Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.

BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

Lenalidomide treatment of myelodysplastic syndromes with chromosome 5q deletion: Results from the National Registry of the Italian Drug Agency.

OBJECTIVE: The most typical cytogenetic aberration in myelodysplastic syndromes is del(5q), which, when isolated, is associated with refractory anaemia and good prognosis. Based on high rates of erythroid response and transfusion independence, Lenalidomide (LEN) became the standard treatment. This multi-centre study was designed to supplement Italian Registry data on LEN by addressing prescription, administration appropriateness, haematological and cytogenetic responses and disease evolution. METHODS: MORE study was an observational, non-interventional, multi-centre, retrospective and prospective study. Cases were recruited from 45 Haematological Centres throughout Italy. Data were collected from the Italian National Registry for Lenalidomide administration and supplemented by a MORE data form. RESULTS: Data from 190/213 patients were analysed. In all, 149 had been diagnosed by conventional cytogenetics (GROUP A) and 41 only by FISH (GROUP B). Overall erythroid response was obtained in 92.8% of cases. Overall cytogenetic remission was achieved in 22.6% of cases. Disease progression occurred in 15.6% of cases. Clonal cytogenetic evolution characterised progression to AML but not to higher risk MDS. CONCLUSIONS: Erythroid response to Lenalidomide was similar in MDS with isolated del(5q) and with del(5q) plus one anomaly. Progression to AML or higher risk MDS showed different cytogenetic features.

Comparative risk/benefit profile of biosimilar and originator erythropoiesis-stimulating agents (ESAs): data from an Italian observational study in nephrology.

PURPOSE: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD). METHODS: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results. RESULTS: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001). CONCLUSIONS: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators.

Web-based international studies in limited populations of pediatric leukemia.

BACKGROUND: Recent progress in cancer research leads to the characterization of small subgroups of patients by genetic/biological features. Clinical studies in this setting are frequently promoted by international networks of independent researchers and are limited by practical and methodological constraints, not least the regulations recently issued by national and international institutions (EU Directive 2001/20/EC). PROCEDURE: We reviewed various methods in the design of international multicenter studies, with focus on randomized clinical trials. RESULTS: This paper reports our experience in planning and conducting international studies in childhood leukemia. We applied a decentralized study conduct based on a two-level structure, comprising a national and an international coordinating level. For the more recent trials this structure was implemented as a web-based system. This approach accommodates major legal requirements (e.g., safety reporting) and ensures Good Clinical Practice principles by implementing risk-oriented monitoring procedures. CONCLUSIONS: Setting up international non-commercial trials is increasingly complicated. Still, they are strongly needed for answering relevant questions in limited populations.

Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry.

OBJECTIVES: This study was designed to investigate the prevalence and prognostic significance of right heart thrombi (RHTh) in pulmonary embolism. BACKGROUND: Most reports about patients with RHTh are small case series. We analyzed data referring to RHTh among 2,454 consecutive pulmonary embolism patients enrolled in the International Cooperative Pulmonary Embolism Registry. METHODS: Of the 2,454 patients, 1,113 had results available from baseline echocardiography. We compared the 42 patients with RHTh versus 1,071 without RHTh. RESULTS: Patients with RHTh had shorter duration of symptoms (2.2 +/- 2.9 days vs. 4.3 +/- 6.0 days, p = 0.013), lower systolic blood pressure (BP) (116.0 +/- 28.8 vs. 125.7 +/- 25.0 mm Hg, p = 0.008), and more frequent right ventricular hypokinesis (64% vs. 40%, p = 0.002) and congestive heart failure (26% vs. 13%, p = 0.024); but they had similar age (62.9 vs. 62.5 years), arterial oxygen pressure (71.3 +/- 26.0 vs. 69.5 +/- 30.5 mm Hg), and prevalence of cancer (14% vs. 19%). The overall mortality rate at 14 days and at three months was higher in patients with RHTh (21% vs. 11%, p = 0.032, and 29% vs. 16%, p = 0.036). The difference in early mortality was observed almost entirely within the subgroup of patients treated with heparin alone (23.5% vs. 8%, p = 0.02), despite similar clinical severity at presentation (systolic BP 122.2 +/- 24.2 vs. 127.8 +/- 24.1 mm Hg, hypotension in 5.9% vs. 3.4% patients). CONCLUSIONS: Among patients with acute pulmonary embolism, RHTh is usually found in those more hemodynamically compromised but is also a marker of worse prognosis in initially apparently stable patients treated with heparin alone.

