Search

Objectives To assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC). Patients and methods We performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results One hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70–85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3–4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1–2 skin rash (49.1%), G1–2 diarrhea (21.1%) and G1–2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5–11.4), while the median OS was 18.0 months (95% CI: 16.0–19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832). Conclusion This study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m

Diastolic dysfunction (DD) is an early manifestation of cancer drug cardiotoxicity. Anthracyclines are considered as more cardiotoxic than other chemotherapeutics, but previous studies have shown that both anthracycline-based and nonanthracycline chemotherapy can cause an early DD, detected 1 week after the end of chemotherapy. Here we characterized if DD also occurred in a delayed form, detected 6 months after chemotherapy. Sixty-seven comorbidity-free patients were examined. DD was diagnosed by echocardiography and cardiac biomarkers. Early or delayed DD occurred in 26 or 13 patients, respectively, sharing a pattern of grade I DD (impaired relaxation at echocardiography) or elevated B-type natriuretic peptide. Binary logistic analysis showed that age, gender, and type of chemotherapy (anthracycline-based vs. nonanthracycline) did not independently increase the probability of early or delayed DD. Early DD was predicted by the patient's cardiovascular profile and in particular by diastolic indices that were in ranges of normality but showed measurable discrepancies from mean control values. Delayed DD was not predicted by the patient's cardiovascular profile but was predicted by postchemotherapy adjuvant treatments (e.g., chest radiation or hormone therapy). Early and delayed DD were accompanied by moderate left ventricular ejection fraction decrements. These findings show that anthracycline-based and nonanthracycline chemotherapy can induce early or delayed DD, which are governed by different patient- or treatment- related factors. Pharmacologic interventions that prevent DD or mitigate its progression toward a more serious cardiac dysfunction should be considered. SIGNIFICANCE STATEMENT: Predictors of early or delayed diastolic dysfunction (DD) were investigated in patients with cancer treated with anthracycline-based or nonanthracycline chemotherapy. The type of chemotherapy did not predict the risk of DD. Early DD was predicted by the patient's cardiovascular profile. Delayed DD was predicted by the adjuvant treatments the patient received after chemotherapy. These findings show that any chemotherapeutic can cause DD; however, the trajectories of DD are differently influenced by patients' characteristics or postchemotherapy exposure to additional cardiotoxic hits.

ObjectivesOlder people are not traditionally expected to become caregivers. For this reason, the experience of caregiving in older persons has not been explored adequately in the research on gender differences. The objective of this study was to assess the caregiver burden among older family members who care for cancer patients facing the end of their lives, in order to compare their differences according to gender (male vs. female).MethodsThis is a cross-sectional study. A total of 102 older caregivers (aged ≥65 years) of hospice patients were interviewed through the Caregiver Burden Inventory (CBI). The sample group was divided into two gender subgroups.ResultsCompared with male caregivers, the older female group reported significantly higher scores in the CBI–physical subscale (P = 0.028), and in the CBI, the overall score (P = 0.0399) confirmed by the generalized linear model (multivariate) evaluation that included possible predictors in the model. There were no significant differences in the other CBI subscale scores (time-dependent, developmental, social, and emotional).Significance of resultsOlder female caregivers are at higher risk of experiencing burden and worse physical health compared with men. Further research is needed in modern palliative care to assess the role of gender differences in the experience of caregiving when the caregiver is an older person.

Background We describe our experience from a multi-national application of a European Union-funded research-driven paediatric trial (DEEP-2, EudraCT 2012-000353-31; NCT01825512). This paper aims to evaluate the impact of the local and national rules on the trial authorisation process in European and non-European countries. National/local provisions and procedures, number of Ethics Committees and Competent Authorities to be addressed, documentation required, special provisions for the paediatric population, timelines for completing the authorisation process and queries received were collected; compliance with the European provisions were evaluated. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model analysis were used to determine factors potentially influencing the timelines. The Cluster Analysis procedure was used to identify homogenous groups of cases. Result The authorisation process was completed in 7.7 to 53.8 months in European countries and in 17.1 to 27.1 months in non-European countries. The main factors influencing these timelines were the requests for changes/clarifications in European countries and the different national legislations in non-European countries. Conclusion This work confirms that the procedures and requirements for the clinical trial application of a paediatric trial are different. In the European Union, the timeframes for submission were generally harmonised but longer. In non-European countries, delays were caused by national dispositions but the entire authorisation process resulted faster with less requests from ECs/CAs. The upcoming application of Regulation (EU) 536/2014 is expected to harmonise practices in Europe and possibly outside. Networks on paediatric research acting at international level will be crucial in this effort.

Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.

