The purpose of the present paper is to provide an overview of current resources in the field of toxicology in Italy. The discussion will begin with a brief history of toxicology in this country, which includes the study of the toxicity of plants and other natural substances, and the birth of industrial and forensic toxicology. We will also provide information on research, education, and hazard control in the field of toxicology. Within this context we will examine the public bodies responsible for surveillance and regulatory activities, state-owned and private structures involved in toxicological research, and the educational programs and research activities of universities. Particular emphasis will be placed on the activities of the National Health Service, which plays an important role in areas such as clinical toxicology, food safety, and animal health, as well as those of national and regional agencies dedicated to the protection of the environment. The presentation will be organized as follows: (1) A Brief History of Toxicology in Italy; (2) Professional Societies; (3) National Health Service; (4) National Bodies; (5) Resources for the Environment; (6) Biomedical Websites; (7) Recent Publications; (8) Research Structures; (9) Graduate and Postgraduate Programs; (10) Legislation.

A careful assessment of “life expectancy” from past centuries to the present day leads one to consider how it has gradually increased since the early 19th century, from 35 to 40 years in the period of the Roman Empire to about 53 years for men and 56 for women in 1930-35, to 66 and 70 years respectively from 1955 to 1960, with a tendency at the present time for a further modest increase especially in the female sex.

Here, we report the case of a young patient admitted to the emergency department because of abdominal pain. Computed tomography revealed a mass within her right heart. Through serial multimodality imaging testing, including computed tomography, three-dimensional (2D)- and three-dimensional echocardiography, as well as cardiac magnetic resonance, the diagnosis of cardiac involvement in the course of Echinococcus granulosus infection was hypothesized.

To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for pancreatic iron overload assessment.

We determined the prevalence of incidental extracardiac findings (IEF) at Magnetic Resonance Imaging (MRI) potentially related to anemia and hypoxia in age- and sex-matched populations (N = 318) with thalassemia major (TM) and thalassemia intermedia (TI) enrolled in the Myocardial Iron Overload in Thalassemia network. Overall, IEFs were detected in 33.3% and 25.8% of patients with TI and TM, respectively (P = 0.114). TI and TM patients had elevated but comparable prevalence of renal, splenic and liver cysts, and vertebral hemangiomas while TI patients had a significant higher frequency of extramedullary hematopoiesis (EMH) (15.1% vs 4.4%; P = 0.002). The prevalence of total IEFs increased with advancing age. TI non-transfusion-dependent patients had a significantly lower frequency of renal cysts than TI transfusion-dependent patients (8.8% vs 26.4%; P = 0.005). The prevalence of renal cysts in the thalassemic population was significantly higher than that in the general population (19.2% vs 1.9%; P < 0.0001). Our data on renal cysts indicate a significant higher prevalence of these IEFs compared to the general population, suggesting the role of the inappropriate activation of the hypoxia-inducible factor system linked to the chronic hypoxia. The significant prevalence of IEF in thalassemia patients undergoing MRI for iron quantification should prompt the discussion of the inclusion of IEF in the MRI report.

