to recent research, ferroptosis activation is crucial for tumor therapeutic strategies. In this work, we explored the solution to chemoresistance in gastric cancer by investigating the effects of the Chinese medicine monomer baicalin on ferroptosis. Baicalin with different concentrations was used to treat the parent HGC27 and drug-resistant HGC27/L cells of gastric cancer. Cell viability was measured by CCK8, and synergistic effects of baicalin combined with oxaliplatin were evaluated using Synergy Finder software. The effects of baicalin on organelles and cell morphology were investigated using projective electron microscopy. Iron concentration, MDA production and GSH inhibition rate were measured by colorimetry. ROS accumulation was detected by flow cytometry. The ferroptosis-related genes (IREB2, TfR, GPX4, FTH1), P53, and SLC7A11 were analysed by Western blot, and the expression differences of the above proteins between pretreatment and pretreatment of different concentrations of baicalin, were assayed in both parental HGC27 cells and Oxaliplatin-resistant HGC27/L cells. Mechanically, Baicalin disrupted iron homeostasis and inhibits antioxidant defense, resulting in iron accumulation, lipid peroxide aggregation, and specifically targeted and activated ferroptosis by upregulating the expression of tumor suppressor gene p53, thereby activating the SLC7A11/GPX4/ROS pathway mediated by it. Baicalin activates ferroptosis through multiple pathways and targets, thereby inhibiting the viability of oxaliplatin-resistant gastric cancer HGC27/L cells and enhancing the sensitivity to oxaliplatin chemotherapy.

Iron Oxide Nanoparticles Inhibit Tumor Progression and Suppress Lung Metastases in Mouse Models of Breast Cancer.

Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape, leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed the activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-ß (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent, induced significant antitumor effects, suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases supports a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anticancer immune (nano)adjuvant properties to generate a therapeutic benefit without requiring uptake by cancer cells.

Lower risks of cirrhosis and hepatocellular carcinoma with GLP-1RAs in type 2 diabetes: A nationwide cohort study using target trial emulation framework.

BACKGROUND: To assess the association of cirrhosis and hepatocellular carcinoma (HCC) with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs), which are the two commonly prescribed injectable glucose-lowering agents (GLAs) for patients with type 2 diabetes (T2D) after the failure of multiple oral GLAs. METHODS: We emulated a target trial using the nationwide data of a Taiwanese cohort with T2D. Incident new users of GLP-1RAs and LAIs during 2013-2018 were identified, and propensity score (PS) matching was applied to ensure between-group comparability in baseline patient characteristics. The primary outcome was the composite liver disease including cirrhosis or HCC. Each patient was followed until the occurrence of a study outcome, death, or the end of 2019, whichever came first. Subdistribution hazard models were employed to assess the treatment-outcome association. Sensitivity (e.g., stabilized inverse probability of treatment weighting analysis, time-dependent analysis), E-value, and negative control outcome analyses were performed to examine the robustness of study findings. RESULTS: We included 7171 PS-matched pairs of GLP-1RA and LAI users with no significant between-group differences at baseline. Compared with LAIs, the use of GLP-1RAs was associated with significantly reduced risks of composite liver disease (subdistribution hazard ratio [95% confidence interval]: 0.56 [0.42-0.76]), cirrhosis (0.59 [0.43-0.81]), and HCC (0.47 [0.24-0.93]). Results were consistent across sensitivity analyses and among patients with different baseline characteristics. CONCLUSION: Among T2D patients who require injectable GLAs, the use of GLP-1RAs versus LAIs was associated with lower risks of cirrhosis and HCC.

EMT-related gene risk model establishment for prognosis and drug treatment efficiency prediction in hepatocellular carcinoma.

This study was designed to evaluate the prognosis and pharmacological therapy sensitivity of epithelial mesenchymal transition-related genes (EMTRGs) that obtained from the EMTome database in hepatocellular carcinoma (HCC) using bioinformatical method. The expression status of EMTRGs were also investigated using the clinical information of HCC patients supported by TCGA database and the ICGC database to establish the TCGA cohort as the training set and the ICGC cohort as the validation set. Analyze the EMTRGs between HCC tissue and liver tissue in the TCGA cohort in the order of univariate COX regression, LASSO regression, and multivariate COX regression, and construct a risk model for EMTRGs. In addition, enrichment pathways, gene mutation status, immune infiltration, and response to drugs were also analyzed in the high-risk and low-risk groups of the TCGA cohort, and the protein expression status of EMTRGs was verified. The results showed a total of 286 differentially expressed EMTRGs in the TCGA cohort, and EZH2, S100A9, TNFRSF11B, SPINK5, and CCL21 were used for modeling. The TCGA cohort was found to have a worse outcome in the high-risk group of HCC patients, and the ICGC cohort confirmed this finding. In addition, EMTRGs risk score was shown to be an independent prognostic factor in both cohorts by univariate and multivariate COX regression. The results of GSEA analysis showed that most of the enriched pathways in the high-risk group were associated with tumor, and the pathways enriched in the low-risk group were mainly associated with metabolism. Patients in various risk groups had varying immunological conditions, and the high-risk group might benefit more from targeted treatments. To sum up, the EMTRGs risk model was developed to forecast the prognosis for HCC patients, and the model might be useful in assisting in the choice of treatment drugs for HCC patients.

Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study.

BACKGROUND: Effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) on preventing progressive chronic kidney outcomes is uncertain for type 2 diabetes (T2D) patients requiring intensive glycemic control. This study aimed to evaluate comparative effectiveness of GLP-1RA versus LAI therapies on progressive chronic kidney outcomes among patients having poor glycemic control and requiring these injectable glucose-lowering agents (GLAs). METHODS: 7279 propensity-score-matched pairs of newly stable GLP-1RA and LAI users in 2013-2018 were identified from Taiwan's National Health Insurance Research Database and followed until death or 12/31/2019 (intention-to-treat). Subdistributional hazard model was utilized to assess the comparative effectiveness on a composite renal outcome (i.e., renal insufficiency [eGFR < 15 mL/min/1.73 m2], dialysis-dependent end-stage renal disease [ESRD], or renal death) and its individual components. Sensitivity analyses with the as-treated scenario, PS weighting, high-dimensional PS techniques, using cardiovascular diseases (CVDs) as positive control outcomes, and interaction testing were performed. RESULTS: In primary analyses, subdistribution hazard ratios (95% CIs) for initiating GLP-1RAs versus LAIs for the composite renal outcome, renal insufficiency, dialysis-dependent ESRD, and renal death were 0.39 (0.30-0.51), 0.43 (0.32-0.57), 0.29 (0.20-0.43), and 0.28 (0.15-0.51), respectively. Sensitivity analysis results were consistent with the primary findings. CVD history and the medication possession ratio of prior oral GLAs possessed modification effects on GLP-1RA-associated kidney outcomes. CONCLUSION: Using GLP-1RAs versus LAIs was associated with kidney benefits in T2D patients requiring intensive glycemic control and potentially at high risk of kidney progression. GLP-1RAs should be prioritized to patients with CVDs or adherence to prior oral GLAs to maximize kidney benefits.

Assessment of subclinical cardiac dysfunction by speckle-tracking echocardiography among people living with human immunodeficiency virus.

Background: People living with HIV (PLWH) have an increased risk of developing cardiovascular diseases (CVD). As speckle-tracking echocardiography (STE) has been used to detect subclinical myocardial abnormalities, this study aims to detect early cardiac impairment among Asian PLWH using STE and to investigate the associated risk factors. Methods: We consecutively recruited asymptomatic PLWH without previous CVD from a medical center of Taiwan, and their cardiac function was evaluated by conventional echocardiogram and STE. Enrolled PLWH were classified as antiretroviral therapy (ART)-experienced and ART-naive, and multivariable regressions were used to assess the association between myocardial strain and risk factors including traditional CVD and HIV-associated factors. Results: A total of 181 PLWH (mean age: 36.4 ± 11.4 years, 173 males) were recruited and conventional echocardiogram parameters were within normal ranges. Decreased myocardial strain across the myocardium was found, with a mean left ventricular (LV) global longitudinal strain of -18.7 ± 2.9%. The LV strain in the ART-experienced group (-19.0 ± 2.9%) was significantly better than the ART-naive group (-17.9 ± 2.8%), despite a younger age and lesser CVD risk factors in the ART-naive group. Hypertension [B = 1.92, 95% confidence interval (95% CI) 0.19-3.62, p = 0.029] and ART-naive with both low and high viral loads (VL) (B = 1.09, 95% CI 0.03-2.16, p = 0.047; and B = 2.00, 95% CI, 0.22-3.79, p = 0.029) were significantly associated with reduced myocardial strain. Conclusion: This is the first and largest cohort using STE to investigate myocardial strain in Asian PLWH. Our results suggest that hypertension and detectable VL are associated with impaired myocardial strain. Thus, timely ART administration with VL suppression and hypertension control are crucial in preventing CVD when making the management parallel with the improved life expectancy of PLWH on ART.

Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review).

