Negative impacts of COVID-19 lockdown on mental health service access and follow-up adherence for immigrants and individuals in socio-economic difficulties.

OBJECTIVES: Lockdown measures in response to the coronavirus disease 2019 (COVID-19) pandemic can have serious mental health effects on the population, especially in vulnerable groups, such as those living in poor socio-economic conditions, those who are homeless, migrant workers and asylum seekers/refugees. In addition, these vulnerable groups frequently have greater difficulty accessing health services and in treatment adherence. The aim of this study is to estimate the impact of the COVID-19-related lockdown on service utilisation and follow-up adherence in an Italian mental health outpatient service for migrants and individuals in socio-economic difficulties. STUDY DESIGN: The design of this study is a retrospective cross-sectional study. METHODS: All patients who visited the mental health outpatient service in the months of February and March in the years 2017-2020 were included in the study. To compare service utilisation before and after the lockdown, the number of patients who visited the mental health outpatient service for psychiatric interview were recorded. Follow-up adherence was calculated as the percentage of patients who visited in February and subsequently attended a follow-up visit in March of the same year. RESULTS: The number of patients who visited the outpatient service between February 2017 and February 2020 was continuously increasing. In March 2020, fewer patients visited the service for psychiatric interview, in line with the introduction of lockdown measures. In addition, the number of the patients who visited in February 2020 and returned for their follow-up visits in March 2020 declined from approximately 30% over the same months in 2017-2019 to 17.53% in March 2020. CONCLUSIONS: The lockdown-related reduction in numbers of patients accessing the mental health service makes it difficult to help vulnerable populations during a period of time in which their mental health needs are expected to increase. Moreover, the reduction seen in follow-up compliance increases the risk of treatment discontinuation and possible relapse. Proactive alternative strategies need to be developed to reach these vulnerable populations.

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling.

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

Dose intercomparison at Italian hadrontherapy centers.

PURPOSE: To perform the first dosimetric intercomparison for proton beams in Italy using ionization chambers, according to the IAEA TRS-398 code of practice. METHODS: Measurement sites included: National Center for Oncological Hadron Therapy (CNAO, Pavia), Center for Proton Therapy (CTP, Trento) and Center for Hadron Therapy and for advanced Nuclear Applications (CATANA, Catania). For comparison we also included a 6 MV photon beam produced at Istituti Clinici Scientifici Maugeri (ICSM, Pavia). For proton beams, both single pseudo-monoenergetic layers (in order to obtain a planned dose of 2 Gy at the reference depth of 2 cm in a water phantom) and Spread-out Bragg peaks (SOBP) have been delivered. Measurements were performed with a PTW Farmer 30010-1 and a PTW Advanced Markus type 34,045 ionization chamber. RESULTS: Data obtained at CATANA, CNAO and CPT in terms of absorbed dose to water depth show good consistency within the experimental uncertainties, with a weighted mean of 1.99 ± 0.01 Gy and a standard error of 0.003 Gy, with reference to a nominal dose of 2 Gy as designed by the treatment planning system. CONCLUSIONS: The results showed a standard deviation of less than 1% for single layer and SOBP beams, for all chambers and a percent deviation less than 1.5% for single layer measurements. The weighted means of the absorbed doses for clinical proton beams (118.19 MeV and 173.61 MeV) are consistent within less than 1%. These results agree within the 1.5% difference considered acceptable for national dose intercomparison.

A prospective study for the treatment of proximal humeral fractures with the Galaxy Fixation System.

