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Purpose Intravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC. Methods In this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy. Results At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%. Conclusions Safety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies. Trial registration NCT02402712

Objective: To investigate the care management and continuity from child to adult mental health service for young adults with ADHD. Method: A questionnaire survey from 18 Regional ADHD Pediatric Centers (RAPC) in Lombardy, Italy, was used to collect data on transition protocols and population served, and to track the pathway of care of ADHD patients once they reached adulthood. Results: Twenty-eight percent of RAPC had transition protocols and 3% of the population annually served were potential referrals to adult service. Of 52 patients who turned 18 years, just over 70% were monitored by the general practitioner, of those 5 with RAPC support. One fifth of patients continued to use mental health services, the majority was still monitored by the RAPC, and only three by services for adult. Conclusion: Managing the process of transition to adult services in mental health care remains a need to be prioritized and better defined for ADHD patients.

To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year. A cohort study analyzing data from the national ADHD register on patients from the Lombardy Region treated with MPH or atomoxetine. A total of 229 children (median age 11 years, range 6–17), enrolled in 15 regional centers between June 2007 and May 2010. The prevalence rate of pharmacological treatment for ADHD was 0.23%, whereas the estimated ADHD prevalence in the population was 0.95%. In total, 73.8% of patients had been treated with atomoxetine (10–90 mg daily) or MPH (10–75 mg daily); 22% of patients also received an additional psychotropic drug. Of the treated children, 26.9% discontinued the drug prior to 1 year of treatment, mostly because of adverse effects (28.6%). No new or unexpected adverse events (rate 39.2%) were encountered. Decreased appetite, headache, and unstable mood were the leading events. The most severe events occurred in two boys: one experienced absence seizures for the first time with MPH, the other experienced hallucinations with atomoxetine. Therapy was discontinued in ten male patients (7.7%) because of adverse events. All patients with adverse effects recovered well. A very low rate of ADHD prevalence was estimated in Italian children compared to that reported in other countries. Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can only be guaranteed by disseminating and monitoring evidence-based practices and by monitoring the safety and efficacy of treatments in both the short and long terms with appropriate tools and approaches.

To compare family paediatricians’ and general practitioners’ habits on drug prescribing to children. Prescriptions reimbursed by the Health Service and dispensed by the retail pharmacies of 15 local health units in the Lombardy Region of Italy during 2005 were analysed. Only family paediatricians and general practitioners who were in charge of children aged 6–13 years were included. During 2005, 239,296 children (43.6% of the selected population) received at least one drug prescription. The prevalence was higher in children treated by general practitioners (44.2 versus 43.4%), in particular in children 13 years old, with a prevalence of 38.7 versus 31.8% in children cared for by general practitioners and family paediatricians respectively. The prevalence of the most prescribed therapeutic classes was similar in the two groups. Some differences were found concerning the antibiotic classes, with family paediatricians prescribing penicillins more frequently and general practioners prescribing macrolides and cephalosporins more frequently. A total of 542 drugs were prescribed, 78% of which were prescribed by both the family paediatricians and the general practitioners. In all, only four drugs were prescribed by 75% or more physicians. The chance of receiving a drug prescription, adjusted for age, gender and local health unit of residence, was slightly higher in children cared for by general practitioners (OR 1.16; 95%CI 1.14–1.17). Few differences were found between the prescribing patterns of family paediatricians and those of general practitioners. Differences exist in particular for older children and for some drug classes.

To evaluate the intraregional differences in drug prescribing to children and adolescents.Prescriptions reimbursed by the National Health System, involving 1543 203 children and adolescents18 years old and dispensed during 2005 by the retail pharmacies of 15 local health units (LHU) in the Lombardy Region, were analysed. Logistic regression analysis was performed to evaluate the association between drug prescription and age, gender, prescriber, and setting.A total of 747 790 youths (48%) received at least one drug prescription. The prescription prevalence rate was highest in children 1-5 years old (65%), decreased with increasing age to 38% in adolescents, and was slightly higher in boys than in girls. Antibiotics and anti-asthmatics were the most prescribed therapeutic classes. Amoxicillin + clavulanic acid was the most prescribed drug (18% of children; 20% of packages). Large differences were found in the drug prescription prevalence rate between the different LHUs. The rate ranged between 38.4 and 54.8%, and was not correlated to hospitalization rate in the paediatric population. Being 1-5 years old [odds ratio (OR) 4.51, 95% confidence interval (CI) 4.43, 4.58] and living in the eastern part of the region (OR 2.06, 95% CI 1.99, 2.13) were the factors associated with the highest risk of drug exposure.The results resemble the profiles observed in other Italian contexts, in particular concerning the wide use of antibiotics and anti-asthmatics. However, large differences were found between LHUs, highlighting the need for more detailed investigations on therapeutic needs, drug use, and related variables in different geographic contexts.

