Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe.

PURPOSE: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe. METHODS: Data were from two multi-center, retrospective patient chart review studies conducted in the United Kingdom, Germany, Italy, France and Spain: The Endometrial Cancer Health Outcomes-Europe-First-Line (ECHO-EU-1L) study and the ECHO-EU-Second-Line (ECHO-EU-2L) study. ECHO-EU-1L included recurrent/advanced endometrial cancer patients who received first-line systemic therapy between 1/JUN/2016 and 31/MAR/2020 after recurrent/advanced diagnosis. ECHO-EU-2L included patients with recurrent/advanced endometrial cancer who progressed between 1/JUN/2016 and 30/JUN/2019 following prior first-line systemic therapy. Data collected included patient demographics, MSI/MMR tumor testing and results, and clinical/treatment characteristics. RESULTS: ECHO-EU-1L included 242 first-line patients and ECHO-EU-2L included 475 s-line patients. For all patients, median age at recurrent/advanced diagnosis was 69 years, roughly half had endometrioid carcinoma histology and over 75% had Stage IIIB-IV disease at initial diagnosis. The prevalence of MSI/MMR testing in the first-line and second-line cohorts was similar (36.4 and 34.9%, respectively). Among those tested, a majority had non-MSI-high/MMR proficient tumors (80.7 and 74.7% among first- and second-line patients, respectively). About 15% had MSI-high/MMR deficient tumors in both cohorts, and a few patients had discordant results (3.4 and 10.8% among first- and second-line patients, respectively). CONCLUSION: Prior to the approvals of biomarker-directed therapies for recurrent/advanced endometrial cancer patients in Europe, there were low MSI/MMR testing rates for these patients of just over one-third. Given the availability of biomarker-directed therapies, increased MSI/MMR testing may help inform treatment decisions for recurrent/advanced endometrial cancer patients in Europe.

The impact of an interprofessional care transitions clinic on readmission rates and costs.

The objective of this study was to assess the effectiveness of the Interprofessional Care Transitions Clinic (ICTC) in reducing preventable readmissions and their associated costs among Medicare/Medicaid patients. A prospective cohort study was conducted among adults who were discharged from the University of Maryland Prince George's Hospital Center to assess the comparative effectiveness of a clinic-based intervention in terms of readmission events, potentially avoidable utilization, length of stay, and hospital charges. Outcomes were evaluated at 1 month, 3 months, and 6 months post-discharge. There were statistically significant differences in the following outcomes (follow-up period): proportion of readmissions (3 months), potentially avoidable utilization (1 month), and mean medical charges for ICTC patients compared to non-ICTC patients (1 month). This program was aimed at testing the impact of having an interprofessional team focused on providing holistic patient-centered care.

Impact of the naloxone standing order on trends in opioid fatal overdose: an ecological analysis.

Background: Maryland expanded its "Statewide Naloxone Standing Order" (NSO) in 2017 to eliminate training and prescription requirements for obtaining naloxone, improve naloxone access, help reverse opioid overdose, and reduce overdose fatality rates.Objectives: To assess the change in the trends of fatal opioid overdose rates following the expansion of the Naloxone Standing Order (eNSO) and its association with the social determinants of health (SDoH).Methods: Data on overdose deaths and SDoH from 2015-2019 was collected and analyzed using interrupted time series and multivariate Poisson regression models to study the change in trends and the associations.Results: There was a significant decrease in the rate of fatal overdoses after the intervention: prescription opioid estimate number of deaths declined by .25 per 100,000 (p = .02), heroin estimate number of deaths declined by 1.83 per 100,000 (p < .001), fentanyl estimate number of deaths declined by 2.54 per 100,000 (p < .001). After controlling for eNOS implementation in Maryland, state-level estimates with high proportions of female residents and those with bachelor's degree or higher were associated with reduction in overdose, while state-level estimates with high proportions of African Americans and higher employment rates were associated with an increase in overdose.Conclusions: Our analysis shows that the expanded naloxone standing order is associated with reducing opioid-related overdose death rates. Even though we observed a significant reduction in overdose death rate in fentanyl-related deaths, the rate of deaths post-eNSO was still increasing, suggesting the need for additional measures to impact the rates of fentanyl.