BACKGROUND: Fractures of the proximal humerus represent a common problem in clinical practice; in particular for three- or four-part fractures, there is no consensus regarding which is the best treatment. The aim of our study was to report clinical and radiological outcomes in patients treated with the Galaxy Fixation System™ for a proximal humerus fracture. MATERIALS AND METHODS: Thirty-two patients of which 18 (56.25%) women, and 14 (43.75%) men suffering from proximal humerus fractures were treated using the Galaxy Fixation System™. Fractures were classified according to Neer and only patients with a three- or four-part fracture with two-thirds of the methaphysis intact were included. Clinical examination included the Constant-Murley score, UCLA score and Quick DASH evaluated at 6, 12 and 24 months after surgery. In addition, at the final follow-up, patients were asked to complete the SF-12 questionnaire. The humeral head-shaft angle was evaluated by radiographs the day after surgery, as well as after 12 and 24 months. RESULTS: All 32 patients were available for the 6th, 12th and 24th month follow-up examination. The mean interval between trauma and surgery was 2.7 days (range 0-6 days). The period of hospital stay ranged from 2 to 8 days with an average of three days. The time of healing ranged from 4 to 10 weeks with an average of 7 weeks. The mean Constant score increased from 72.9 after 6 months to a mean of 82.8 at 12 months (p < 0.05) to 88.9 at 24 months (p < 0.05). UCLA score ranged from 27.5 at 6 months to 29.5 at 12 months (p < 0.05) and finally improved to 32.3 at final follow-up (p < 0.05). Quick DASH varied from 7.2 at 6 months after surgery to 5.2 at 12 months after surgery (p > 0.05) and reached the value of 3.1 after 24 months (p > 0.05). Mean Mental Component (MCS) resulted in a value of 48.1, while the Physical Component (PCS) was 52.7. The mean head-shaft angulation was 137.6° the day after surgery compared with 137.5° (p > 0.05) measured 12 months later, and 137.2° measured 24 months later (p > 0.05). CONCLUSIONS: Galaxy Fixation System™ is a safe and efficient procedure for the treatment of three- or four-part proximal humerus fractures, providing an excellent outcome. LEVEL OF EVIDENCE: Prospective case series, Level IV.

Prevalence and determinants of resistant hypertension in a sample of patients followed in Italian hypertension centers: results from the MINISAL-SIIA study program.

The aim of this study was to detect the prevalence of resistant hypertension (RH), allowing for adherence to appropriate lifestyle measures according to European Society of Hypertension-European Society of Cardiology (ESH-ESC) 2013 guidelines, in a sample of 1284 hypertensive subjects participating at the MINISAL-SIIA study. Hypertensive patients were recruited in 47 Italian centres, recognised by the Italian Society of Hypertension. Anthropometric indexes, blood pressure and 24-h urinary sodium (Na24h) and potassium (K24h) excretion were measured. Data on antihypertensive therapy were available for 1177 (92%) subjects. The population was divided into three groups (North, Central and South), according to their geographical location. Accounting only at the treatment criteria, the prevalence of RH was 8.2% (96/1177). RH prevalence in the southern, central and northern regions was respectively: 1, 3.8 and 3.3% (P<0.001). Participants with RH were older and showed a higher body mass index (BMI) and waist circumference compared with other subjects (P<0.005). RH risk was statistically significant (P<0.01) increased of 1.52-fold (95% confidence interval (CI):1.20-1.92) for one unit increase in s.d. score of age (11 years), and 1.50-fold (95% CI:1.22-1.83) for one unit increase in s.d. score of BMI (4.5 kg m-2). Including in RH diagnosis also the adherence to appropriate lifestyle measures, such as dietary salt restriction (Na24h <100 mmol) and normal BMI (18-25 kg m-2), RH prevalence felt respectively to 2.2% (26/1177) and 0.8% (9/1177). In conclusion in this national sample of Italian hypertensive population, among participants following both drug treatment and lifestyle modifications advises, the 'true' RH prevalence appears to be particularly low.

Metabolic syndrome and drug discontinuation in schizophrenia: a randomized trial comparing aripiprazole olanzapine and haloperidol.

OBJECTIVE: To determine whether the prescription of aripiprazole, compared with olanzapine and haloperidol, was associated with a lower frequency of metabolic syndrome (MS) and treatment discontinuation at 1 year. METHOD: Patients were randomly assigned to be treated open-label and according to usual clinical practice with either aripiprazole, olanzapine, or haloperidol and followed up for 1 year. RESULTS: Three hundred out-patients with persistent schizophrenia were recruited in 35 mental health services. The intention-to-treat (ITT) analysis found no significant differences in the rate of MS between aripiprazole (37%), olanzapine (47%), and haloperidol (42%). Treatment discontinuation for any cause was higher for aripiprazole (52%) than for olanzapine (33%; OR, 0.41; P = 0.004), or haloperidol (37%; OR, 0.51; P = 0.030). No significant difference was found between olanzapine and haloperidol. Time to discontinuation for any cause was longer for olanzapine than for aripiprazole (HR, 0.55; P < 0.001). No significant differences were found between haloperidol and aripiprazole, or between olanzapine and haloperidol. CONCLUSION: The prescription of aripiprazole did not significantly reduce the rates of MS, but its treatment retention was worse. Aripiprazole cannot be considered the safest and most effective drug for maintenance treatment of schizophrenia in routine care, although it may have a place in antipsychotic therapy.

Mucociliary clearance techniques for treating non-cystic fibrosis bronchiectasis: Is there evidence?

Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. An impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and treatment involves antibiotics, mucoactive agents, and airway clearance techniques (ACTs). Traditional ACTs have four components: postural drainage, percussion, vibration of the chest wall, and coughing. Reviewing the international medical literature on the use of ACTs for patients with nCFb from 1989 to the present day, we retrieved 93 articles, of which 35 met our selection criteria for this analysis. We reviewed active cycle of breathing techniques (ACBT), forced expiration techniques (FET), autogenic drainage, postural drainage, oscillating positive expiratory pressure (OPep), high frequency chest wall oscillation (HFCWO), and exercise or pulmonary rehabilitation. Overall, ACTs appear to be safe for individuals (adults and children) with stable bronchiectasis; where there may be improvements in sputum expectoration, selected measures of lung function, and health-related quality of life. Unfortunately, there is a lack of RCTs in nCFb patients, especially in children. Moreover, none of the studies describes long-term effects of ACTs. It should be noted that a single intervention might not reflect the longer-term outcome and there is no evidence to recommend or contest any type of ACTs in nCFb management. Multicenter RCTs are necessary to evaluate the different techniques of ACTs especially in children with nCFb.

Lithium use from 2000 to 2010 in Italy: a population-based study.

INTRODUCTION: Lithium is a highly specific and evidence-supported drug for the acute and maintenance treatment of bipolar disorder. METHODS: The purpose of this study was to calculate the prevalence and incidence of lithium use and to investigate the prescribing patterns of other mood-stabilizing agents in lithium users. We analyzed lithium utilization from 2000 to 2010 in a large area in Italy on the basis of dispensing data drawn from the regional administrative database. For each calendar year those who had at least one recorded dispensation of lithium were defined as lithium users. Those who received more than 4 dispensations per year were defined as lithium-treated. RESULTS: Rates of lithium utilization did not change during the observation period, but the amount of drug prescribed increased as a result of longer treatment and higher doses. The prevalence of use showed an initial increase of 8% (2000-2002), followed by a 13% decrease (2002-2006) and a subsequent rise of 11% (2006-2010). The prevalence of treatment grew by 38% during the whole observation period. The proportion of former lithium users who received other drugs or discontinued any treatment increased from 41% in 2002 to 52% in 2006, and then fell to 40% in 2010. CONCLUSION: The initial decline (2002-2006) and the subsequent rise (2006-2010) of lithium use can be explained by a fall and rise of new prescriptions. This finding together with a similar but opposite change in prescriptions of the other mood-stabilizing agents suggests a temporary change in prescribing attitudes which was subsequently reconsidered.

Prevalence of mental disorders in a Greek island.

In Greece, the need for epidemiological data became evident at the beginning of the mental health reform during 1983 with the emergence of the necessity to develop community-based mental health services. This survey was conducted in 2005 by the Association for Regional Development and Mental Health (EPAPSY), supported by the local authorities. It followed the methodology of the survey "Mental Health in the General Population: Images and Realities" (MHGP), a large scale multisite epidemiological research conducted by the World Health Organization Collaborative Centre of Lille in France and other countries. The aim of this study was to assess prevalence, sociodemographic and comorbidity patterns of mental disorders in the general adult population of Evia Island, Greece. This was a cross-sectional survey investigating point, period and lifetime prevalence of mental disorders. The target population was the non-institutionalized adult population of island of Evia (population 230,000 people). The Mini International Neuropsychiatric Interview and a sociodemographic data questionnaire were administered by trained interviewers to 900 residents of Evia. The quota sampling method was used to obtain a sample representative of the target population. Lifetime prevalence of any disorder, as identified by the MINI, was 29%. The prevalence of depression was high, with 17.5% of women and 14.6% of men currently meeting the criteria for diagnosis. Affective and anxiety disorders were found to be more frequent in women than men, except for dysthymia, social phobia and post-traumatic stress disorder which were slightly more frequent in men. The prevalence of psychiatric disorders in Evia was much higher than the prevalence found by other epidemiological studies in Greece and among the highest in Southern Europe. The high prevalence of mental disorders found in Evia means that almost one third of the population will suffer from a clinically significant disorder in their lifetime. Therefore, the resulting social burden is very relevant and requires the inclusion of mental health care among the main goals of a public health strategy. Methodological issues concerning the comparison of results between different countries, the limitations of the study and the rates of alcohol use disorders discussed. High rates of mental disorders are related to demographic changes, such as the increasing are size of elderly population, and probably to economic hardship and rise in unemployment. Results should be taken into consideration for the planning and development of interventions for vulnerable groups.

Inhaled mucoactive drugs for treating non-cystic fibrosis bronchiectasis in children.

Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. Medical treatment basically involves antibiotics and chest physiotherapy. An impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and inhaled therapy with mucoactive agents has frequently been used to try to correct it. The most often used mucoactive agents in this setting are N-acetylcysteine, hypertonic saline solution (HS), mannitol powder and recombinant human DNase (rhDNase). Reviewing the international medical literature on the use of these drugs for patients with nCFb from 1992 to the present day, we retrieved 88 articles, only 12 of which met our selection criteria for this analysis. We found only 2 papers and 2 reviews on the use of rhDNase in children, and in adults 3 trials on HS, 5 on mannitol powder and 2 on rhDNase. In conclusion, no observational or randomized controlled trials (RCT) have been published on the use of these drugs in children with nCFb, while the few conducted on adult patients report some evidence of their effects. Further studies are needed on inhaled mucoactive drugs for the treatment of children with nCFb.

Pediatric chronic lower respiratory disorders: microbiological and immunological phenotype.

The role of infectious agents in children with recurrent/chronic lower respiratory disorders (R/CLRDs) is not clear, whereas it has been largely studied in acute respiratory diseases. The purpose of the study was to evaluate the frequency of infections, in particular viral infections, in children with R/CLRDs correlating their presence with clinical/biohumoral parameters. Eighty children affected by R/CLRDs underwent bronchoscopy and analysis of bronchoalveolar lavage (BAL) for cells, mediators (eosinophil cationic protein-ECP, interleukin-IL-8, tumor necrosis factor-TNFα) and pathogens (viruses and bacteria). Viral genomes were detected in 50/80 (62.5%) children. Rhinovirus, the principal detected virus (26/50, 52%), occurred more frequently in male children. Higher percentages of BAL neutrophils and IL-8 values were detected in virus positive than negative children. ECP values resulted significantly higher in the children with rhinovirus than in those with other viruses. No other statistically significant correlation between viral findings and clinical/biohumoral data were found. Respiratory viruses, especially rhinovirus, seem to play an important role in children with R/CLRDs. They are associated with changes in BAL cellularity and inflammatory cytokines. Further studies are needed to confirm the persistence of viruses in these patients and to identify eventual therapeutic strategies.

Validation of the Italian version of the Functioning Assessment Short Test (FAST) for bipolar disorder.

Aim. The Functioning Assessment Short Test (FAST) is a useful instrument for the assessment of overall functioning of people with bipolar disorder, showing good psychometric properties. The aim of this study is to validate the Italian version of FAST. Methods. Translation and back-translation of the original FAST Spanish version were performed. Participants with bipolar disorder (n = 132) and healthy controls (n = 132) completed the FAST as a part of an assessment package including the Montgomery-Asberg Depression Rating Scale and the Young Mania Rating Scale. Internal consistency, inter-rater reliability, construct and discriminant validity were assessed. Results. The FAST Italian version showed good internal consistency, inter-rater reliability and discriminant validity. The cut-off discriminating patients from controls was 15, with a sensitivity of 0.79 and a specificity of 0.80. Principal component analysis with oblique rotation showed factor loadings consistent with the a priori structure of the instrument. Conclusions. This study confirmed the psychometric properties of FAST and extended its generalization and validity to the Italian population.

Beyond waist circumference in an adult male population of Southern Italy: Is there any role for subscapular skinfold thickness in the relationship between insulin-like growth factor-I system and metabolic parameters?

BACKGROUND: Apart from waist circumference, other adiposity measures, such as subscapular skin fold (SST), arouse growing interest due to their relationship to metabolic complications and cardiovascular risk. The IGF-I system is deregulated in obese subjects in proportion to their degree of visceral adiposity. AIM: To examine the association among IGF-I, IGF-binding protein (BP)-1 and -3 levels and different measures of adiposity in a sample of adult male population in Southern Italy. MATERIALS AND METHODS: A complete database for this analysis was available for 229 (age range 50-82 yr) participating at 2002-2004 Olivetti Heart Study follow-up. RESULTS: After adjustment for age, IGF-I was inversely associated with body mass index (BMI) and waist circumference (p<0.05). IGFBP-1 was inversely associated with BMI, waist circumference, SST, homeostasis model assessment (HOMA) index, fat mass. HOMA index, age, and SST significantly predicted the IGFBP-1 plasma levels, with 24% of IGFBP-1 variability explained at a linear regression analysis. CONCLUSIONS: IGFBP-1 inversely correlated to adiposity and HOMA index. Among adiposity indexes, SST was the best predictor of IGFBP-1 levels. The evaluation of some components of the IGF system, and simple measures of body adiposity, such as SST, may represent a further tool to better evidence phenotype profiles associated to the pathogenetic mechanism of cardiovascular risk factor clustering in male adults.