Tumor multidrug resistance (MDR) remains one of the most challenging barriers to successful cancer treatment. Several previous studies have suggested that high mobility group box 1 (HMGB1) may be a promising therapeutic target for overcoming cancer drug resistance. Emerging evidence has indicated that HMGB1 functions as a 'double­edged sword' that plays both pro­ and anti­tumor roles in the development and progression of multiple types of cancer. HMGB1 has also been found to be a key regulator of several cell death and signaling pathways, and is involved in MDR by mediating cell autophagy and apoptosis, ferroptosis, pyroptosis and multiple signaling pathways. Additionally, HMGB1 is regulated by a variety of non­coding RNAs (ncRNAs), such as microRNAs, long ncRNAs and circular RNAs that are involved in MDR. Thus far, studies have been conducted to identify strategies with which to overcome HMGB1­mediated MDR by the targeted silencing of HMGB1 and the targeted interference of HMGB1 expression using drugs and ncRNAs. Therefore, HMGB1 is closely associated with tumor MDR and is a promising therapeutic target.

Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data.

AIMS: To evaluate the cost-effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) in patients with type 2 diabetes (T2D) using real-world data. METHODS: A Markov model was utilized to estimate healthcare costs (US$) and quality-adjusted life-years (QALYs) of receiving treatments over 10 years from the healthcare sector perspective. Model inputs were derived from the analyses of Taiwan's National Health Insurance Research Database or published literature on Taiwanese T2D populations. Base-case analysis was performed for the overall study cohort and subgroup analyses were stratified by the presence or absence of established cardiovascular diseases (CVDs) or chronic kidney diseases (CKDs). RESULTS: Overall, using GLP-1RAs versus LAIs cost $6,053 per QALY gained. Results were robust across sensitivity and scenario analyses. Among patients with established CVDs and CKDs, GLP-1RA versus LAI therapy saved $673 (cost-saving) and cost $1,675 per QALY gained, respectively. Among patients without established CVDs and CKDs, GLP-1RA versus LAI therapy cost $9,093 and $7,659 per QALY gained, respectively. CONCLUSIONS: Using GLP-1RAs versus LAIs for T2D patients represented good economic value in real-world practice. Pronounced economic benefits of GLP-1RA therapy among those with prior CVDs or CKDs support rational treatment decisions and optimal healthcare resource allocation for these patients.

Cost-effectiveness of Intensive vs Standard Blood Pressure Control Among Older Patients With Hypertension.

Importance: Older patients with hypertension receiving intensive systolic blood pressure control (110-130 mm Hg) have lower incidences of cardiovascular events than those receiving standard control (130-150 mm Hg). Nevertheless, the mortality reduction is insignificant, and intensive blood pressure management results in more medical costs from treatments and subsequent adverse events. Objective: To examine the incremental lifetime outcomes, costs, and cost-effectiveness of intensive vs standard blood pressure control in older patients with hypertension from the health care payer's perspective. Design, Setting, and Participants: This economic analysis was conducted with a Markov model to examine the cost-effectiveness of intensive blood pressure management among patients aged 60 to 80 years with hypertension. Treatment outcome data from the Trial of Intensive Blood-Pressure Control in Older Patients With Hypertension (STEP trial) and different cardiovascular risk assessment models for a hypothetical cohort of STEP-eligible patients were used. Costs and utilities were obtained from published sources. The incremental cost-effectiveness ratio (ICER) against the willingness-to-pay threshold was used to evaluate whether the management was cost-effective. Extensive sensitivity, subgroup, and scenario analyses were performed to address uncertainty. The US and UK population using race-specific cardiovascular risk models were conducted in the generalizability analysis. Data for the STEP trial were collected from February 10 to March 10, 2022, and were analyzed for the present study from March 10 to May 15, 2022. Interventions: Hypertension treatments with a systolic blood pressure target of 110 to 130 mm Hg or 130 to 150 mm Hg. Main Outcomes and Measures: Incremental lifetime quality-adjusted life-years (QALYs), costs, and ICER are discounted at the given rates annually. Results: After simulating 10 000 STEP-eligible patients assumed to be 66 years of age (4650 men [46.5%] and 5350 women [53.5%]) in the model, the ICER values were ¥51 675 ($12 362) per QALY gained in China, $25 417 per QALY gained in the US, and £4679 ($7004) per QALY gained in the UK. Simulations projected that the intensive management in China being cost-effective were 94.3% and 100% below the willingness-to-pay thresholds of 1 time (¥89 300 [$21 364]/QALY) and 3 times (¥267 900 [$64 090]/QALY) the gross domestic product per capita, respectively. The US had 86.9% and 95.6% probabilities of cost-effectiveness at $50 000/QALY and $100 000/QALY, respectively, and the UK had 99.1% and 100% of probabilities of cost-effectiveness at £20 000 ($29 940)/QALY and £30 000 ($44 910)/QALY, respectively. Conclusions and Relevance: In this economic evaluation, the intensive systolic blood pressure control in older patients produced fewer cardiovascular events and had acceptable costs per QALY gained, well below the typical willingness-to-pay thresholds. The cost-effective advantages of intensive blood pressure management in older patients were consistent over various clinical scenarios across different countries.