Introduction The inhalational analgesic low-dose methoxyflurane has been widely used by Australian ambulance services since 1975 and is now approved in Europe for emergency relief of moderate-to-severe trauma-related pain in conscious adult patients. The use of methoxyflurane in hostile environments is of special interest given its portability, ease of use and rapid onset of action. This trial will investigate the efficacy, tolerability and practicality of use of inhaled methoxyflurane in patients with moderate-to-severe trauma-related pain rescued from hostile mountainous environments by the Helicopter Emergency Medical Service (HEMS) in Italy. Methods METEORA is a phase IIIb, prospective, single-arm, multicentre trial. Approximately 200 adult patients with a pain score of at least 4 on the numerical rating scale (NRS) due to limb trauma rescued by HEMS will be enrolled. Patients will receive up to 2 × 3 mL methoxyflurane, self-administered by the patient by inhalation under medical supervision. Rescue medication will be permitted if required. Planned Outcomes Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline, at 5, 10, 15, 20, 30, 45 and 60 min after the start of methoxyflurane inhalation and when positioning the patient on a spinal board or stretcher; and also using the NRS at enrolment and at 10 min. Use of rescue medication (yes/no) will be recorded. The patient will rate efficacy and the healthcare professional will rate practicality of methoxyflurane treatment at 30 and 60 min using a 5-point Likert scale. Vital signs will be measured at baseline, 10, 30 and 60 min. Assessments after 30 min will only be performed for patients using a second inhaler. Adverse events will be recorded until safety follow-up at 3 ± 1 days. The primary endpoint is the percentage of patients achieving at least 30% improvement from baseline in VAS pain intensity within the first 10 min of methoxyflurane administration. Trial Registration EudraCT number: 2017-004601-40. Funding Mundipharma Pharmaceuticals, srl. Plain Language Summary Plain language summary available for this article. Electronic supplementary material The online version of this article (10.1007/s12325-018-0816-8) contains supplementary material, which is available to authorized users., Plain language summary The treatment of pain is an essential part of the management of injured patients. In emergency rescue situations, rapid and effective pain relief can reduce the patient’s stress and discomfort, making it easier to assess, treat and extricate them. Currently available painkillers have limitations such as being slow to work (oral medications), requiring needles (intravenous medications) or prolonged monitoring and observation (e.g. opioids). An inhaled painkiller (methoxyflurane) is now available in Europe for emergency relief of moderate-to-severe pain in conscious adult patients with trauma (injury) and associated pain. Methoxyflurane is administered via a hand-held inhaler, which provides pain relief within 6–10 inhalations and lasts for 25–30 min, on average, when used continuously. The patient can control his/her own level of pain relief and a second inhaler may be used if required. Methoxyflurane has been widely used by Australian ambulance services since 1975 and its effectiveness and safety are well established. Considering its ease of use and rapid action, inhaled methoxyflurane may be useful in emergency situations in remote and hostile environments. A new trial (METEORA) will assess the use of methoxyflurane in 200 patients with limb injuries who are rescued from mountainous environments by the Helicopter Emergency Medical Service (HEMS) in Italy. Patients with moderate-to-severe pain will receive inhaled methoxyflurane under medical supervision. A second inhaler and/or additional pain-relieving medication will be provided if necessary. The trial will assess the reduction in pain intensity and whether additional pain-relieving medication is needed. The practicality of use of methoxyflurane in the emergency rescue situation and any side effects will also be evaluated. Electronic supplementary material The online version of this article (10.1007/s12325-018-0816-8) contains supplementary material, which is available to authorized users.

We have reported that cancer patients treated with anthracycline-based or nonanthracycline chemotherapy developed an early impairment of myocardial relaxation at echocardiography or persistent elevations of the cardiac hormone B-type natriuretic peptide (BNP). Post-hoc pharmacologic analyses showed that BNP elevations were induced by impaired relaxation and caused positive lusitropic effects that maintained normal relaxation. High BNP levels and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction, but high BNP levels resulted in positive chronotropism and inappropriate tachycardia. Some patients developed increased circulating levels of cardiac troponin I isoform (cTnI), a marker of cardiomyocyte necrosis. Here we have characterized whether cTnI elevations correlated with diastolic dysfunction that manifested as impaired relaxation or a high level of BNP. The effects of high BNP levels on cTnI elevations were also characterized. We show that impaired relaxation or high BNP levels were significantly more frequent in patients with cTnI elevations. High BNP levels diminished the plasma peak and area under the curve of cTnI, but this result was accompanied by inappropriate tachycardia. cTnI elevations occurred only in patients treated with anthracyclines; moreover, the association of impaired relaxation or high BNP levels with cTnI elevations was significantly more frequent in doxorubicin-treated patients compared with patients treated with its analog, epirubicin. These findings describe cause-and-effect relations between impaired relaxation and cardiomyocyte necrosis, illuminate the role of anthracycline analogs, denote that the beneficial effects of BNP in relieving impaired relaxation and cardiomyocyte necrosis are counterbalanced by inappropriate tachycardia. Patients showing troponin elevations and impaired relaxation or high BNP levels should be treated with lusitropic drugs that lack a positive chronotropism.

B-type natriuretic peptide (BNP) is widely used as a diagnostic marker of systolic dysfunction. We previously conducted a clinical study in which anthracycline or nonanthracycline chemotherapy did not cause systolic dysfunction in cancer patients; however, some patients showed asymptomatic alterations in diastolic relaxation, whereas others showed persistent elevations of BNP, measured as prohormone BNP amino-terminal fragment. Here we describe post hoc pharmacologic analyses showing that: 1) impaired relaxation and persistent elevations of BNP were mutually exclusive manifestations of diastolic dysfunction; 2) in some patients, BNP elevations were induced by an early compromise of myocardial relaxation; 3) BNP elevations then halted further deterioration of relaxation in a concentration-dependent manner; and 4) high BNP increased heart rate (HR). BNP elevations therefore caused positive lusitropy and chronotropism, which might be explained by activation of natriuretic receptor-associated guanylyl cyclase and production of cGMP in ventricular myocytes and sinoatrial node, respectively. BNP levels also influenced responses to a lusitropic drug, ranolazine, that was given to treat diastolic dysfunction. For patients with impaired relaxation and normal or only transiently high levels of BNP, ranolazine improved myocardial relaxation without inducing chronotropic effects. For patients in whom relaxation abnormalities were corrected by persistently high BNP levels, ranolazine substituted for BNP and decreased HR by diminishing BNP levels. These findings describe a pharmacologic scenario in which cancer drugs cause an early diastolic dysfunction that in some patients is both heralded and modulated by BNP elevations. Patients showing BNP elevations should therefore receive the adequate pharmacologic treatment of correcting diastolic dysfunction and tachycardia.

Asymptomatic diastolic dysfunction (DD) with preserved left ventricular ejection fraction (LVEF) is suspected to precede late cardiac events in cancer survivors treated by chemotherapy. We conducted the first multicenter study of early DD induced by chemotherapy. Patients who were candidates for standard dose chemotherapy were screened for the absence of cardiovascular risk factors, LVEF ≥50%, normal-for-age diastolic function at echocardiography (E/A ratio, E wave deceleration time; DT), normal levels of potential DD biomarkers like Nt-proBNP (≤125 pg/mL), and cardiac troponin I (cTnI, ≤0.05 ng/mL). Mitral Doppler (E/E’) was left at the investigator’s discretion. Chemotherapy-induced DD with preserved LVEF was diagnosed for patients showing LVEF ≥50% and any of the following: Nt-proBNP > 125 pg/mL, cTnI > 0.05 ng/mL, and out-of-range E/A and DT. Eighty patients (68 males, 12 females, median age 49 years) were evaluated at 1 week after chemotherapy (T1). Thirty-three protocol-defined diastolic events were observed (15 Nt-proBNP > 125 pg/mL, 14 grade I DD by E/A and DT, 4 cTnI > 0.05 ng/mL). The events occurred in 29 asymptomatic patients with LVEF ≥50% (36% incidence of DD with preserved LVEF). Interactions occurred between biomarkers and grade I DD. E/E’ abnormalities were not observed. Both anthracycline-based and nonanthracycline regimens induced DD. These findings show that biomarkers and echocardiography intercept early DD in otherwise asymptomatic low-risk cancer patients treated by standard dose chemotherapy. These findings therefore call for the adequate cardiac management of cancer patients.

Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox.DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (100 mg/kg per day) or deferasirox (40 mg/kg per day; deferasirox is not registered for use in children aged2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512.435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group.In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group.EU Seventh Framework Programme.

Context: The aging of the world’s population increasingly calls on older people to care for their cancer relatives. This scenario confronts clinicians involved with end-of-life care with an imposing challenge: elderly family caregivers could have a different perception of the burdens associated with assistance compared to their younger counterparts. Palliativists need to know what limits and resources of these new age categories of caregivers could be for a global management of dying patients with cancer and their family. Objectives: To evaluate the caregiver burden in family caregivers supporting dying patients with cancer in order to compare the differences between 2 different caregivers age groups (younger vs elderly population). Methods: This is a cross-sectional study. A total of 174 family caregivers of hospice patients were interviewed through the Caregiver Burden Inventory (CBI). The sample group was divided into 2 subgroups aged Results: Compared with younger caregivers, the elderly group reported significantly higher scores in the CBI–developmental subscale ( P = .009) confirmed by the generalized linear model (multivariate) evaluation that included possible predictors in the model. No further differences were found between the 2 age groups in the other CBI scores (time-dependent, physical, social, emotional, and overall score). Conclusion: Elderly caregivers are at high risk for experiencing developmental burden. This finding could prompt mental health professionals to pay greater attention to the value that assistance to the family member can have on their personal story and on that of the family or couple.

We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug ranolazine shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low-risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or the investigator's choice of common cardiovascular drugs, such as β-blockers and/or angiotensin-converting enzyme inhibitors or loop diuretics (best standard therapy, BST). After 5 weeks, 12 of 12 patients on ranolazine recovered from diastolic dysfunction, whereas 3 of 12 patients on BST did not improve; however, adverse events (not serious) were apparently more frequent for ranolazine than for BST (4/12 vs. 1/12). Ranolazine did not lower blood pressure, whereas BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. Most patients at randomization showed tachycardia resulting from chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in the ranolazine arm developed tachycardia through chronotropic effects of high BNP levels and returned to a normal heart rate through the effects of ranolazine on decreasing BNP levels. This minitrial describes the potential effects of ranolazine on relieving chemotherapy-related diastolic dysfunction; however, clinical implications of these findings need to be characterized by studies with an adequate sample size. SIGNIFICANCE STATEMENT: The antianginal drug ranolazine causes cardiac relaxant effects that might relieve diastolic dysfunction. In a clinical pharmacology study, 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs to treat early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine relieved diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients is similar to that of the general population. Compared with common cardiovascular drugs, ranolazine relieved diastolic dysfunction without lowering blood pressure. The sample size of this study was nonetheless too small to permit considerations about the potential clinical value of ranolazine for oncologic patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics. This information should be obtained by studies with an adequate sample size.

Claudio Borghi,1 Stefano Omboni,2 Giorgio Reggiardo,3 Stefano Bacchelli,1 Daniela Degli Esposti,1 Ettore Ambrosioni1 On behalf of the SMILE Working Project 1Unit of Internal Medicine, Policlinico S. Orsola, University of Bologna, Bologna, Italy; 2Clinical Research Unit, Italian Institute of Telemedicine, Varese, Italy; 3Mediservice S.r.l., Agrate Brianza, Italy Background: In the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) studies, early administration of zofenopril after acute myocardial infarction (AMI) was prognostically beneficial as compared to placebo and other angiotensin-converting enzyme inhibitors (ACEIs), such as lisinopril and ramipril. Here, we investigated whether zofenopril efficacy could be affected by a concomitant use of thiazide diuretics (TDs). Methods: This was a post hoc analysis of pooled individual patient data from the SMILE studies. Patients treated with other diuretics than TDs were excluded. The primary study endpoint was the 1-year combined occurrence of death or hospitalization for CV causes, with or without TD. Results: Among 2,995 patients, 263 (8.8%) were treated with a combination including a TD (TD+), whereas 2,732 (91.2%) were not treated with any diuretic (TD-). Proportions of subjects who were treated with TD were equally distributed (p=0.774) within the placebo, zofenopril, and other ACEIs groups. The 1-year risk of major cardiovascular events was similar in TD+ (18.3%) and TD- (16.8%) patients (hazard ratio [HR] 1.04; 95% CI 0.74–1.45; p=0.838). After stratifying per concomitant treatment and TD, the 1-year risk of CV events was significantly lower with zofenopril than with placebo (HR 0.70; 95% CI 0.55–0.88; p=0.002) and other ACEIs (HR 0.58; 95% CI 0.46–0.74; p=0.0001). Treatment with ACEIs and TD as concomitant therapy was associated with a larger blood pressure (BP) reduction (p=0.0001 for systolic BP and p=0.045 for diastolic BP). Conclusion: In post AMI patients, zofenopril maintained its positive impact on prognosis compared to placebo or other ACEIs, regardless concomitant TD administration. In this setting, TD shows advantages in managing the most difficult hypertensive patients. Keywords: acute myocardial infarction, drug therapy, angiotensin-converting enzyme inhibitors, thiazide diuretics, cardiovascular risk