Antenatal and postnatal management of congenital cystic adenomatoid malformation.

Congenital thoracic malformations (CTMs) are a heterogeneous group of rare disorders that may involve the airways or lung parenchyma. The authors have focused on the condition that causes the most controversy, namely, congenital cystic adenomatoid malformation (CCAM). The reported incidence is 3.5 and 0.94 per 10,000 live births for CTMs and CCAMs respectively. Ultrasound is the antenatal imaging modality of choice for screening for CCAMs whilst magnetic resonance imaging is complimentary for morphological and volumetric evaluation of the foetal lung. Most CCAMs are detected antenatally with only a small proportion presenting postnatally. Only a few CCAMs cause foetal problems, with foetal hydrops being the best predictor of death. Although many CCAMs regress during pregnancy, most remain detectable postnatally by CT scans. Surgical excision of symptomatic lesions is relatively straightforward, but management of asymptomatic lesions is controversial. Some surgeons adopt a "wait and see" approach operating only on those patients who develop symptoms, but others operate on asymptomatic patients usually within the first year of life. Due to the potential of malignant transformation, children should have long term follow up. There is an urgent need to delineate the natural history of antenatally detected CCAMs to guide future management.

Congenital diaphragmatic hernia.

Infants with congenital diaphragmatic hernia (CDH) have significant mortality and long-term morbidity. Only 60-70% survive and usually those in high-volume centres. The current Task Force, therefore, has convened experts to evaluate the current literature and make recommendations on both the antenatal and post-natal management of CDH. The incidence of CDH varies from 1.7 to 5.7 per 10,000 live-born infants depending on the study population. Antenatal ultrasound scanning is routine and increasingly complemented by the use of magnetic resonance imaging. For isolated CDH, antenatal interventions should be considered, but the techniques need vigorous evaluation. After birth, management protocols are often used and have improved outcome in nonrandomised studies, but immediate intubation at birth and gentle ventilation are important. Pulmonary hypertension is common and its optimal management is crucial as its severity predicts the outcome. Usually, surgery is delayed to allow optimal medical stabilisation. The role of minimal invasive post-natal surgery remains to be further defined. There are differences in opinion about whether extracorporeal membrane oxygenation improves outcome. Survivors of CDH can have a high incidence of comorbidities; thus, multidisciplinary follow-up is recommended. Multicentre international trials are necessary to optimise the antenatal and post-natal management of CDH patients.

Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where?

There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma. Data have to be largely extrapolated from trials in children with mild asthma, and adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). In the first category are high-dose inhaled corticosteroids (ICS) (≤ 2,000 µg · day(-1) fluticasone equivalent), oral prednisolone, the anti-immunoglobulin (Ig)E antibody omalizumab, high-dose long-acting ß(2)-agonists, low-dose oral theophylline and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, intravenous infusions of Ig, subcutaneous ß(2)-agonist treatment and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole. Those with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat; baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS, leukotriene receptor antagonists or both at the time of exacerbations can be considered. There is no evidence regarding which therapeutic option to recommend. Better evidence is required for all these treatment options, underscoring the need for the international and co-ordinated approach which we have previously advocated.

Schizophrenia trial participation: perceived inclusion barriers and beliefs about antipsychotics.

BACKGROUND: Patient recruitment is the universal rate-limiting factor for randomized controlled trials (RCTs) in all medical specialties. This study examined the opinions on perceived inclusion barriers and beliefs about antipsychotics of a group of psychiatrists participating in a pragmatic RCT on antipsychotic drugs in schizophrenia (the GiSAS trial). METHODS: A survey of all clinicians working in the trial recruiting centers was performed exploring factors associated to the respondents' opinions. RESULTS: Of 465 clinicians, 278 (59.8%) responded to the questionnaire. Respondents (n=278) were mainly influenced by clinical and trial-related barriers (89%). Factors such as work setting and antipsychotic prescription choices appeared to be related to perceived inclusion barriers. Most respondents believed in the superiority of SGAs (62.9%), one-third indicating drug company representatives as the most important source of information; this was related to further optimism towards SGAs. CONCLUSIONS: Respondents were affected mainly by system-related barriers, whereas personal barriers were given less weight. The influence of industry-mediated information could have affected opinions on SGAs and the lack of uncertainty about antipsychotics attitudes towards trial participation.

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer.

AIM: To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF). RESULTS: The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline>15%. LVEF median values remained stable from baseline to the end of the study (60%). CONCLUSIONS: The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.