Economic evaluation of new blood pressure target for hypertensive patients in Taiwan according to the 2022 hypertension clinical practice guidelines of the Taiwan society of cardiology: a simulation modeling study.

With the promising cardiovascular benefits in the STEP and SPRINT trials, the 2022 Taiwan's hypertension guidelines redefined the hypertension threshold as 130/80 mmHg and a universal blood-pressure target of <130/80 mmHg. This study's objective was to examine the cost-effectiveness of the intensive blood-pressure target for hypertensive patients using estimated lifetime medical costs and quality-adjusted life years (QALY) from the Taiwan national payer's perspective. We developed a lifetime Markov model comparing the intensive and conservative blood-pressure targets. Incremental cost-effectiveness ratio (ICER) against the willing-to-pay thresholds at the one-time [US$34,000(NT$1,020,000)] and three-time [US$100,000(NT$3,000,000)] gross domestic product per capita were defined as very cost-effect and only cost-effective. The cost-effectiveness in different age stratifications and cardiovascular risks treated with a more intensive target (120 mmHg) were examined in the subgroup analyses. The new blood-pressure treatment target produced more lifetime medical costs [US$31,589(NT$947,670) versus US$26,788(NT$803,640)] and QALYs (12.54 versus 12.25), and the ICER was US$16,589(NT$497,670), which was 99.1% and 100% probability of a very cost-effective and cost-effective strategy. The ICERs in all age stratifications had more than a 90% probability of being very cost-effective, and ICERs decreased with age. More intensive control in patients with high cardiovascular risks produced a lower ICER [US$14,547(NT$436,410)]. In conclusion, Taiwan's new blood-pressure treatment target can prevent more cardiovascular events with acceptable costs per QALY below the willing-to-pay thresholds. The cost-effectiveness of intensive control is consistent across different ages and more pronounced with the increase in age and cardiovascular risk.

Restricted Mean Survival Time Analysis to Estimate SGLT2i-Associated Heterogeneous Treatment Effects on Primary and Secondary Prevention of Cardiorenal Outcomes in Patients With Type 2 Diabetes in Taiwan.

Importance: Increasing numbers of post hoc analyses have applied restricted mean survival time (RMST) analysis on the aggregated-level data from clinical trials to report treatment effects, but studies that use individual-level claims data are needed to determine the feasibility of RMST analysis for quantifying treatment effects among patients with type 2 diabetes in routine clinical settings. Objectives: To apply RMST analysis for assessing sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated cardiovascular (CV) events and estimating heterogenous treatment effects (HTEs) on CV and kidney outcomes in routine clinical settings. Design, Setting, and Participants: This comparative effectiveness study of Taiwan's National Health Insurance Research Database examined 21 144 propensity score (PS)-matched pairs of patients with type 2 diabetes with SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment for assessing CV outcomes, and 19 951 PS-matched pairs of patients with type 2 diabetes with SGLT2i and DPP4i treatment for assessing kidney outcomes. Patients were followed until December 31, 2018. Statistical analysis was performed from August 2021 to April 2022. Exposures: Newly stable SGLT2i or DPP4i use in 2017. Main Outcomes and Measures: Study outcomes were CV events including hospitalization for heart failure (HHF), 3-point major adverse CV events (3P-MACE: nonfatal myocardial infarction [MI], nonfatal stroke, and CV death), 4-point MACE (4P-MACE: HHF and 3P-MACE), and all-cause death, and chronic kidney disease (CKD). RMST and Cox modeling analyses were applied to estimate treatment effects on study outcomes. Results: After PS matching, the baseline patient characteristics were comparable between 21 144 patients with stable SGLT2i use (eg, mean [SD] age: 58.3 [10.7] years; 11 990 [56.7%] male) and 21 144 patients with stable DPP4i use (eg, mean [SD] age: 58.1 [11.6] years; 12 163 [57.5%] male) for assessing CV outcomes, and those were also comparable between 19 951 patients with stable SGLT2i use (eg, mean [SD] age: 58.1 [10.7] years; 11 231 [56.2%] male) and 19 951 patients with stable DPP4i use (eg, mean [SD] age: 57.9 [11.5] years; 11 340 [56.8%] male) for assessing kidney outcome. The 2-year difference in RMST between patients with SGLT2i use and patients with DPP4i use was 4.99 (95% CI, 3.56-6.42) days for HHF, 4.12 (95% CI, 2.72-5.52) days for 3P-MACE, 7.72 (95% CI, 5.83-9.61) days for 4P-MACE, 1.26 (95% CI, 0.47-2.04) days for MI, 2.70 (95% CI, 1.57-3.82) days for stroke, 0.69 (95% CI, 0.28-1.11) days for CV death, 6.05 (95% CI, 4.89-7.20) days for all-cause death, and 14.75 (95% CI, 12.99-16.52) days for CKD. Directions of hazard ratios from Cox modeling analyses were consistent with RMST estimates. No association was found between study treatment and the negative control outcome (dental visits for tooth care). Consistent results across sensitivity analyses using high-dimensional PS-matched and PS-weighting approaches supported the validity of primary analysis results. Largest difference in RMST of SGLT2i vs DPP4i use for HHF and CKD was found among patients with established heart failure (30.80 [95% CI, 5.08-56.51] days) and retinopathy (40.43 [95% CI, 31.74-49.13] days), respectively. Conclusions and Relevance: In this comparative effectiveness study, RMST analysis was feasible for translating treatment effects into more clinical intuitive estimates and valuable for quantifying HTEs among diverse patients in routine clinical settings.