Introduction: Cardiac magnetic resonance (CMR) is the non-invasive gold standard for the quantification of biventricular functional parameters and for myocardial tissue characterization. The aim of this study was to prospectively assess the predictive value of CMR parameters for cardiovascular complications in sickle cell disease (SCD) patients. Methods: We considered 102 white SCD patients (34.38±12.67 years, 53 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Results: At baseline CMR only two patients had MIO (global heart T2*<20 ms). During a mean follow-up was of 63.29±24.41 months, 10 cardiac events (9.8%) were registered: 3 pulmonary hypertension, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, 2 supraventricular arrhythmias, 1 heart failure, and 1 death after acute chest syndrome. CMR predictors of cardiovascular events at univariate analysis were left ventricular ejection fraction and right ventricular mass index (see Table). Both variables remained independent predictors at multivariate analysis (see Table). Conclusions: Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that also CMR could be added as screening tool for identifying SCD patients at high risk for pulmonary and systemic vasculopathy and death. Table Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Background:Some preliminary data have postulated a correlation between pancreatic iron overload and heart iron and function in thalassemia major (TM) patients.Aims:In the present multicenter study we explored systematically the link between pancreatic iron and heart disease in a large cohort of TM patients.Methods:We considered 880 TM patients (467 M, mean age 37.83 ± 10.05 years) enrolled in the E‐MIOT (Extension‐Myocardial Iron Overload in Thalassemia) project. T2∗ measurements were performed over pancreatic head, body and tail and global value was the mean. Myocardial iron overload (MIO) was quantified using a T2∗ segmental approach. Biventricular function parameters were assessed by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.Results:A significant correlation between pancreatic and cardiac iron was reconfirmed in this more numerous population and a normal pancreas T2∗ showed negative predictive value of 100% for cardiac iron.LGE sequences were acquired in 273 TM patients and 84 (30.77%) of them showed macroscopic myocardial fibrosis. Global pancreas T2∗ values were significantly lower in patients with fibrosis (7.38 ± 6.19 ms vs 11.91 ± 9.79 ms; P < 0.0001).Sixty‐four patients had at least one cardiac complication (arrhythmias, heart failure, pulmonary hyperthension, vascular disease). Patients with cardiac complications showed a significant lower global pancreas T2∗ (7.83 ± 5.61 ms vs 12.76 ± 10.34 ms; P = 0.024). Specifically, global pancreas T2∗ values were significantly lower in patients with heart failure as well as in patients with arrhythmias and all patients with one of these two diseases had a pathologic global pancreas T2∗ value (see Figure).Summary/Conclusion:Pancreatic iron is a strong predictor not only for cardiac iron, but also for cardiac complications supporting a more profound link between pancreatic iron and heart disease in TM.image

Background.The MIOT (Myocardial Iron Overload in Thalassemia) project is a multicentric study aimed to validate the T2* Magnetic Resonance Imaging (MRI) technique as non invasive approach for the cardiac and hepatic iron overload assessment in patients with hemoglobinopathies and to correlate the T2* values with other clinical-instrumental parameters. More recently, the E-MIOT (Extension-MIOT) project has been approved, with the aim of adding the assessment of the pancreatic iron

Introduction: More rapid drug premarketing procedures pose a challenge for regulatory agencies in terms of innovation and improving real-world safety and effectiveness Areas covered: This review considers the blockbuster drugs used over the previous fifteen years with adverse reactions after marketing, the elements and time span of risk identification and the measures implemented or considered, based on the existing literature and reports from the agencies Expert opinion: Risk prediction is founded on several factors: randomization, sample size, a well-established endpoint for safety, use of a comparator rather than placebo and a longer Phase-III period, in which a serious illness may be identified by early signs of alteration in the primary parenchyma with the latest biochemical, instrumental and imaging techniques. In comparative non-inferiority evaluations, increased safety should be preferred, with the exception of drugs that may be useful in serious or life-threatening diseases for which there are few or no effective existing therapies. A period of restricted use may be required to test and dispense new drugs, as well as to implement specific methods for the early detection of adverse events. It is important not to regard a new medicine axiomatically as the best treatment before it comes into wide use.

BACKGROUND:Hypertrophic cardiomyopathy (HCM), the most common genetic heart disease, is characterized by heterogeneous phenotypic expression. Body mass index has been associated with LV mass and heart failure symptoms in HCM. The aim of our study was to investigate whether regional (trunk, appendicular, epicardial) fat distribution and extent could be related to hypertrophy severity and pattern in HCM.METHODS:Cardiovascular magnetic resonance was performed in 32 subjects with echocardiography-based diagnosis of HCM (22M/10F, 57.2±12.6 years) characterized by predominant hypertrophy at the interventricular septum (IVS). Regional fat distribution was assessed by dual-energy X-ray absorptiometry.RESULTS:Gender differences were detected in maximum IVS thickness (M: 18.3±3.8 mm vs. F: 14.3±4 mm, p = 0.012), right ventricle (RV) systolic function (M: 61.3±6.7%; F: 67.5±6.3%, p = 0.048), indexed RV end-diastolic (M: 64.8±16.3 ml/m2; F: 50.7±15.5 ml/m2, p = 0.04) and end-systolic volumes (M: 24.3±8.3 ml/m2; F: 16.7±7.4 ml/m2, p = 0.04). After adjusting for age and gender, maximum IVS thickness was associated with truncal fat (Tr-FAT) (β = 0.43, p = 0.02), but not with either appendicular or epicardial fat. Epicardial fat resulted independently associated with NT-proBNP levels (β = 0.63, p = 0.04). Late Gadolinium Enhancement-positive subjects displayed greater maximum IVS thickness (p = 0.02), LV mass index (p = 0.015) and NT-proBNP levels (p = 0.04), but no associations with fat amount or distribution were observed.CONCLUSION:Truncal, but not appendicular or epicardial fat amount, seems to be related with maximum IVS thickness, the hallmark feature in our cohort of HCM patients. Further prospective researches are needed to assess a potential causative effect of central adiposity on HCM phenotype.