BACKGROUND: Improved technology, as well as professional and parental awareness, enable many ventilator-dependent children to live at home. However, the profile of this growing population, the quality and adequacy of home care, and patients' needs still require thorough assessment. OBJECTIVES: To define the characteristics of Italian children receiving long-term home mechanical ventilation (HMV) in Italy. METHODS: A detailed questionnaire was sent to 302 National Health Service hospitals potentially involved in the care of HVM in children (aged

Many hospitalizations for asthma could potentially be avoided with appropriate management. The aim of this study was to analyze data on disease management of a paediatric population with a hospitalization for asthma. The study population comprised 6-17 year old subjects belonging to three local health units of the Lombardy Region, northern Italy. Regional administrative databases were used to collect data on: the number of children with an incident hospitalization for asthma during the 2004-2006 period, anti-asthma therapy, specialist visit referrals, and claims for spirometry, released in the 12 months before and after hospitalization. Each patient's asthma management profile was compared with GINA guideline recommendations. Among the 183 hospitalized subjects, 101 (55%) received therapy before hospitalization and 82 (45%) did not. 10% did not receive any therapy either before or after hospital admission and in 13% the therapy was discontinued afterward. Based on GINA guidelines, asthma management adhered to recommendations only for 55% of subjects. Results may suggest that for half of hospitalized subjects, inaccurate diagnosis, under-treatment/scarce compliance with asthma guidelines by physicians, and/or scarce compliance to therapy by patients/their parents occurred. In all these cases, hospitalization would be a proxy indicator of preventable poor control of disease, rather than a proxy indicator of severity.

To evaluate the quality of data reporting and statistical methods performed in drug utilization studies in the pediatric population.Drug utilization studies evaluating all drug prescriptions to children and adolescents published between January 1994 and December 2011 were retrieved and analyzed. For each study, information on measures of exposure/consumption, the covariates considered, descriptive and inferential analyses, statistical tests, and methods of data reporting was extracted. An overall quality score was created for each study using a 12-item checklist that took into account the presence of outcome measures, covariates of measures, descriptive measures, statistical tests, and graphical representation.A total of 22 studies were reviewed and analyzed. Of these, 20 studies reported at least one descriptive measure. The mean was the most commonly used measure (18 studies), but only five of these also reported the standard deviation. Statistical analyses were performed in 12 studies, with the chi-square test being the most commonly performed test. Graphs were presented in 14 papers. Sixteen papers reported the number of drug prescriptions and/or packages, and ten reported the prevalence of the drug prescription. The mean quality score was 8 (median 9). Only seven of the 22 studies received a score of ≥10, while four studies received a score of6.Our findings document that only a few of the studies reviewed applied statistical methods and reported data in a satisfactory manner. We therefore conclude that the methodology of drug utilization studies needs to be improved.

Summary Aim To estimate how many asthmatic children underwent spirometry testing in one year in a large Italian region, and evaluate sociodemographic determinants. Methods Data were retrieved from the administrative databases that store all pharmacological and diagnostic prescriptions issued to individuals living in the Lombardy Region. The analysis involved prescriptions dispensed to all 6–17 year olds (1,047,241 subjects) during 2008. Youths were identified as asthmatics by a previously validated strategy. Number of subjects having ≥1 spirometry claims was calculated, and factors associated with the probability of undergoing spirometry were evaluated by multivariate analysis. Results A total of 40,528 (3.9%) asthmatic subjects were identified. Only 30% of them underwent ≥1 spirometry during 2008, with differences between local health units (range 22–45%) and degree of anti-asthmatic use (26–35%). Moreover, in a multivariate analysis, the chance of undergoing spirometry was greater in boys than in girls (OR = 2.3). Conclusions A low percentage of asthmatic children, especially girls (who are more at risk of developing severe disease in adulthood), underwent spirometry during 1-year period. This highlights a low compliance with guidelines in the monitoring of childhood asthma. Educational intervention is needed in order to encourage use of spirometry in primary care settings.

In order to estimate the burden of mental disorders in a representative Italian pediatric population, an epidemiological study was performed using three administrative databases: a drug prescription, a hospital discharge form, and an outpatient ambulatory visit database. The population target was 1,616,268 children and adolescents under 18 years living in the Lombardy Region, Italy. A youth was defined as a case if during 2008 he/she received at least one psychotropic drug prescription or was hospitalized for a psychiatric disorder (International Classification of Disease codes 290–319), or attended a child neuropsychiatric outpatient unit for a visit and/or a psychological intervention or rehabilitation at least once. Epileptic children were excluded. In all, 63,550 youths (39.3 per 1000; 95%CI 39.1–39.7‰) were identified as users of health care resources for a putative mental disorder. The prevalence was higher in boys than in girls (47.0‰ versus 31.3‰) and the highest value was recorded in children 8 years old (60.2‰). A total of 59,987 youths (37.1‰) attended a child and adolescent neuropsychiatry service at least once, 3605 (2.2‰) were admitted to hospital, and 2761 (1.7‰) received at least one psychotropic drug prescription, 57% of which did not attend a child neuropsychiatry service. In all, 14,741 youths (23.1% of users) had a disorder that required a high intensity of care (e.g. recurrent prescriptions for drugs and/or ambulatory care). The proportion of youths who received care for mental disorders in the Lombardy Region seems lower than in other countries. However, the fact that many children were prescribed psychotropic drugs without the supervision of a child psychiatrist is a reason for concern.