A Predictive Pharmacokinetic Model for Immune Cell-Mediated Uptake and Retention of Nanoparticles in Tumors.

A promise of cancer nanomedicine is the "targeted" delivery of therapeutic agents to tumors by the rational design of nanostructured materials. During the past several decades, a realization that in vitro and in vivo preclinical data are unreliable predictors of successful clinical translation has motivated a reexamination of this approach. Mathematical models of drug pharmacokinetics (PK) and biodistribution (BD) are essential tools for small-molecule drugs development. A key assumption underlying these models is that drug-target binding kinetics dominate blood clearance, hence recognition by host innate immune cells is not explicitly included. Nanoparticles circulating in the blood are conspicuous to phagocytes, and inevitable interactions typically trigger active biological responses to sequester and remove them from circulation. Our recent findings suggest that, instead of referring to nanoparticles as designed for active or passive "tumor targeting", we ought rather to refer to immune cells residing in the tumor microenvironment (TME) as active or passive actors in an essentially "cell-mediated tumor retention" process that competes with active removal by other phagocytes. Indeed, following intravenous injection, nanoparticles induce changes in the immune compartment of the TME because of nanoparticle uptake, irrespective of the nature of tumor targeting moieties. In this study, we propose a 6-compartment PK model as an initial mathematical framework for modeling this tumor-associated immune cell-mediated retention. Published in vivo PK and BD results obtained with bionized nanoferrite® (BNF®) nanoparticles were combined with results from in vitro internalization experiments with murine macrophages to guide simulations. As a preliminary approximation, we assumed that tumor-associated macrophages (TAMs) are solely responsible for active retention in the TME. We model the TAM approximation by relating in vitro macrophage uptake to an effective macrophage avidity term for the BNF® nanoparticles under consideration.

Identification of Gene-Environment Interactions by Non-Parametric Kendall's Partial Correlation with Application to TCGA Ultrahigh-Dimensional Survival Genomic Data.

BACKGROUND: In biomedical and epidemiological studies, gene-environment (G-E) interactions play an important role in the etiology and progression of many complex diseases. In ultra-high-dimensional survival genomic data, two common approaches (marginal and joint models) are proposed to determine important interaction biomarkers. Most existing methods for detecting G-E interactions (marginal Cox model and marginal accelerated failure time model) are limited by a lack of robustness to contamination/outliers in response outcome and prediction biomarkers. In particular, right-censored survival outcomes and ultra-high-dimensional feature space make relevant feature screening even more challenging. METHODS: In this paper, we utilize the non-parametric Kendall's partial correlation method to obtain pure correlation to determine the importance of G-E interactions concerning clinical survival data under a marginal modeling framework. RESULTS: A series of simulated scenarios are conducted to compare the performance of our proposed method (Kendall's partial correlation) with some commonly used methods (marginal Cox's model, marginal accelerated failure time model, and censoring quantile partial correlation approach). In real data applications, we utilize Kendall's partial correlation method to identify G-E interactions related to the clinical survival results of patients with esophageal, pancreatic, and lung carcinomas using The Cancer Genome Atlas clinical survival genetic data, and further establish survival prediction models. CONCLUSIONS: Overall, both simulation with medium censoring level and real data studies show that our method performs well and outperforms existing methods in the selection, estimation, and prediction accuracy of main and interacting biomarkers. These applications reveal the advantages of the non-parametric Kendall's partial correlation approach over alternative semi-parametric marginal modeling methods. We also identified the cancer-related G-E interactions biomarkers and reported the corresponding coefficients with p-values.

