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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

Background Previous trials showed that fixed-dose subcutaneous trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™; H SC) was non-inferior to weight-based intravenous trastuzumab (Herceptin®; H IV) in terms of pathologic complete response and serum trough concentration in HER2-positive early breast cancer (BC), with a comparable safety profile (NCT00950300), and demonstrated a compelling patient (pt) preference for H SC (NCT01401166). IV pertuzumab (PERJETA®; P IV) + H IV + docetaxel (D IV) was also shown to significantly improve progression-free survival (PFS) and overall survival vs. placebo + H IV + D IV in HER2-positive metastatic BC (NCT00567190). Here we report results from the final analysis of MetaPHER (NCT02402712), the largest study to evaluate safety and tolerability of first-line H SC + P IV + D IV for HER2-positive metastatic/locally advanced BC. Earlier analyses have been reported (Kümmel SABCS 2016; P4-21-42; Kümmel ESMO 2018; 323P). Methods Pts were ≥18-year-old females who had received no previous systemic non-hormonal anticancer therapy for their disease, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and a left ventricular ejection fraction (LVEF) ≥50%. Brain metastases and concomitant hormone therapy were allowed. Pts received 600 mg H SC + 840 mg loading/420 mg maintenance doses of P IV + ≥6 cycles of D IV (75 mg/m2→100 mg/m2; >6 cycles were given at the investigator’s discretion) every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. The primary objective was to evaluate safety and tolerability. Adverse events (AEs) were graded per National Cancer Institute - Common Terminology Criteria for Adverse Events version 4.0; left ventricular systolic dysfunction (LVSD) was classified according to the New York Heart Association Functional Classification system. Safety results are descriptive. Exploratory efficacy endpoints were PFS and objective response rate (ORR). Results Four hundred eighteen pts were enrolled; 412 were treated and analyzed for safety, and 160 remained on treatment at study end. Data cutoff was May 23, 2019 with median follow-up of 27 months (max. 45 months). Baseline demographics were similar to the interim analysis. Median cycles of H SC, P IV, and D IV were 22.0, 21.5, and 6.0, respectively (some discontinued P IV due to toxicity but remained on H SC per the protocol). Most pts experienced ≥1 any-grade AE (406; 98.5%); 221 (53.6%), grade ≥3 AEs; 107 (26.0%), serious AEs; 87 (21.1%), AEs leading to withdrawal from any study treatment; 87 (21.1%), investigator-reported administration-related and local injection-site reactions (21 [5.1%] H SC-related). There were 87 deaths (21.1% of pts): 73 (17.7%) from disease progression, nine (2.2%) due to AEs, and five (1.2%) due to other causes after treatment discontinuation. Three pts (0.7%) experienced grade ≥3 cardiac AEs, and one (0.2%) a serious AE suggestive of congestive heart failure. Of the 396 pts with LVEF measurements at baseline and ≥1 post-baseline visit, 40 (10.1%) had LVEF drops (to Citation Format: Sherko Kümmel, Carlo A Tondini, Jacinta Abraham, Zbigniew Nowecki, Bartosz Itrych, Erika Hitre, Bogusława Karaszewska, Alejandro Juarez, Flavia Morales-Vásquez, Jose Manuel Pérez García, Servando Cardona-Huerta, Mark Benyunes, Eleonora Restuccia, Adam Knott, Estefanía Monturus, Marco Sequi, Miguel Martín. Subcutaneous trastuzumab and hyaluronidase-oysk with intravenous pertuzumab and docetaxel in HER2-positive advanced breast cancer: Final analysis of the phase IIIb, multicenter, open-label, single-arm MetaPHER study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-05.

Purpose To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area. Methods The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs. Results A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54 % of total). Ciprofloxacin is used in 25 % of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25 % of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70 % of responding units that use fluconazole to treat fungal infection, 45 % administer 6 mg/kg unit doses while 33 % administer 12 mg/kg; 41 % of NICUs use a 24-h interval between administrations while 20 % wait 72 h. Among the responding NICUs, 57 % were willing to participate in a project on ciprofloxacin and 59 % would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin. Conclusions Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres’ interest in off-patent medicine research.

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.