Use of aliskiren in a 'real-life' model of hypertension management: analysis of national Web-based drug-monitoring system in Italy.

INTRODUCTION: In Italy, prescriptions of the direct renin inhibitor aliskiren (aliskiren) to high-risk hypertensive patients must be electronically filled by specialized physicians only when at least two antihypertensive drug classes (independently of the dosages), fails to normalize blood pressure (BP) levels. AIM: To analyze the effects of the addition of aliskiren 150-300 mg daily to antihypertensive therapy in a population of high cardiovascular risk hypertensive patients with uncontrolled BP levels. METHODS: Clinical data were derived from patients included in the national Web-based drug-monitoring system. Follow-up visits were required for measuring BP levels, and collecting data on drug safety and tolerability. RESULTS: Between March 2009 and February 2010, aliskiren was prescribed by 6464 specialized physicians to 11 511 treated, uncontrolled hypertensive patients (47.6% women, aged 68.0 ±â€Š11.1 years, BMI 28.4 ±â€Š4.9 kg/m) with organ damage or comorbidities. During 6-month observation, only a few drug-related side-effects were reported (n = 33). At the entry and 1-month follow-up visits (n = 8197; 70.6%), BP levels were 158.9 ±â€Š16.8 and 142.1 ±â€Š15.2 mmHg for SBP and 90.8 ±â€Š9.6 and 83.1 ±â€Š8.5 mmHg for DBP, respectively. At 6-month (n = 4907; 42.3%), SBP and DBP levels were 137.9 ±â€Š13.9 and 81.3 ±â€Š8.0 mmHg, respectively. A consistent reduction in the use of all classes of concomitant antihypertensive drugs was recorded. CONCLUSION: Although data derived from national registries need to be interpreted with caution, the Italian Web-based drug-monitoring system provided information on 'real-life' use of aliskiren in hypertension. In this uncontrolled, high-risk treated hypertensive population, SBP and DBP levels recorded during treatment with aliskiren were consistently lower than those recorded at entry visits in a context of a very low rate of reported side-effects.

Natalizumab: a country-based surveillance program.

Natalizumab is a humanized monoclonal antibody with a selective adhesion-molecule inhibitor effect, and a demonstrated efficacy in decreasing the frequency of relapses and progression of disability in relapsing-remitting multiple sclerosis (RR MS). After the approval of FDA and EMEA in MS cases unresponsive to immunomodulating therapy or in severe MS patients also not previously treated with interferons, and considering the concern on the possible side effects, an accurate program of surveillance was organized in our country by a combined effort of AIFA, Cineca, Department of Pharmacology of University of Bologna, and a group of neurologists appointed by the National Society of Neurology (SIN). After 15 months from the authorization of natalizumab therapy in MS, as of 31 March 2008, 908 cases have been treated with natalizumab and enrolled in this pharmaco-vigilance study. The mean age is 35 years, while the duration of disease is longer and disability is higher than that reported in the registrative study. Side effects are at the moment mild and similar to those previously described. At follow-up, the majority of treated cases are stable or ameliorated. The treatment was discontinued in 6% of patients.

Disease management of the metabolic syndrome in a community: study design and process analysis on baseline data.

BACKGROUND: A comprehensive lifestyle approach is suggested as first-line treatment for the individual features of the metabolic syndrome, but the results in community medicine are usually discouraging. No study has tested the feasibility of an integrated approach between general practitioners (GPs) and specialist centers. METHODS: We report the process analysis on baseline data of a randomized study based on the integration between GPs, selecting patients on the basis of a pre-defined grid and specific targets, and a specialist center, providing informative material and arranging courses of counseling and cognitive-behavioral therapy, using a shared database. After initial visits by GPs for clinical assessment and motivation to treatment, patients were randomly assigned to: (a) prescriptive diet, managed by GPs; (b) counseling (four group lessons); (c) cognitive-behavioral treatment (12 group lessons), both managed by specialist center. Data of the first 503 subjects were compared with those of 139 cases self-referring to the specialist center for the treatment of obesity. RESULTS: Subjects enrolled by GPs were more frequently males, had lower obesity grades, and a higher number of features of metabolic syndrome, compared with the control group. Only 10% of subjects randomized to counseling and 27% randomized to behavior declined participation in the intensive treatments; attendance at sessions averaged 90%. GPs were satisfied with their participation and reported that treatments met patients' needs. CONCLUSIONS: An integrated approach to lifestyle changes between GPs and a specialist center is feasible in the metabolic syndrome and may be cost-effective, considering the high burden of disease.