National Trends in the Achievement of Recommended Strategies for Stroke Prevention in U.S. Adults With Type 2 Diabetes, 2001-2018.

OBJECTIVE: To assess the national prevalence of and trends in achieving current guideline-recommended treatment goals and pharmacotherapies for primary and secondary prevention of stroke among U.S. adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We performed serial cross-sectional analyses in 4,834 adults aged ≥45 years with T2D who participated in the 2001-2018 National Health and Nutrition Examination Survey. With stratification by stroke history, we estimated the proportion of adults with T2D who achieved current guideline-recommended strategies for stroke prevention. Preventive strategies for stroke were benchmarked against diabetes care and cardiovascular risk reduction guidelines. RESULTS: Overall in 2001-2018, among those without stroke history, the proportion who achieved primary stroke prevention strategies ranged from 8.4% (95% CI 6.8-10.1) for aspirin/clopidogrel treatment in those with a higher cardiovascular disease risk to 80.5% (78.8-82.2) for nonsmoking. Among those with stroke history, the proportion who achieved secondary stroke prevention strategies ranged from 11.8% (8.7-14.8) for weight control to 80.0% (74.9-84.9) for glycemic control. From 2001 to 2018, among those without stroke history, there was a significant increase in statin therapy (Ptrend < 0.0001), smoking abstinence (Ptrend = 0.01), and ACE inhibitor/angiotensin receptor blocker treatment for hypertension (Ptrend = 0.04) but a substantial decline in weight control (Ptrend < 0.001). Among those with stroke history, only statin therapy (Ptrend = 0.01) increased significantly over time. CONCLUSIONS: During 2001-2018, the achievement of some current guideline-recommended strategies for stroke prevention among U.S. adults with T2D improved but remains a challenge overall. Efforts are needed to improve implementation of strategies for stroke prevention in this population.

Cost-effectiveness of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors among patients with type 2 diabetes with and without established cardiovascular diseases: A model-based simulation analysis using 10-year real-world data and targeted literature review.

AIM: We conducted a model-based economic analysis of sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in patients with type 2 diabetes (T2D), with and without established cardiovascular diseases (CVDs), using 10-year real-world data. MATERIALS AND METHODS: A Markov model was utilized to estimate healthcare costs and quality-adjusted life-years (QALYs) over a 10-year simulation time horizon from a healthcare sector perspective, with both costs and QALYs discounted at 3% annually. Model inputs were derived from analyses of Taiwan's National Health Insurance Research Database or published studies of Taiwanese populations. The primary outcome measure was the incremental cost-effectiveness ratios (ICERs). Incorporated with our study findings, a targeted literature review was conducted to synthesize updated evidence on the cost-effectiveness of SGLT2is versus DPP4is. RESULTS: Over 10 years, use of SGLT2is versus DPP4is yielded ICERs of $3244 and $4186 per QALY gained for patients with T2D, with and without established CVDs, respectively. Results were robust across a series of sensitivity and scenario analyses, showing ICERs between $-1074 (cost-saving) and $8467 per QALY gained for patients with T2D with established CVDs and between $369 and $37 122 per QALY gained for patients with T2D without established CVDs. CONCLUSIONS: Use of SGLT2is versus DPP4is was highly cost-effective for patients with T2D regardless of their CVD history in real-world clinical practice. Our results extend current evidence by showing SGLT2is as an economically rational alternative over DPP4is for T2D treatment in routine care. Future research is warranted to explore the heterogeneous economic benefits of SGLT2is given diverse patient characteristics in clinical settings.

Cardiovascular Benefits With Favorable Renal, Amputation and Hypoglycemic Outcomes of SGLT-2 Inhibitors in Type 2 Diabetes From the Asian Perspective: A Population-Based Cohort Study and Systematic Review.

