Real-world management practices and characteristics of patients with advanced melanoma initiated on immuno-oncology or targeted therapy in the first-line setting during the period 2015-2018 in Greece. The 'SUMMER' study: a retrospective multicenter chart review project.

This study primarily aimed to generate real-world evidence (RWE) on the profile and first-line treatment (1LT) patterns of patients with advanced (unresectable Stage III/metastatic) cutaneous melanoma initiated on immuno-oncology (IO)- or targeted therapy (TT)-based 1LT between 1 January 2015 and 1 January 2018 (index period), in routine settings of Greece. This was a multicenter, retrospective chart review study. Eligible consented (unless deceased, for whom consent was waived by the hospital) patients were consecutively included by six oncology clinics. The look-back period extended from informed consent or death to initial melanoma diagnosis. Between 9 Junuary 2021 and 9 February 2022, 225 eligible patients (all Caucasians; 60.4% male; 35.6% diagnosed with de novo advanced melanoma) were included. At 1LT initiation, median age was 62.6 years; 2.7/6.7/90.7% of the patients had Stage IIIB/IIIC/IV disease and 9.3% were unresected. Most frequent metastatic sites were the lung (46.7%), non-regional nodes (33.8%), and liver (20.9%). Among patients, 98.2% had single primary melanoma, 45.6% had disease localized on the trunk, and 63.6% were BRAF-mutant. Of the patients, 45.3% initiated 1LT with an IO-based, 53.3% with a TT-based regimen, and three patients (1.3%) received TT-based followed by IO-based or vice versa. Most common 1LT patterns (frequency ≥10%) were BRAFi/MEKi combination (31.6%), anti-PD-1 monotherapy (25.3%), BRAFi monotherapy (21.8%), and anti-CTLA-4 monotherapy (17.8%). Most frequent regimens were Dabrafenib+Trametinib in 25.3%, and monotherapies with Pembrolizumab/Ipilimumab/Vemurafenib/Dabrafenib in 23.6/17.8/11.1/10.7% of patients, respectively. SUMMER provides RWE on 1LT strategies and profile of patients initiated 1L IO- or TT-based therapy in Greece during the 3-year index period.

Attainment of cholesterol target values in Greece: results from the Dyslipidemia International Study II.

INTRODUCTION: Current European guidelines recommend treatment with lipid-lowering therapy (LLT) to a low-density lipoprotein cholesterol (LDL-C) target of < 70 mg/dl for patients at very high risk. LDL-C target attainment and use of LLTs in these patients in Greece is not known. MATERIAL AND METHODS: The Dyslipidemia International Study (DYSIS) II was a multicenter observational study. The coronary heart disease (CHD) cohort was divided into two groups based on treatment status (on LLT for ≥ 3 months or not on LLT). The acute coronary syndrome (ACS) cohort was evaluated at the time of admission and again 120 ±15 days after admission. RESULTS: In the CHD cohort (n = 499), 457 (91.6%) patients were on LLT. The LDL-C target value was attained by 26.5% of LLT users. Statin monotherapy was used by 77.5% of treated patients, with a mean ± SD atorvastatin dose equivalent of 24 ±16 mg/day. In the ACS cohort (n = 200), 159 (79.5%) patients were on LLT at admission. Mean ± SD LDL-C levels were 108 ±40 mg/dl at admission and 86 ±25 mg/dl at follow-up. LDL-C target value attainment rates were 16.2% at admission and 25.0% at follow-up. At admission, statin monotherapy was used by 86.8% of treated patients. The mean ± SD atorvastatin dose equivalent increased from 20 ±14 mg/day at admission to 29 ±15 mg/day at follow-up. The statin dose was associated with higher odds of LDL-C target value attainment (OR = 1.05, 95% CI: 1.02-1.08). CONCLUSIONS: The LDL-C target attainment by very high risk patients in Greece is suboptimal. Increasing the statin dose or combining it with non-statins may improve target value attainment.

Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial deformation imaging: The role of endothelial glycocalyx damage.

BACKGROUND: First-degree relatives of type-2 diabetes patients (FDR) present insulin resistance. We investigated whether FDR and dysglycaemic subjects demonstrate abnormal endothelial glycocalyx and LV deformation during postprandial hyperglycemia. METHODS: We studied 40 FDR with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic). At 0 and 120min of OGTT we measured: a) LV longitudinal strain (LS) of subendocardial, mid-myocardial and subepicardial layers, global LS (GLS), peak twisting (pTw), untwisting velocity (pUtwVel), by speckle tracking echocardiography b) perfused boundary region (PBR) of the sublingual arterial microvessels; high PBR values represent reduced glycocalyx thickness. Insulin resistance was evaluated using insulin sensitivity index (ISI). RESULTS: ISI was related with baseline PBR, GLS and pTw in all subjects (p<0.05). Compared to normoglycaemics, FDR and dysglycaemics had higher PBR, lower ISI, GLS (-18.4±2.6 and -16.8±2.0 vs. -19.2±2.4%), subendocardial LS (-19.0±4.2 and -17.9±3.0 vs. -20.1±3.4%), pTw (14.4±4.4 and 15.6±6.4 vs. 16.9±6.5deg) and pUtwVel (p<0.05 for all comparisons). A GLS<-18% identified FDR with LV dysfunction (p=0.016). Post-OGTT, GLS and the subendocardial LS decreased while pTw and pUtwVel increased in FDR and dysglycaemics (p<0.05) indicating prevalence of the motion of the subepicardial over a dysfunctioning subendocardial myocardial helix. Increased PBR was related with impaired deformation markers at baseline and 120min of OGTT (p<0.05). CONCLUSION: First-degree relatives and dysglycaemics have reduced glycocalyx thickness related with impaired LV longitudinal, twisting-untwisting function. Postprandial hyperglycemia when combined with insulin resistance causes LV longitudinal dysfunction leading to increased LV twisting.