We assessed the antibiotic patterns of use and geographical distribution of prevalence and consumption by age in 15 Local Health Units (LHUs) of Italy’s Lombardy region. A retrospective analysis of reimbursement data for the community-dwelling population in 2005 was performed. Prescriptions reimbursed by the National Health System and consumption as defined daily doses (DDD) per 1,000 inhabitants per day (DID) were analyzed. A logistic regression was performed to evaluate the association between antibiotic drug prescription and age, gender, and LHU of residence of the population. During 2005, a total of 3,120,851 people (34% of the population) received at least one antibiotic drug prescription. The highest prescription prevalence was observed in the 0–17 and 80 or more years age ranges (41.6 and 41.9%, respectively). Large differences were found in the prevalence rates between different LHUs (ranging from 28.7% in Milan to 39.4% in Brescia) and in DID (ranging from 12.6 DID in Sondrio to 18.9 DID in Brescia). The age and residence of the population were the main determinants of drug exposure. In particular, patients aged

Background The diagnosis of Strongyloides stercoralis (S. stercoralis) infection is hampered by the suboptimal sensitivity of fecal-based tests. Serological methods are believed to be more sensitive, although assessing their accuracy is difficult because of the lack of sensitivity of a fecal-based reference (“gold”) standard. Methods The sensitivity and specificity of 5 serologic tests for S. stercoralis (in-house IFAT, NIE-ELISA and NIE-LIPS and the commercially available Bordier-ELISA and IVD-ELISA) were assessed on 399 cryopreserved serum samples. Accuracy was measured using fecal results as the primary reference standard, but also using a composite reference standard (based on a combination of tests). Results According to the latter standard, the most sensitive test was IFAT, with 94.6% sensitivity (91.2–96.9), followed by IVD-ELISA (92.3%, 87.7–96.9). The most specific test was NIE-LIPS, with specificity 99.6% (98.9–100), followed by IVD-ELISA (97.4%, 95.5–99.3). NIE-LIPS did not cross-react with any of the specimens from subjects with other parasitic infections. NIE-LIPS and the two commercial ELISAs approach 100% specificity at a cut off level that maintains ≥70% sensitivity. Conclusions NIE-LIPS is the most accurate serologic test for the diagnosis of S. stercoralis infection. IFAT and each of the ELISA tests are sufficiently accurate, above a given cut off, for diagnosis, prevalence studies and inclusion in clinical trials., Author Summary The diagnosis of Strongyloides stercoralis infection is usually made by finding larvae of the parasite in the feces. The larval output is orders of magnitude lower than, say, the egg output of Ancylostoma duodenale, therefore the sensitivity of conventional techniques is poor. Sensitivity is enhanced by specific techniques, but the infection can still be missed. Several serologic methods (Strongyloides antibody detection in blood) are considered more sensitive, but they have been assessed so far with fecal tests as the gold standard, which is obviously unsatisfactory considering, precisely, their suboptimal sensitivity. Using a bank of sera from patients surely infected, not infected or doubtful, we assessed the accuracy of five different serologic tests also using a composite reference standard, obtained by combining the results of different tests. The recently developed NIE-LIPS resulted virtually 100% specific, with sensitivity >80%. Two commercially available ELISA tests were also highly specific above a given cut-off. Cross reactions with other parasitic infections were rarer than in previous studies. In conclusion, serologic tests are accurate tools, both for diagnostic purposes and for prevalence studies. Whether or not they can also be reliable markers of cure is currently under study.

Background Although anti-asthma medications are amongst those most frequently under or over prescribed it is generally accepted that prescriptions for such agents can be used as a proxy for disease prevalence. The aims of this study were to estimate prevalence and incidence of childhood asthma in a representative Italian area by analysing three years of anti-asthmatic prescriptions and hospitalizations of subjects with chronic or first time treatment, and to underline appropriateness of therapeutic choices. Methods The analysis involved prescriptions given to 6-17 year olds between 2003 and 2005 in Italy's Lombardy Region. The youths were classified as potential asthmatics, based on the different degree of drug utilization: occasional, low or high users, and grouped as 'new onset' or 'chronic' cases based on the duration of therapy dispensed. The analysis of prescriptions and hospitalization rate of these groups provided an estimate of the 2005 asthma prevalence and incidence and allowed an estimation of the level of appropriateness of treatments. Results During 2005, the estimated incidence of potential asthmatics was 0.8% and the estimated prevalence was 3.5%. When viewed retrospectively for two years, records showed that 47% of potential asthmatics received prescriptions also during 2004 and 30% also during 2003. During the three years considered, 7.5%, 2.8%, and 1.5% of high, low, and occasional users, respectively, were hospitalized for asthma. The most important inappropriateness found was the prescription of long acting beta adrenergics as first time treatment. Conclusions This study allowed a proxy of asthma incidence, prevalence, and severity. The analyses highlighted a low compliance with the guidelines, suggesting that educational interventions are needed to obtain a more rational management of childhood asthma, especially in subjects starting therapy.