Objective: We assessed the effects of sodium glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in a large real-world Asian cohort with type 2 diabetes (T2D) and performed a systematic review with integrating the present study findings to provide up-to-date evidence from the Asian perspective. Methods: New users of SGLT2is or DPP4is were identified from the Taiwan's National Health Insurance Research Database and followed until 2018. Primary outcomes were hospitalization for heart failure (HHF) and three-point major adverse cardiovascular event (3P-MACE; namely, myocardial infarction [MI], stroke, or cardiovascular death). Other outcomes included all-cause death, chronic kidney disease (CKD), amputation, and hospitalized hypoglycemia. Subdistribution hazard models were employed to assess treatment-associated clinical outcomes. Results: A total of 21,329 SGLT2i and DPP4i propensity-score-matched pairs were analyzed. SGLT2is versus DPP4is showed lower risks of HHF (hazard ratio [95% CI]: 0.52 [0.45-0.59]), 3P-MACE (0.62 [0.55-0.70]), MI (0.63 [0.50-0.79]), stroke (0.60 [0.51-0.70]), all-cause death (0.57 [0.49-0.67]), CKD (0.46 [0.43-0.50]), amputation (0.64 [0.42-0.98]), and hospitalized hypoglycemia (0.54 [0.45-0.64]). Our results were consistent with findings from a systematic review. Conclusion: Among Asian patients with T2D, SGLT2is versus DPP4is showed benefits for several clinical outcomes. More research is warranted to explore the heterogeneous treatment effects of SGLT2is and DPP4is by race/ethnicity.

Treatment-associated survival outcomes in real-world patients with de novo metastatic triple-negative breast cancer: Age as a significant treatment effect-modifier.

PURPOSE: Evidence for optimizing the first-line chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC) is lacking. This study assessed the utilization patterns of chemotherapy and associated survival outcomes in de novo mTNBC patients. METHODS: Taiwan's cancer registry was utilized to extract study patients with newly-diagnosed breast cancer during 2011-2015 and confirmed metastatic triple-negative status. The patients' medical records (e.g., diseases, treatments) and death status were obtained from the National Health Insurance Research Database. Utilization of first-line chemotherapy regimens was analyzed and associated survival outcomes were assessed using Cox models. RESULTS: 93.60% of the mTNBC patients (n = 297) received chemotherapy, where combination regimens (75.54%) were more common than single-agent regimens (24.46%) in the first-line setting. A non-statistically lower all-cause death associated with combination versus single-agent chemotherapy (hazard ratio: 0.830 [0.589, 1.168]) was observed. Age was identified as a significant effect-modifier in treatment-associated survival outcomes (p = 0.008); younger patients (aged < 40 and 40-59 years) versus older patients (aged ≥ 60 years) had a lower all-cause mortality when receiving combination versus single-agent chemotherapy. A lower all-cause mortality associated with taxane- versus non-taxane-based therapy was revealed among those on single-agent chemotherapy (hazard ratio: 0.557 [0.311, 0.999]). CONCLUSION: Generally, single-agent and combination chemotherapies yielded comparable survival outcomes as the first-line treatment for de novo mTNBC. Younger patients may benefit more from combination regimens, in terms of better survival outcomes. Single-agent chemotherapy may be preferable as the first-line choice for elderly patients who are vulnerable to the toxicity of multiple chemotherapy agents.

Exploring Structural Uncertainty and Impact of Health State Utility Values on Lifetime Outcomes in Diabetes Economic Simulation Models: Findings from the Ninth Mount Hood Diabetes Quality-of-Life Challenge.

BACKGROUND: Structural uncertainty can affect model-based economic simulation estimates and study conclusions. Unfortunately, unlike parameter uncertainty, relatively little is known about its magnitude of impact on life-years (LYs) and quality-adjusted life-years (QALYs) in modeling of diabetes. We leveraged the Mount Hood Diabetes Challenge Network, a biennial conference attended by international diabetes modeling groups, to assess structural uncertainty in simulating QALYs in type 2 diabetes simulation models. METHODS: Eleven type 2 diabetes simulation modeling groups participated in the 9th Mount Hood Diabetes Challenge. Modeling groups simulated 5 diabetes-related intervention profiles using predefined baseline characteristics and a standard utility value set for diabetes-related complications. LYs and QALYs were reported. Simulations were repeated using lower and upper limits of the 95% confidence intervals of utility inputs. Changes in LYs and QALYs from tested interventions were compared across models. Additional analyses were conducted postchallenge to investigate drivers of cross-model differences. RESULTS: Substantial cross-model variability in incremental LYs and QALYs was observed, particularly for HbA1c and body mass index (BMI) intervention profiles. For a 0.5%-point permanent HbA1c reduction, LY gains ranged from 0.050 to 0.750. For a 1-unit permanent BMI reduction, incremental QALYs varied from a small decrease in QALYs (-0.024) to an increase of 0.203. Changes in utility values of health states had a much smaller impact (to the hundredth of a decimal place) on incremental QALYs. Microsimulation models were found to generate a mean of 3.41 more LYs than cohort simulation models (P = 0.049). CONCLUSIONS: Variations in utility values contribute to a lesser extent than uncertainty captured as structural uncertainty. These findings reinforce the importance of assessing structural uncertainty thoroughly because the choice of model (or models) can influence study results, which can serve as evidence for resource allocation decisions.HighlightsThe findings indicate substantial cross-model variability in QALY predictions for a standardized set of simulation scenarios and is considerably larger than within model variability to alternative health state utility values (e.g., lower and upper limits of the 95% confidence intervals of utility inputs).There is a need to understand and assess structural uncertainty, as the choice of model to inform resource allocation decisions can matter more than the choice of health state utility values.