Background Oxidative stress is increased in hyperuricemic patients with acute myocardial infarction (AMI). Use of sulfhydryl ACE-inhibitors (ACEIs), such as zofenopril or captopril, plus xanthine oxidase inhibitors (XOIs), may potentially result in enhanced antioxidant effects and improved survival. Objective We verified the benefit of such combination in a randomly stratified sample of 525 of the 3630 post-AMI patients of the four randomized prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies. Methods One hundred sixty-five (31.4%) patients were treated with XOIs (79 under zofenopril, 86 placebo, lisinopril or ramipril), whereas 360 were not (192 zofenopril, 168 placebo or other ACEIs). In these four groups, we separately estimated the 1-year combined risk of major cardiovascular events (MACE, death or hospitalization for cardiovascular causes). Results MACE occurred in 10.1% of patients receiving zofenopril + XOIs, in 18.6% receiving placebo or other ACEIs + XOIs, in 13.5% receiving zofenopril without XOIs and in 22.0% receiving placebo or other ACEIs, but no XOIs (p = 0.034 across groups). Rate of survival free from MACE was significantly larger under treatment with zofenopril + XOIs than with other ACEIs with no XOIs [hazard ratio: 2.29 (1.06–4.91), p = 0.034]. A non-significant trend for superiority of zofenopril + XOIs combination was observed vs. zofenopril alone [1.19 (0.54–2.64), p = 0.669] or vs. placebo or other ACEIs + XOIs [1.82 (0.78–4.26), p = 0.169]. Conclusions Our retrospective analysis suggests an improved survival free from MACE in post-AMI patients treated with a combination of an urate lowering drug with antioxidant activity and an ACEI, with best effects observed with zofenopril.

Aim: This study evaluated adherence to treatment, quality of life and subjective well-being in patients with psychosis treated with long-acting injectable risperidone. Subjects enrolled were part of a larger study where patients were observed in an adherence to treatment program of the University of Rome Tor Vergata. Materials and methods: A total of 27 nonadherent patients (21 men, six women; mean age: 36.1 years; range: 23–63 years) were enrolled. Maximum observational period was 30 months. Results: A total of 12 patients were under treatment for 30 months (44.44%) but only nine had a valid 30-month follow up, while the remaining three patients initially treated at our unit continued long-acting risperidone at their local centre. Reductions of monthly mean values of Scale for the Assessment of Positive Symptoms (SAPS) [repeated measures analysis of variance (rm-ANOVA): p < 0.0001] and Scale for Assessment of Negative Symptoms (SANS) ( p < 0.0001), increase of monthly mean values of Subjective Well-Being Under Neuroleptic Treatment Scale (SWN) ( p < 0.0001) and Schizophrenia Quality of Life Scale (S-QoL) ( p < 0.01) were observed. Significant differences with respect to SAPS baseline values from the sixth month, SANS baseline values from the seventh month, SWN baseline values from the eighth month, S-QoL baseline values from the eighteenth month were shown in post hoc tests. Reduction of SAPS mean values was associated with increase of SWN ( p < 0.0001) and S-QoL ( p < 0.0001) mean values as demonstrated by correlation analysis. The same inverse correlation was found between reduction of SANS mean values and increases of SWN ( p < 0.0001) and S-QoL ( p = 0.0001) mean values. Conclusions: Long-term treatment with long-acting risperidone may be associated with improvement to adherence to therapy and quality of life. Patients may show improvement in psychopathological symptoms, subjective well-being and quality of life.

Background Urinary homovanillic and vanillylmandelic acid (HVA and VMA) are well known biomarkers for the management of neuroblastoma (NB). Very few and contradictory publications on their diagnostic performance are present in the literature. The aim of this study is to review the results of HVA/Cr and VMA/Cr obtained by the reference laboratory of the Italian Cooperative Group for NB within a 7-year period using HPLC-EC. Procedure Updated reference intervals based on age as a continuous variable were calculated by using a multivariate statistical analysis. The diagnostic performance of the two biomarkers has been established by calculating their specificity and sensitivity and by receiver operating characteristics (ROC) curves for different ages and stages of disease. Results Accurate age-related reference intervals were obtained from 648 HVA/Cr and 671 VMA/Cr results derived from patients in which the diagnosis of neuroendocrine tumors was excluded. Sensitivity, specificity and ROC curves were obtained from 169 HVA/Cr and 179 VMA/Cr results from confirmed NB patients. The best diagnostic performance was obtained in stage 4S tumors and in children Conclusions This is the first report, to our knowledge, that analyzes in depth the diagnostic performance of HVA/Cr and VMA/Cr for NB in different stages and age subgroups. In addition, the present work provides cut-off points able to discriminate between NB patients and negative subjects suspected to have NB and could be of help in taking medical decisions.

Migraine is three times as common in females as in males, and attacks may be more severe and difficult to treat in women. However, no study specifically addressed possible gender differences in response to antimigraine therapy. The objective of this study was to review the efficacy of frovatriptan vs. other triptans, in the acute treatment of migraine in subgroups of subjects classified according to gender (men vs. women) through a pooled analysis of three individual randomized Italian studies. 414 patients suffering from migraine with or without aura were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). All studies had a multicenter, randomized, double-blind, crossover design. After treating 1–3 episodes of migraine in no more than 3 months with the first treatment, patients switched to the other treatment for the next 3 months. In this analysis, traditional migraine endpoints were compared between the 66 men and 280 women of the intent-to-treat population. At baseline, long-term and debilitating migraine attacks were more frequently reported by women than men. During the observation period, the proportion of pain-free attacks at 2 h did not significantly differ between frovatriptan and the comparators in either men (32 vs. 38 %, p = NS) or women (30 vs. 33 %, p = NS). Pain relief was also similar between treatments for both genders (men: 56 % frovatriptan vs. 57 % comparators; women: 55 vs. 57 %; p = NS for both). The rate of relapse was significantly lower with frovatriptan than with the comparators in men (24 h: 10 vs. 30 %; 48 h: 21 vs. 39 %; p

