Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study

Background: Molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. Patients and methods: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. Results: High PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15-1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). Conclusions: To our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors

Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study

Introduction In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and >= 3 (late add-on) prior antiseizure medications. Results A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. Conclusion Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy

IL TRATTAMENTO DELLE DISLIPIDEMIE NELLA PREVENZIONE PRIMARIA DELLE MALATTIE CARDIOVASCOLARI: LE INDICAZIONI PER LA PRATICA CLINICA

Le dislipidemie rappresentano uno dei più importanti fattori causali della arteriosclerosi e delle sue complicanze d’organo, come l’infarto del miocardico, l’ictus e la vasculopatia periferica. Il loro appropriato trattamento rappresenta la base degli interventi di prevenzione primaria delle malattie cardiovascolari su base ischemica. In generale, per dislipidemia si intende una condizione clinica nella quale sono presenti alterazioni qualitative e/o quantitative dei lipidi e delle lipoproteine plasmatiche

Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter retrospective study in Italian specialist care

Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI

Similar effectiveness of dapagliflozin and GLP-1 receptor agonists concerning combined endpoints in routine clinical practice: A multicentre retrospective study

Aims According to cardiovascular outcome trials, some sodium-glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are recommended for secondary cardiovascular prevention in type 2 diabetes (T2D). In this real-world study, we compared the simultaneous reductions in HbA1c, body weight and systolic blood pressure after initiation of dapagliflozin or GLP-1RA as second or a more advanced line of therapy. Materials and methods DARWIN-T2D was a retrospective multi-centre study conducted at diabetes specialist clinics in Italy that compared T2D patients who initiated dapagliflozin or GLP-1RA (exenatide once weekly or liraglutide). Data were collected at baseline and at the first follow-up visit after 3 to 12 months. The primary endpoint was the proportion of patients achieving a simultaneous reduction in HbA1c, body weight and systolic blood pressure. To reduce confounding, we used multivariable adjustment (MVA) or propensity score matching (PSM). Results Totals of 473 patients initiating dapagliflozin and 336 patients initiating GLP-1RA were included. The two groups differed in age, diabetes duration, HbA1c, weight and concomitant medications. The median follow-up was 6 months in both groups. Using MVA or PSM, the primary endpoint was observed in 30% to 32% of patients, with no difference between groups. Simultaneous reduction of HbA1c, BP and SBP by specific threshold, as well as achievement of final goals, did not differ between groups. GLP-1RA reduced HbA1c by 0.3% more than the reduction achieved with dapagliflozin. Conclusion In routine specialist care, initiation of dapagliflozin can be as effective as initiation of a GLP-1RA for attainment of combined risk factor goals

Long-term effects of evolocumab in participants with HIV and dyslipidemia: results from the open-label extension period

Objectives: People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52\u200aweeks in PWH. Design: This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420\u200amg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24\u200aweeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART. Methods: Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined. Results: Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4\u200ayears, 82.5% male, mean duration with HIV of 17.4\u200ayears). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP. Conclusion: Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events. Trail registration: NCT02833844. Video abstract: http://links.lww.com/QAD/C441

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe