Degradation rate of 5-fluorouracil in metastatic colorectal cancer. A new predictive outcome biomarker?

BACKGROUND: 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival. MATERIALS AND METHODS: Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome. RESULTS: 133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed. CONCLUSION: 5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes

Multi-Omics Integrative Approach of Extracellular Vesicles: A Future Challenging Milestone

In the era of multi-omic sciences, dogma on singular cause-effect in physio-pathological processes is overcome and system biology approaches have been providing new perspectives to see through. In this context, extracellular vesicles (EVs) are offering a new level of complexity, given their role in cellular communication and their activity as mediators of specific signals to target cells or tissues. Indeed, their heterogeneity in terms of content, function, origin and potentiality contribute to the cross-interaction of almost every molecular process occurring in a complex system. Such features make EVs proper biological systems being, therefore, optimal targets of omic sciences. Currently, most studies focus on dissecting EVs content in order to either characterize it or to explore its role in various pathogenic processes at transcriptomic, proteomic, metabolomic, lipidomic and genomic levels. Despite valuable results being provided by individual omic studies, the categorization of EVs biological data might represent a limit to be overcome. For this reason, a multi-omic integrative approach might contribute to explore EVs function, their tissue-specific origin and their potentiality. This review summarizes the state-of-the-art of EVs omic studies, addressing recent research on the integration of EVs multi-level biological data and challenging developments in EVs origin

Two-Tier Care Pathways for Liver Fibrosis Associated to Non-Alcoholic Fatty Liver Disease in HIV Mono-Infected Patients

(1) Background: Developing strategies to identify significant liver fibrosis in people with HIV (PWH) is crucial to prevent complications of non-alcoholic fatty liver disease (NAFLD). We aim to investigate if five simple serum biomarkers applied to PWH can optimize a care pathway to identify significant liver fibrosis defined by transient elastography (TE). (2) Methods: A two-tier fibrosis pathway was applied to three prospective cohorts of PWH undergoing TE with CAP. NAFLD was diagnosed as a controlled attenuation parameter ≥ 248 dB/m. Five simple fibrosis biomarkers (FIB-4 < 1.3, BARD score 0–1, NAFLD fibrosis score < −1.455, AST:ALT ratio < 0.8 and APRI < 0.5) were applied as first-tiers to exclude significant liver fibrosis. We determined the decrease in referral for TE that would have occurred based on biomarker assessment and the discordance between low simple fibrosis biomarkers and high TE (≥7.1 kPa), indicating significant liver fibrosis. (3) Results: Of the 1749 consecutive PWH, 15.1% had significant liver fibrosis by TE and 39.1% had NAFLD. The application of the fibrosis biomarkers as first tiers would have resulted in a decrease in TE referrals between 24.9% (BARD score) and 86.3% (APRI). The lowest discordance rate was with NAFLD fibrosis score (8.5%). After adjustments, BMI (odds ratio (OR) 1.12, 95% CI: 1.08–1.17) and triglycerides (OR 1.26, 95% CI: 1.11–1.44) were independent predictors of discordance for APRI < 0.5 and TE ≥ 7.1. The performance of the two-tier pathways was similar in PWH with and without NAFLD. (4) Conclusions: Implementing a two-tier pathway could save a substantial proportion up of TE examinations, reducing costs and helping resource optimization in HIV care. Patients with metabolic risk factors for NAFLD and low fibrosis biomarker may still be considered for TE referral

Two-tier care pathways for liver fibrosis associated to non-alcoholic fatty liver disease in HIV mono-infected patients

(1) Background: Developing strategies to identify significant liver fibrosis in people with HIV (PWH) is crucial to prevent complications of non-alcoholic fatty liver disease (NAFLD). We aim to investigate if five simple serum biomarkers applied to PWH can optimize a care pathway to identify significant liver fibrosis defined by transient elastography (TE). (2) Methods: A two-tier fibrosis pathway was applied to three prospective cohorts of PWH undergoing TE with CAP. NAFLD was diagnosed as a controlled attenuation parameter ≥ 248 dB/m. Five simple fibrosis biomarkers (FIB-4 \u3c 1.3, BARD score 0-1, NAFLD fibrosis score \u3c -1.455, AST:ALT ratio \u3c 0.8 and APRI \u3c 0.5) were applied as first-tiers to exclude significant liver fibrosis. We determined the decrease in referral for TE that would have occurred based on biomarker assessment and the discordance between low simple fibrosis biomarkers and high TE (≥7.1 kPa), indicating significant liver fibrosis. (3) Results: Of the 1749 consecutive PWH, 15.1% had significant liver fibrosis by TE and 39.1% had NAFLD. The application of the fibrosis biomarkers as first tiers would have resulted in a decrease in TE referrals between 24.9% (BARD score) and 86.3% (APRI). The lowest discordance rate was with NAFLD fibrosis score (8.5%). After adjustments, BMI (odds ratio (OR) 1.12, 95% CI: 1.08-1.17) and triglycerides (OR 1.26, 95% CI: 1.11-1.44) were independent predictors of discordance for APRI \u3c 0.5 and TE ≥ 7.1. The performance of the two-tier pathways was similar in PWH with and without NAFLD. (4) Conclusions: Implementing a two-tier pathway could save a substantial proportion up of TE examinations, reducing costs and helping resource optimization in HIV care. Patients with metabolic risk factors for NAFLD and low fibrosis biomarker may still be considered for TE referral

Development and Implementation of the AIDA International Registry for Patients With Still's Disease

Objective: Aim of this paper is to present the design, construction, and modalities of dissemination of the AutoInflammatory Disease Alliance (AIDA) International Registry for patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), which are the pediatric and adult forms of the same autoinflammatory disorder. Methods: This Registry is a clinical, physician-driven, population- and electronic-based instrument implemented for the retrospective and prospective collection of real-world data. The collection of data is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain evidence drawn from routine patients' management. The collection of standardized data is thought to bring knowledge about real-life clinical research and potentially communicate with other existing and future Registries dedicated to Still's disease. Moreover, it has been conceived to be flexible enough to easily change according to future scientific acquisitions. Results: Starting from June 30th to February 7th, 2022, 110 Centers from 23 Countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 4449 fields organized into 14 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. Conclusions: This international Registry for patients with Still's disease will allow a robust clinical research through collection of standardized data, international consultation, dissemination of knowledge, and implementation of observational studies based on wide cohorts of patients followed-up for very long periods. Solid evidence drawn from "real-life " data represents the ultimate goal of this Registry, which has been implemented to significantly improve the overall management of patients with Still's disease. NCT 05200715 available at

Influence of antisynthetase antibodies specificities on antisynthetase syndrome clinical spectrum time course

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition

Covid-19 and the role of smoking: the protocol of the multicentric prospective study COSMO-IT (COvid19 and SMOking in ITaly).

The emergency caused by Covid-19 pandemic raised interest in studying lifestyles and comorbidities as important determinants of poor Covid-19 prognosis. Data on tobacco smoking, alcohol consumption and obesity are still limited, while no data are available on the role of e-cigarettes and heated tobacco products (HTP). To clarify the role of tobacco smoking and other lifestyle habits on COVID-19 severity and progression, we designed a longitudinal observational study titled COvid19 and SMOking in ITaly (COSMO-IT). About 30 Italian hospitals in North, Centre and South of Italy joined the study. Its main aims are: 1) to quantify the role of tobacco smoking and smoking cessation on the severity and progression of COVID-19 in hospitalized patients; 2) to compare smoking prevalence and severity of the disease in relation to smoking in hospitalized COVID-19 patients versus patients treated at home; 3) to quantify the association between other lifestyle factors, such as e-cigarette and HTP use, alcohol and obesity and the risk of unfavourable COVID-19 outcomes. Socio-demographic, lifestyle and medical history information will be gathered for around 3000 hospitalized and 700-1000 home-isolated, laboratory-confirmed, COVID-19 patients. Given the current absence of a vaccine against SARS-COV-2 and the lack of a specific treatment for -COVID-19, prevention strategies are of extreme importance. This project, designed to highly contribute to the international scientific debate on the role of avoidable lifestyle habits on COVID-19 severity, will provide valuable epidemiological data in order to support important recommendations to prevent COVID-19 incidence, progression and mortality

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog

Clinical and laboratory features associated with macrophage activation syndrome in Still's disease: data from the international AIDA Network Still's Disease Registry

: To characterize clinical and laboratory signs of patients with still's disease experiencing macrophage activation syndrome (MAS) and identify factors associated with MAS development. patients with still's disease classified according to internationally accepted criteria were enrolled in the autoInflammatory disease alliance (AIDA) still's disease registry. clinical and laboratory features observed during the inflammatory attack complicated by MAS were included in univariate and multivariate logistic regression analysis to identify factors associated to MAS development. A total of 414 patients with Still's disease were included; 39 (9.4%) of them developed MAS during clinical history. At univariate analyses, the following variables were significantly associated with MAS: classification of arthritis based on the number of joints involved (p = 0.003), liver involvement (p = 0.04), hepatomegaly (p = 0.02), hepatic failure (p = 0.01), axillary lymphadenopathy (p = 0.04), pneumonia (p = 0.03), acute respiratory distress syndrome (p &lt; 0.001), platelet abnormalities (p &lt; 0.001), high serum ferritin levels (p = 0.009), abnormal liver function tests (p = 0.009), hypoalbuminemia (p = 0.002), increased LDH (p = 0.001), and LDH serum levels (p &lt; 0.001). at multivariate analysis, hepatomegaly (OR 8.7, 95% CI 1.9-52.6, p = 0.007) and monoarthritis (OR 15.8, 95% CI 2.9-97.1, p = 0.001), were directly associated with MAS, while the decade of life at Still's disease onset (OR 0.6, 95% CI 0.4-0.9, p = 0.045), a normal platelet count (OR 0.1, 95% CI 0.01-0.8, p = 0.034) or thrombocytosis (OR 0.01, 95% CI 0.0-0.2, p = 0.008) resulted to be protective. clinical and laboratory factors associated with MAS development have been identified in a large cohort of patients based on real-life data