Insulin resistance and acute glucose changes determine arterial elastic properties and coronary flow reserve in dysglycaemic and first-degree relatives of diabetic patients.

BACKGROUND: Insulin resistance is linked to endothelial dysfunction. We investigated whether first-degree relatives of type-2 diabetes patients (FDR) present differences in vascular function at baseline and during postprandial hyperglycemia compared to dysglycaemic or normoglycaemic subjects. METHODS: We studied 40 FDR with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic) with similar clinical characteristics. Glucose, insulin, pulse wave velocity (PWV), central systolic blood pressure (cSBP) and augmentation index (AI) were measured at 0, 30, 60, 90 and 120min during OGTT. Coronary flow reserve (CFR) was assessed using Doppler echocardiography at 0 and 120min after OGTT. Insulin sensitivity was evaluated using Matsuda and insulin sensitivity index (ISI). RESULTS: FDR and dysglycaemics had higher fasting insulin, reduced ISI, Matsuda index as well as reduced CFR (2.54 ± 0.5 vs. 2.45 ± 0.3 vs. 2.74 ± 0.5), increased PWV, (8.9 ± 1.1 vs. 10.3 ± 2.4vs. 8.0 ± 1.5 m/sec), AI (23.8 ± 13.6 vs. 26.5 ± 14.4vs.17.7  ±  14%) and cSBP than normoglycaemics (p < 0.05 for all comparisons). During OGTT, AI was similarly reduced in both normoglycaemic and FDR (p < 0.05) at peak insulin levels (60 min) though FDR had 2-fold higher insulin than normoglycaemics. AI was increased in dysglycaemics after peak glucose levels, at 120 min (p < 0.05). CFR was reduced by 10% and 15% at 120min in FDR and dysglycaemic respectively, while remained unchanged in normoglycaemics (p < 0.05). The percent reduction of CFR was related with the percent increase of glucose levels, ISI and Matsuda index(p < 0.05). CONCLUSION: First-degree relatives and dysglycaemic patients have impaired arterial and coronary microcirculatory function. Insulin resistance determines acute vascular responses during postprandial hyperglycemia. CLINICALTRIALS. GOV IDENTIFIER: NCT02244736.

Vinegar Consumption Increases Insulin-Stimulated Glucose Uptake by the Forearm Muscle in Humans with Type 2 Diabetes.

BACKGROUND AND AIMS: Vinegar has been shown to have a glucose-lowering effect in patients with glucose abnormalities. However, the mechanisms of this effect are still obscure. The aim of this randomised, crossover study was to investigate the effect of vinegar on glucose metabolism in muscle which is the most important tissue for insulin-stimulated glucose disposal. MATERIALS AND METHODS: Eleven subjects with DM2 consumed vinegar or placebo (at random order on two separate days, a week apart), before a mixed meal. Plasma glucose, insulin, triglycerides, nonesterified fatty acids (NEFA), and glycerol were measured preprandially and at 30-60 min for 300 min postprandially from the radial artery and from a forearm vein. Muscle blood flow was measured with strain-gauge plethysmography. Glucose uptake was calculated as the arteriovenous difference of glucose multiplied by blood flow. RESULTS: Vinegar compared to placebo (1) increased forearm glucose uptake (p = 0.0357), (2) decreased plasma glucose (p = 0.0279), insulin (p = 0.0457), and triglycerides (p = 0.0439), and (3) did not change NEFA and glycerol. CONCLUSIONS: In DM2 vinegar reduces postprandial hyperglycaemia, hyperinsulinaemia, and hypertriglyceridaemia without affecting lipolysis. Vinegar's effect on carbohydrate metabolism may be partly accounted for by an increase in glucose uptake, demonstrating an improvement in insulin action in skeletal muscle. This trial is registered with Clinicaltrials.gov NCT02309424.

Metabolic effects of renal denervation.

In the present review article we address the issue of the potential effect of renal sympathetic denervation (RSD) on metabolic states associated with resistant hypertension. So far, there is an established pathophysiological background denoting that abnormalities in glucose metabolism especially in obese patients and in those with sleep apnea are constantly accompanied by increased sympathetic firing, as assessed by markers of sympathetic activity. Since resistant hypertension is also characterized by enhanced sympathetic activity, it seems logical and biologically plausible, that RSD might favorably influence impaired glucose metabolism, sleep disorders and increased body adiposity beyond BP lowering. Despite the limited evidence from clinical trials, there are promising data suggesting that RSD indeed ameliorates glucose metabolism-related measures in resistant hypertension. Well-designed randomized trials recruiting a larger number of patients with hypertension, and focused on metabolic parameters, may refine the role of RSD as a potential intervention to treat dysmetabolic states associated with hypertension.