Real-life analysis of neoadjuvant-therapy-associated benefits for pathological complete response and survival in early breast cancer patients - role of trastuzumab in HER2+ BC and platinum in TNBC.

Background: Neoadjuvant therapy, which aims to achieve a pathological complete response (pCR) for better overall survival (OS) has several advantages for patients with early breast cancer (eBC) and subtypes of HER2-positive (HER2+) and triple-negative breast cancer (TNBC). However, there has been no large-scale real-world investigation on the clinical outcomes associated with trastuzumab-based and platinum-based neoadjuvant treatments for patients with HER2+ and TNBC, respectively. Material and methods: Taiwan Cancer Registry and National Health Insurance Research Database were utilized in this study. Patients diagnosed with clinically lymph-node-positive (LN+) HER2+ or TNBC were identified for analysis. Logistic regression and Cox proportional hazard models were employed to estimate the adjusted odds ratios (aOR) of achieving pCR and adjusted hazard ratios (aHR) of overall survival associated with treatment agents, respectively. Results: A total of 1,178 HER2+ eBC and 354 early TNBC patients were identified, respectively. Neoadjuvant trastuzumab significantly increased the pCR rates by 3.87-fold among HER2+ patients. Trastuzumab-associated survival benefit was found in HER2+ patients who achieved pCR (aHR [95% CI]: 0.30 [0.11-0.84]) but not in those without pCR (1.13 [0.77-1.67]). Among the TNBC patients, platinum was associated with a 1.6-fold increased pCR rate; however, it did not improve OS regardless of pCR status. Conclusions: Trastuzumab improved pCR and OS for patients with HER2+ subtype. Using platinum agents for TNBC patients increased pCR rates but was not linked to better survival. Optimal neoadjuvant anti-HER2 therapy for patients with HER2+ eBC and the introduction of novel therapy for patients with TNBC should be considered.

Clinical efficacy of SGLT2 inhibitors with different SGLT1/SGLT2 selectivity in cardiovascular outcomes among patients with and without heart failure: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Some sodium-glucose co-transporter-2 (SGLT2) inhibitors showed benefits on heart failure (HF), but different SGLT2/SGLT1 selectivity might influence the treatment effect. This study aimed to meta-analyze the treatment effects of SGLT2 inhibitors and the diversity of receptor selectivity for patients with and without HF. METHODS: Randomized controlled trials were searched in PubMed, Embase, Cochrane databases and ClinicalTrials.gov registry from inception to October 2020. The interest outcomes were analyzed with random-effects models and presented with a risk ratio (RR) and 95% confidence interval (CI). Subgroup analyses examined the treatment effects among SGLT2 inhibitors with different SGLT2/SGLT1 selectivity. RESULTS: The final analyses included 10 trials and 52,607 patients. The RR of total cardiovascular (CV) death or hospitalization for HF (HHF) between SGLT2 inhibitors and placebo was 0.79 (95% CI 0.74-0.84, I2 = 31%). With SGLT2 inhibitors, HF patients had reduced mortality risks (RR 0.89, 95% CI 0.80-0.99, I2 = 0), and non-HF patients had lower risks of major adverse CV events (RR 0.92, 95% CI 0.85-0.99, I2 = 0). The risk reduction of HHF was consistent in groups of HF (RR 0.72, 95% CI 0.64-0.80, I2 = 8%) and non-HF (RR 0.74, 95% CI 0.61-0.89, I2 = 0), but the effect of the low SGLT2/SGLT1 selectivity inhibitor was insignificant in non-HF patients. CONCLUSION: The efficacy of SGLT2 inhibitors on risk reduction of total CV death or HHF is consistent with the previous studies. The regimen is beneficial for reducing mortality in patients with HF and major adverse CV events in those without HF. Different SGLT2/SGLT1 selectivity may differ in the treatment effects in patients with and without HF.