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

Better results have been recently reported in clinical pancreatic islet transplantation (ITX) due mostly to improved isolation techniques and immunosuppression; however, some limitations still exist. It is known that following transplantation, 30% to 60% of the islets are lost. In our study, we have investigated 1) the role of size as a factor affecting islet engraftment and 2) potential procedural manipulations to increase the number of smaller functional islets that can be transplanted. C57/BL10 mice were used as donors and recipients in a syngeneic islet transplant model. Isolated islets were divided by size (large, >300 μm; medium 150–300 μm; small

The goal of this study was to evaluate the effectiveness of nebulized beclomethasone in preventing the recurrence of viral wheezing. METHODS: The study was designed as a randomized, double-blind, placebo-controlled trial. Outpatient children aged 1 to 5 years with at least 1 episode of viral wheezing in the last 12 months, presenting to any of 40 Italian pediatricians for an upper respiratory tract infection, were randomly allocated to receive beclomethasone 400 mg or placebo twice daily for 10 days. Medications were administered through a nebulizer. A clinical evaluation was performed by the pediatrician at the start and end of the treatment period. A subjective evaluation of symptoms and efficacy of treatment was performed by the parents. The primary endpoint was the incidence of viral wheezing diagnosed by the pediatricians during the 10-day treatment period. RESULTS: A total of 525 children were enrolled in the study, 521 of whom were visited at the end of the treatment period. Wheezing was diagnosed by the pediatricians in 47 children (9.0% (95% confi- dence interval: 6.7 to 11.3)), with no statistically significant differences between treatment groups (beclomethasone versus placebo relative risk: 0.61 (95% confidence interval: 0.35 to 1.08)).The treatment was considered helpful by 63% of parents (64% in the beclomethasone group vs 61% in the placebo group). In all, 46% of children still had infection symptoms at the end of the treatment period, with no differ- ences between groups. CONCLUSIONS: The findings from this study confirm that inhaled ste- roids are not effective in preventing recurrence of viral wheezing. Moreover, no benefits were found in reducing symptoms of respiratory tract infections. Pediatrics 2014;133:e505-e512 ABBREVIATIONS CI—confidence interval RCT—randomized controlled trial RR—relative risk URTI—upper respiratory tract infection Dr Clavenna conceptualized and designed the study, and drafted the initial manuscript; Drs Sequi and Cartabia conducted the statistical analyses, and reviewed and revised the manuscript; Drs Borghi and Fortinguerra were involved in the data management and reviewed and revised the manuscript; and Dr Bonati contributed to defining the protocol, supervised the study, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted.

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.

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.

Background Traditional faecal-based methods have poor sensitivity for the detection of S. stercoralis, therefore are inadequate for post-treatment evaluation of infected patients who should be carefully monitored to exclude the persistence of the infection. In a previous study, we demonstrated high accuracy of five serology tests for the screening and diagnosis of strongyloidiasis. Aim of this study is to evaluate the performance of the same five tests for the follow up of patients infected with S. stercoralis. Methods Retrospective study on anonymized, cryo-preserved samples available at the Centre for Tropical Diseases (Negrar, Verona, Italy). Samples were collected before and from 3 to 12 months after treatment. The samples were tested with two commercially-available ELISA tests (IVD, Bordier), two techniques based on a recombinant antigen (NIE-ELISA and NIE-LIPS) and one in-house IFAT. The results of each test were evaluated both in relation to the results of fecal examination and to those of a composite reference standard (classifying as positive a sample with positive stools and/or at least three positive serology tests). The associations between the independent variables age and time and the dependent variable value of serological test (for all five tests), were analyzed by linear mixed-effects regression model. Results A high proportion of samples demonstrated for each test a seroreversion or a relevant decline (optical density/relative light units halved or decrease of at least two titers for IFAT) at follow up, results confirmed by the linear mixed effects model that showed a trend to seroreversion over time for all tests. In particular, IVD-ELISA (almost 90% samples demonstrated relevant decline) and IFAT (almost 87%) had the best performance. Considering only samples with a complete negativization, NIE-ELISA showed the best performance (72.5% seroreversion). Conclusions Serology is useful for the follow up of patients infected with S. stercoralis and determining test of cure., Author Summary Patients infected by S. stercoralis are at risk of fatal complications. It is therefore mandatory to demonstrate complete response to therapy. Post treatment evaluation should be done with highly sensitive diagnostic methods, which can exclude the persistence of the infection. Serology is more sensitive than fecal examination and coproculture. In this study, we compare the post-treatment performance of five serology tests, and suggest that they can be useful for the follow up of patients with S. stercoralis infection, especially in non-endemic areas, where there is no risk of reinfection. In fact, the results of the tests show a progressive decrease, towards negativization, of the values (expressed in different units, depending on the specific test) through time.

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.