Introduction: The procedures and requirements for the clinical trial application (CTA) to Ethics Committees (ECs) and/or Competent Authorities (CAs) are not fully harmonised, and this is even more evident when non-EU countries are involved. This lack of harmonisation makes more difficult the approach in the case of 'small populations', such as children and patients affected by rare diseases. A phase III efficacy-safety comparative trial (DEEP-2) involving paediatric patients affected by transfusion dependent haemoglobinopathies from seven European and non-European countries (Albania, Cyprus, Greece, Italy, United Kingdom, Egypt, Tunisia) was carried out in the context of a FP7 project (HEALTH-F4-2010-G.A. n. 261483) and included in an agreed Paediatric Investigation Plan. Aims: The aims of this paper are to describe in a complex multi-national/multi-ethnic framework the different provisions and procedures to authorise a paediatric trial in EU/non-EU countries and to evaluate the possible impact of the following key indicators on the timing of ECs approval and CAs authorisation: complexity of the national/local provisions and procedures to authorise a paediatric trial, including the number of ECs and CAs to be addressed; number and type of additional local/national documentation; number of queries from CAs and ECs; geographic setting (EU and non-EU). Methods: The following information was collected from official websites and through a survey addressed to Principal Investigators: The regulatory and legal frameworks in force at the time of the submission of DEEP-2 in each involved country;The procedures required at local/national level (i.e. number of ECs and CAs to be addressed, parallel or subsequent submission to the CA and the EC, preparation of the CTA form and documents required from CAs and ECs);The timing of ECs approval and CAs authorisation, including number and types of queries, were collected from DEEP-2 Trial Master File. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model (GLM) analysis were used to describe results and to analyse significance of the considered indicators. Results: In the EU countries, relevant legislative acts apply and include GCP and specific procedures for paediatric trials, in non-EU countries GCP guidelines apply but have not been implemented in the national laws regulating clinical trials. Moreover, within the 4 EU Member States a different approach was in place, even if under the same rules (i.e. Directive 2001/20/EC as implemented in the national law) with distinctive documents required for the CTA in almost all the EU countries compared with the EC provisions. The CTAs were performed in the period June 2012 - September 2015 in 23 trial sites. The EC approvals and CA authorisations were issued between January 2013 - September 2015. In the EU countries, the authorisation process was completed within 7,3 to 33,8 months (median = 15 months), while in non-EU countries, the authorisation process was completed by 7 months (median = 4 months) (figure 1). In particular, the comparison of the CA time authorisation shows a significant difference between EU and non-EU clusters (p = 0.001); however, if the statistical model is adjusted for the number of EC requests as covariate, the difference is not significant. Thus, it seems that the main factor influencing the time for EC approval is the number of requests for changes/clarifications (mainly on informed consent/assent, study protocol, insurance) (figure 2). Conclusion: Delays in completion of the authorisation phase in many countries seems to be a relevant issue and the timeframes for the authorisation in EU countries are not compliant with the European requirements (60 days for single opinion release and 30 days for its acceptance, as stated in Directive 2001/20/EC). The main reasons for delay is the complexity of the procedures and the requests from the ECs/CAs. In non-EU countries, procedures are different and faster with less requests from ECs and CAs. The upcoming application of a stronger set of rules, CT-Regulation (EU) 536/2014, is expected to harmonise practices in Europe and possibly outside Europe. The final aim of this change should be to assure a good balance between a timely approval and a high-level of children protection. Disclosures Reggiardo: CVBF: Consultancy. Tricta:ApoPharma: Employment.

Introduction: Agranulocytosis/severe neutropenia is an established adverse event during deferiprone (DFP) use. Less is known about milder episodes, which are frequently transient despite continuous deferiprone use. To provide further insight into this topic, we compared the incidence of neutropenia during DFP or deferasirox (DFX) treatment in the randomized Deferiprone Evaluation in Paediatrics (DEEP-2) trial, where blood neutrophil count was regularly monitored in patients randomized to be treated with DFP or DFX. Methods: DEEP-2 was a multicenter, randomized, 12-month, open-label trial comparing DFP vs DFX in pediatric ( Results: 3579 and 4027 neutrophil counts were available for DFP- and DFX-treated patients, respectively. 47 (1.3%) of the total counts in 24 (12.4%) of the 193 DFP-treated patients versus 48 (1.2%) of the total counts in 27 (13.7%) of the 197 DFX-treated patients were below 1,500/mm3. Of these, 28 cases in 23 DFP-treated patients and 15 cases in 11 DFX-treated patients were reported by the treating physician as neutropenia, corresponding to a global incidence rate 11.9% for DFP and 5.6% for DFX (p=0.081, Chi-Square test). 23 (82.1%) of the 28 episodes of neutropenia during DFP use were considered drug related vs 2 (13.3%) of the 15 episodes during DFX use (p-value < 0.001, Fisher Exact test) (table 1). The mean (SD) treatment duration with either DFP or DFX prior to diagnosis of mild or moderated neutropenia was 127 (96.1) days and 101 (85.7) respectively. All those episodes, except for 2, resolved within a mean time of 13 days (1 - 42 days) in DFP-treated patients and 18 days (6 - 46 days) in DFX-treated patients. The 2 cases where neutropenia did not resolve were diagnosed as constitutional neutropenia and bone marrow suppression. There was no significant difference in those results between the two treatment groups as assessed by one-way ANOVA(p = 0.379), Log-Rank test (p = 0.065) or cumulative-hazard and Kaplan-Meier. During the study 3 events of agranulocytosis occurred, all in patients treated with DFP and not included in the present analysis. All 3 episodes resolved. Conclusion: Data from the largest randomized trial of oral chelators in transfusion-dependent pediatric patients provide evidence that, a drop in the neutrophil count below the threshold for mild neutropenia is very common (>10% of patients) for both DFP and DFX treated patients. All episodes of neutropenia, except for 2 with specific etiology, resolved, irrespective of their severity and of chelator used. A causal relationship of neutropenia to chelator use varied based on the chelator; the majority of events observed during DFP use were assessed by the clinician as drug related, whereas the majority of events observed during DFX use were assessed unrelated to its use. These data indicate that while agranulocytosis rate in DFP patients is not changed from previous reports, moderate/mild neutropenia represent discrete events in patients undergoing oral iron chelation therapy. Disclosures Tricta: ApoPharma: Employment. Della Pasqua:GlaxoSmithKline: Employment. Kattamis:Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reggiardo:CVBF: Consultancy. Spino:ApoPharma: Employment. Tsang:Apotex Inc.: Employment.