Iatrogenic pelvic pseudoaneurysm with concomitant arteriovenous fistula has been described as a rare and challenging complication, which may occur during transurethral resection of the prostate. We provide the first report of this complication after holmium laser enucleation of the prostate for the treatment of benign prostatic hyperplasia. The attempt to control the bleeding by conversion to open surgery and placement of haemostatic stitches into the prostatic fossa failed. Angiography with superselective arterial embolization proved to be a modern, quick, safe, and efficient treatment of this uncommon complication.

Background: There are no prospective studies comparing the effectiveness of the three iron chelators commercially available in preventing or decreasing iron overload in the heart and liver in pediatric thalassemia major (TM) patients. Our aim was to evaluate the changes in cardiac and hepatic iron and in cardiac function by quantitative magnetic resonance imaging (MRI) over a follow-up (FU) of 18 months in pediatric TM patients treated with one of the 3 available iron chelators in monotherapy or non chelated.

Abstract Introduction: Cardiovascular Magnetic Resonance (CMR) has an established role in managing and predicting prognosis of patients with Thalassemia Major (TM). Thalassemia Intermedia (TI) is a milder variant of beta-thalassemia showing a different clinical and prognostic profile; pulmonary hypertension (PH) is a more common complication in TI patients. We prospectively determined the predictive value of CMR parameters, including measurement of right ventricular mass, for cardiac complications in TI. Methods: We considered 342 TI patients enrolled in the Myocardial Iron Overload in Thalassemia network; about half of them (178/302, 58.9%) were transfusion-dependent. Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions, left and right ventricular mass and systolic function were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis. Results: Twenty-three patients were excluded because a cardiac complication was present at the time of first CMR, so we prospectively followed 319 patients. All 319 patients were white, with a mean age at time of their first scan of 38.02±11.69 years and 165 (51.7%) of them were females. Mean follow-up time was 52.24±24.87 months (median 54.64 months). Cardiac events were recorded in 22 patients (6.9%): heart failure (HF) in 1 patient, arrhythmias in 12 patients, pulmonary hypertension (PH) in 7 patients and myocardial infarction (MI) in 2 patients. Due to the low number of events, only arrhythmias, PH and cardiac complications globally considered were taken as cardiac outcomes for univariate and multivariate analysis. In the multivariate analysis RV hypertrophy was the only independent predictive factor for arrhythmias (HR=33.83, 95% CI=6.07-188.74, P<0.0001) and PH (HR=73.33, 95% CI=10.00-537.57, P<0.0001). When cardiac complications were considered all together, RV hypertrophy (HR=24.12, 95% CI=5.09-114.12, P<0.0001) and myocardial fibrosis by LGE (HR=6.59, 95% CI=1.33-32.67, P=0.021) were independent prognostic factors in the multivariate analysis. The Figures display the Kaplan-Meier curves showing the impact of the independent predictive factors on each outcome. Conclusions: For the first time we studied the prognostic value of right ventricular mass as part of multiparametric CMR imaging in a population of TI patients. RV hypertrophy identified patients at high risk for arrhythmias and PH. Both RV hypertrophy and fibrosis detected by LGE were independent predictive factor for cardiac complications. Measurement of RV mass should be part of the multi-parametric CMR study of patient with thalassemia intermedia. Figure 1. Figure 1. Disclosures Pepe: ApoPharma Inc: Speakers Bureau; Novartis: Speakers Bureau; Chiesi: Speakers Bureau.