Short-Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Overexpression, Promotes Atherosclerosis Inflammation Resolution in Mice.

Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause endoplasmic reticulum stress, cholesterol crystal formation, and inflammasome activation. Our previous studies showed that long-term partial ACAT inhibition, achieved by dietary supplementation with Fujirebio F1394, delays atherosclerosis progression in apoprotein E-deficient (Apoe -/-) mice by reducing plaque foam cell formation without inflammatory or toxic effects. Here, we determined whether short-term partial inhibition of ACAT, in combination with an enhanced systemic FC acceptor capacity, has synergistic benefits. Thus, we crossbred Apoe -/- with human apoprotein A1-transgenic (APOA1 tg/tg) mice, which have elevated cholesterol-effluxing high-density lipoprotein particles, and subjected Apoe -/- and APOA1 tg/tg/Apoe -/- mice to an atherogenic diet to develop advanced plaques. Then mice were either euthanized (baseline) or fed purified standard diet with or without F1394 for 4 more weeks. Plaques of APOA1 tg/tg/Apoe -/- mice fed F1394 showed a 60% reduction of macrophages accompanied by multiple other benefits, such as reduced inflammation and favorable changes in extracellular composition, in comparison with Apoe -/- baseline mice. In addition, there was no accumulation of cholesterol crystals or signs of toxicity. Overall, these results show that short-term partial ACAT inhibition, coupled to increased cholesterol efflux capacity, favorably remodels atherosclerosis lesions, supporting the potential of these combined therapies in the treatment of advanced atherosclerosis. SIGNIFICANCE STATEMENT: Short-term pharmacological inhibition of acyl-CoA:cholesterol acyltransferase-mediated cholesterol esterification, in combination with increased free cholesterol efflux acceptors, has positive effects in mice by 1) reducing the inflammatory state of the plaque macrophages and 2) favoring compositional changes associated with plaque stabilization. These effects occur without toxicity, showing the potential of these combined therapies in the treatment of advanced atherosclerosis.

Apolipoprotein AI) Promotes Atherosclerosis Regression in Diabetic Mice by Suppressing Myelopoiesis and Plaque Inflammation.

BACKGROUND: Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. METHODS: Aortic arches containing plaques developed in Ldlr-/- mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. RESULTS: Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. CONCLUSIONS: Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.

Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation.

OBJECTIVE: Low to moderate inorganic arsenic (iAs) exposure is independently associated with cardiovascular disease (CVD), particularly for patients with diabetes mellitus (DM). The mechanism of increased CVD risk from iAs exposure in DM has not been adequately characterized. We evaluated whether increasing concentrations of glucose enhance the effects of iAs on platelet and megakaryocyte activity, key steps in atherothrombosis. METHODS: Healthy donor whole blood was prepared in a standard fashion and incubated with sodium arsenite in a range from 0 to 10 µM. iAs-induced platelet activation was assessed by platelet receptor CD62P (P-selectin) expression and monocyte-platelet and leukocyte-platelet aggregation (MPA and LPA, respectively) in the presence of increasing sodium arsenite and glucose concentrations. Megakaryocyte (Meg-01) cell adhesion and gene expression was assessed after incubation with or without iAs and increasing concentrations of D-glucose. RESULTS: Platelet activity markers increased significantly with 10 vs. 0 µM iAs (P < 0.05 for all) and with higher D-glucose concentrations. Platelet activity increased significantly following co incubation of 1 and 5 µM iAs concentrations with hyperglycemic D-glucose (P < 0.01 for both) but not after incubation with euglycemic D-glucose. Megakaryocyte adhesion was more pronounced after co incubation with iAs and hyperglycemic than euglycemic D-glucose, while gene expression increased significantly to iAs only after co incubation with hyperglycemic D-glucose. CONCLUSION: We demonstrate that glucose concentrations common in DM potentiate the effect of inorganic arsenic exposure on markers of platelet and megakaryocyte activity. Our results support recent observational cohort data that DM enhances the vasculotoxic effects of arsenic exposure, and suggest that activation of the platelet-megakaryocyte hemostatic axis is a pathway through which inorganic arsenic confers atherothrombotic risk, particularly for patients with DM.