Background : In Italy, Chronic Obstructive Pulmonary Disease (COPD) is poorly diagnosed. E.DIAL study tested the capability of General Practitioners (GP) to suspect it. Population and methods : In each primary care practice a random sample of 20 patients was enrolled and filled the WHO standardized respiratory questionnaire. After evaluation and visit, GP filled a form and if suspected COPD, referred pts to Pulmonary Unit (PU) for a chest physician (CP) visit and pulmonary function tests (PFT). 22 PUs joined, each one contacting a mean of 10 GPs. Results: D ata were available of 6390 pts. (mean age 56.3 y. women= 53%). 8.7% reported chronic cough, 6.6% chronic phlegm, 17.9% wheezing in the past year, 7.8% wheezing in the absence of a cold, 5.8% breathlessness on walking, 4.1% a diagnosis of emphysema and 9.8% of asthma. Out of 6390, 897 pts reported at least 1 respiratory symptom but no diagnosis. 701 of them (78.1%) (mean age 63.0 y) were referred to PU as suspected of COPD. Among them, 494 patients (70.5%) got a confirmed diagnosis of respiratory diseases (COPD=23,9%; asthma= 20,4%; Chronic bronchitis=23,3%; rhinitis= 9,5%; asthma + rhinitis=6,9%). Among the 701 referred pts, 123 (18%) not diagnosed of a respiratory condition showed obstruction at PFT. Conclusions: In our sample, concordance between the CP and the GP9s diagnosis was 70.5%. But 21.9% (196/897) symptomatic pts were not referred to PU. 18% of obstructed pts were unaware of their condition. Early diagnosis of COPD by GP seems feasible but perfectible. Further patients9 and GP9 education on respiratory diseases and symptoms seems necessary. Bibliography: Protocol for Assessment of Burden of Major Respiratory Diseases at the PHC Level.

Background: COPD is underdiagnosed. To fill the gap is necessary to screen people for Airways Obstructions (AO) with pulmonary function tests (PFT). There is a debate on the best way to diagnose AO: Fixed Ratio (FR) confirms AO when the FEV1/FVC ratio is th percentile of a healthy population of non smokers (i.e. Population and methods: A random sample of out-patients coming to general practices participating in the study filled a self-administered WHO questionnaire for respiratory symptoms, were evaluated by a GP, who sent individuals needing a diagnosis to a Pulmonary Unit (PU) to undergo consultation and PFT. Results: Data were available for 6,390 patients (mean age was 56.3 y. women= 53%). Among the 897 pts.reporting at least one respiratory symptom, 701 were sent to PU. PFT was carried out in 96.4% of patients; 23.9% of them got a confirmed diagnosis of COPD. To diagnose AO, PU used FR in 76.3% of cases and LLN in 22.6%; 1.1,% used both. Analysing afterward all PFT, LLN found AO in 132 pts (18.9%) while FR in 110 (15.7%). Conclusions: In our study, LLN diagnosed more AO than FR and seems to overestimate AO, at least in our sample. Bibliography: 1. Global surveillance, prevention and control of chronic respiratory diseases; Bousquet & Khaltaev eds. WHO 2007; 2. Pellegrino et al. ERJ 2005, 26:948.

©2012 Wiley Periodicals, Inc. Heart failure (HF) is a leading cause of morbidity and mortality. The detection of patients at high risk for death is a major challenge in HF management. The authors compared the prognostic value of 23 clinical Doppler echocardiography and cardiopulmonary exercise indexes in a stable, moderately symptomatic, systolic HF outpatient population receiving optimal medical therapy. The end point was the incidence of overall mortality. Between January 2002 and December 2008, a total of 146 patients with left ventricular (LV) ejection fraction 0.31±0.8 and New York Heart Association functional class II or III were enrolled. The prognostic power of single variables was assessed using chi-square test for categoric variables and t test for continuous variables. Variables associated with the prespecified end point were included as predictors in a binary logistic regression multivariate model. At multivariate analysis, “restrictive” LV filling pattern (P=.004), ischemic etiology (P=.022), pulmonary artery systolic pressure (PASP) ≥50 mm Hg (P=.027), and peak oxygen uptake (VO2)

To cite this article: Melioli G, Marcomini L, Agazzi A, Bazurro G, Tosca M, Rossi GA, Minale P, Rossi R, Reggiardo G, Canonica GW, Passalacqua G. The IgE repertoire in children and adolescents resolved at component level: A cross-sectional study. Pediatr Allergy Immunol 2012: 23: 433–440. Abstract Background: It is well known that allergy evolves at clinical level from the birth to adulthood, and this has been clearly demonstrated also at a level of sensitization. However, little information is available on the evolution of the IgE repertoire directed to single allergenic components. In this cross-sectional, observational study, the evolution of the IgE repertoire was analysed at component level. Methods: Serum samples from 901 allergic patients, stratified in 6 groups according to age, were analysed by ImmunoCAP ISAC, a microarray chip that allows to identify the presence of specific IgE towards 103 different allergen components. Total IgE were also evaluated. Results: The behaviour of total IgE according to age strictly paralleled that of the sum of specific IgE directed to molecular components. As expected, food-related components (in particular those of milk and egg) were the most frequently recognized in the earliest ages, whereas specific IgE to plant allergens appeared invariably later. Nonetheless, IgE specific to mite components was the most represented in all age classes. Of note, specific IgE against cross-reacting allergens was virtually absent in the first years and tended to appear only after the age of 6. Conclusion: Despite this was not a study performed on a cohort of patients followed up from birth to adolescence, the molecular patterns of allergen recognition resulted modified according to age. These findings may support, at molecular level, the clinical features of the allergic march.

Background Bevacizumab significantly improves progression-free survival (PFS) and overall survival (OS) when added to chemotherapy for metastatic colorectal cancer (mCRC). The hypothesis that bevacizumab discontinuation could lead to an angiogenesis flare and eventually to an accelerated tumor progression has not been confirmed in a recent large pooled analysis. Therefore the optimal duration of bevacizumab still remains undefined. Patients and methods PFS and OS were retrospectively analyzed in patients with previously untreated mCRC who received bevacizumab 5 mg/Kg and standard FOLFIRI regimen (leucovorin, infusional fluorouracil and irinotecan) up to a maximum of 12 cycles. Results Data from 209 patients were collected and analyzed. The median follow-up was 24 months. Fifty-five (26.3%) patients received at least 6 administrations and 114 (54.5%) received a maximum of 12 administrations of bevacizumab. Median exposure to bevacizumab was 148 days (4.9 months). Median PFS and OS were 10.7 months [95% confidence interval (CI) 9.2–12.2 months] and 31.6 months (95% CI 25.8–37.3 months), respectively. Overall objective response rate was 49.8% (95% CI 42.9–56.6) and the disease control rate 81.8%. Approximately 65% and 30% of patients received some form of second- and third-line therapy, respectively. The toxicity profile of bevacizumab was consistent with that documented in previous trials. Conclusions In this retrospective analysis remarkably long PFS and OS were obtained with a first-line therapy duration limited to a maximum of 12 cycles. Our data does not support a decreased PFS or increased mortality after discontinuation of bevacizumab in mCRC patients.

The lack of updated neonatal reference values for hematological parameters impacts significantly with clinical management of both healthy and sick newborns. The present pilot study was thus aimed at assessing updated hematological Italian reference values in late preterm and term newborns. From January 2004 to December 2008 hematological laboratory tests were performed in 1175 newborns (820 healthy and 355 sick controls) between 33-41 weeks of gestation, during the first four days after birth. Hematological parameters were sorted for gender and gestational age and statistically analyzed. No gender-related differences were observed at different weeks of gestation and no significant differences were found when study population was sub-grouped for late preterm and term newborns. During the first 4 days of life erythrocytes and platelets remained stable whilst white blood cell counts and differentials were significantly modified. This study shares updated reference values for hematological parameters in the early phases after birth and offers additional support for improving the management of sick infants.

To determine the efficacy and tolerability of capecitabine combined with oxaliplatin (CAPOX) or irinotecan (CAPIRI) as first-line treatment in patients with advanced/metastatic colorectal cancer agedor =70 years.Patients agedor =70 years were randomly assigned to receive CAPOX [oxaliplatin 65 mg/m(2) intravenously (i.v.) days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d] or CAPIRI (irinotecan 80 mg/m(2) i.v. days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d). The primary study end point was overall response rate (ORR).Ninety-four patients were enrolled. In an intent-to-treat analysis, 2 complete responses (CRs) and 16 partial responses (PRs) were reported with CAPOX (ORR 38%), and 2 CRs and 15 PRs with CAPIRI (ORR 36%; P = 0.831). Median time to progression was 8 months for CAPOX and 7 months for CAPIRI (P = 0.195), with median survival times of 19.3 months and 14.0 months (P = 0.165), respectively. Global health status was improved in 45% and in 21% of patients in the CAPOX and CAPIRI arms, respectively. The most common treatment-related grade 3-4 adverse events in CAPIRI versus CAPOX patients were diarrhea (32% versus 15%; P = 0.052) and neutropenia (23% versus 6%; P = 0.021).CAPOX and CAPIRI had similar efficacy in elderly patients, although CAPOX seemed to be better tolerated.

Background Heart failure is one of the main causes of hospitalization in Italy. In some industrialized countries since the second half of 1990s a halt in the grow rate of hospitalization for this pathology has been observed, and in some cases a reversal. The aim of this study was to evaluate the trend of hospitalization for heart failure in Italy in the years 2001, 2002 and 2003. Materials and methods National hospital discharge data for years 2001, 2002 and 2003 were analysed. Results Heart failure hospitalization increased from 193 042 in 2001 to 205 043 in 2002 (+6.2%) and to 211 183 in 2003 (+3% with respect to 2002). In 2003 heart failure was the primary medical cause of hospitalization (1.6%). Hospitalization for heart failure accounted in 2003 for 2% of global hospitalization costs. Conclusions Heart failure is the primary cause of hospitalization in Italy and the rate of hospital admission from 2001 to 2003 continued to increase, as well as related costs. These data indicate the urgent need for implementation of new models for the management of heart failure, based on a healthcare network, including hospital, ambulatory and home care, potentially capable of ameliorating both quality of life and costs of assistance.

Introduction: the SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies demonstrated that early administration of zofenopril following acute myocardial infarction (AMI) is prognostically beneficial compared to placebo or other angiotensin-converting enzyme inhibitors (ACE-inhibitors). Hypothesis: In the present meta-analysis of individual data of four SMILE studies we evaluated the cumulative efficacy of zofenopril on cardiovascular (CV) morbidity and mortality in the subgroup of hypertensive patients. Methods: 1880 (53.1%) of the 3542 patients had a positive history for hypertension. 449 hypertensives and 486 normotensives were treated with placebo (SMILE 1 and 3), 980 and 786 with zofenopril 30-60 mg/die (all four studies), 451 and 390 with lisinopril 5-10 mg/die (SMILE 2) or ramipril 10 mg/die (SMILE 4). Treatment was continued for 6 to 48 weeks. For the purpose of this pooled analysis the primary study endpoint was set to 1-year combined occurrence of death or hospitalization for CV causes. Results: the risk of CV events was significantly reduced by 35% with zofenopril vs. placebo [HR: 0.65; 95% CI: 0.49-0.86; p=0.003) in hypertensive patients and by 41% in normotensive patients (0.59; 0.44-0.79; p=0.0001). The other ACE-inhibitors reduced CV morbidity and mortality as well, though the reduction (-17%) was not statistically significant vs. placebo either in hypertensives (0.83; 0.57-1.21; p=0.338) or normotensives (reduction: -24%; HR: 0.76; 0.50-1.15; p=0.194). Treatment with zofenopril of hypertensive and normotensive patients was associated with a non-statistically significant reduction in the risk of CV outcomes as compared to the other ACE-inhibitors (hypertensives: 0.78; 0.60-1.01; p=0.062; normotensives: 0.77; 0.55-1.10; p=0.1509. Conclusions: in high-risk cardiac patients with arterial hypertension, zofenopril treatment is associated with a clinically relevant reduction in long-term CV morbidity and mortality, compared to placebo, with an efficacy similar to that of other ACE-inhibitors, such as lisinopril and ramipril.

Background Ranolazine is a new anti-anginal drug that acts via late sodium current inhibition, and has been shown to improve diastolic dysfunction in isolated myocytes. Diastolic dysfuntion is common in patients with aortic stenosis (AS), and precedes symptom development and systolic dysfunction. The purpose of this study was to assess the effects of ranolazine on peak early diastolic strain rate (PEDSR) and exercise capacity in patients with AS. Methods Patients with asymptomatic moderate to severe AS and diastolic dysfunction underwent trans-thoracic echocardiography, exercise testing and cardiac magnetic resonance (CMR) imaging at baseline, 6 weeks after commencing ranolazine and at 10 weeks (4 weeks after discontinuation). Diastolic function was assessed using PEDSR measured on tagged CMR images. Results Fifteen patients (peak pressure gradient 48.8 ± 12.4 mmHg, mean pressure gradient 27.1 ± 7.5 mmHg, aortic valve area 1.26 ± 0.31 cm2) completed the week-6 visit and 13 completed the final visit. Global PEDSR did not significantly increase from baseline (0.79 ± 0.15) to week-6 (0.86 ± 0.18, p = 0.198). There was a borderline significant increase in total exercise duration from 10.47 ± 3.68 min to 11.60 ± 3.25 min (p = 0.06). Conclusion This small pilot study did not show a significant improvement in diastolic function with the use of ranolazine in asymptomatic patients with moderate-severe AS. Further studies with a larger population may be indicated. EduraCT number 2011-000111-26 Electronic supplementary material The online version of this article (doi:10.1186/s13104-016-1874-0) contains supplementary material, which is available to authorized users.

Background: Autonomic dysfunction and reduced exercise tolerance are typical features of patients with congestive heart failure (CHF). Baro-chemoreflex balance and organ response may have a common role in conditioning exercise tolerance, ventilation, and chronotropic competence in patients with CHF. Hypothesis: We tested the hypothesis that there is a relationship between functional capacity and chronotropic competence to exercise in CHF. Methods: In all, 48 stable outpatients with CHF (age 65 ± 10 years, 41 men, NYHA class 2.1 ± 0, ejection fraction 31 ± 7%, peak VO2 16 ± 4 ml/kg/min) performed cardiopulmonary exercise testing (CPX). Heart rate (HR) response to exercise was assessed by the chronotropic index (CRI). The CRI was calculated by the following formula: CRI = peak HR - rest HR/220 - age - rest HR × 100 (normal value > 80%). The relationship of CRI to peak oxygen consumption (VO2) and ventilation/carbon dioxide production (VE/VCO2) ratio was examined. A group of 33 healthy controls underwent CPX as well. Results: The CRI correlated directly with peak VO2 (r = 0.638, p 30, 95% CI 0.53–0.88). The CRI was not significantly related either to peak VO2 or to VE/VCO2 in the control group. Conclusions: In patients with mild to moderate CHF, CRI correlates with functional capacity. This relationship adds new data on pathophysiologic grounds and supports the routine incorporation of CRI into CPX interpretation.

The determination of the two urinary catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) is of crucial importance for the diagnosis and follow-up of neuroblastoma (NB). The standard practice for their measurement requires the use of 24-hour collections that are time consuming and difficult to obtain. In this article, we directly demonstrate that 24-hour collections and single spot urines are interchangeable for the determination of HVA and VMA expressed as ratio on creatinine concentration. This study can be useful for a faster management of NB at onset.

Objectives: To evaluate the safety and efficacy of irinotecan (CPT-11) alternated with a weekly treatment for 4 weeks of oxaliplatin (L-OHP), high-dose leucovorin (LV) and a 48-hour 5-fluorouracil infusion (5-FU48h) as first-line chemotherapy for patients with advanced colorectal cancer (ACC). Patients and Methods: Previously untreated patients with ACC received chemotherapy consisting of a weekly treatment for 4 weeks of L-OHP (65 mg/m2), high-dose LV (150 mg/m2) followed by a 5-FU48h infusion (2,300 or 1,800 mg/m2) alternated with CPT-11 (350 mg/m2). A cycle was to be performed every 8 weeks. Treatment was continued up to tolerance, disease progression or patient refusal. Forty consecutive patients with measurable ACC, aged 26–70, performance status ≤2, entered our study. Results: Six complete and 17 partial responses were observed (overall response rate, 57.5%; 95% confidence interval, CI: 38.8–71.1%); an additional 35% of the patients had stable disease. The median duration of response was 10.9 months (range, 6.5–30+ months). The median time to progression and the median overall survival time were 11.4 (95% CI: 10.4–12.3) and 20.3 (95% CI: 16.4–23.7) months, respectively. At the median follow-up period of 24 months, 17 patients (42.5%) are still alive. After a median number of 4 cycles, one toxic death occurred. The incidence of grade 3–4 toxicity per patient in any cycle was: stomatitis 7.5%, nausea/vomiting 2.5% and diarrhea 45% for the infusional part, neutropenia 37.5%, anemia 2.5%, thrombocytopenia 5%, alopecia 5% and diarrhea 10% for the CPT-11 part of the regimen. Gastrointestinal toxicity was different according to the dose of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2,300 mg/m2 with a high incidence of grade 3–4 diarrhea (72.2%) and stomatitis (16.6%), and led to dose reduction of 5-FU in 13 of 18 patients (72.2%). For 22 patients who started 5-FU at a dose of 1,800 mg/m2, a dose reduction of 5-FU was necessary only 5 times (22.7%). No patient discontinued treatment because of severe neurotoxicity. Conclusions: The activity of our alternating regimen of L-OHP/LV/5-FU48h and CPT-11 for not previously treated ACC patients is counterbalanced by a high toxicity and a inconvenient schedule.

Purpose: To evaluate the activity and safety of an alternating schedule of irinotecan (CPT-11) with high-dose 5-fluorouracil (5-FU) given as a weekly 48-hour infusion in combination with leucovorin (LV) in the first-line treatment of metastatic colorectal cancer (MCRC) patients. Patients and Methods: We tested the activity of a regimen consisting of a four times per week schedule of high-dose LV (150 mg/m2) followed by a 48-hour 5-FU infusion (2,600 mg/m2) alternated with CPT-11 (350 mg/m2). An alternating cycle was to be performed every 8 weeks. Treatment was administered until disease progression, unacceptable toxicity or patient refusal occurred. Thirty-five consecutive patients with measurable MCRC, aged 18–80, with a performance status ≤2, were entered into our study from May 1998 to January 2000. Results: Four complete and 9 partial responses were observed (objective response rate was 37%; 95% confidence interval, CI: 21.5–55.1%); an additional 46% of the patients had stable disease. The median duration of response was 6.2 months, median time to progression 8 months (95% CI: 5.9–10.1%), and overall survival was 18.5 months (95% CI: 15.1–21.9%). The 1-year survival was 68%. No toxic deaths occurred. The incidence of grade 3–4 toxicity per patient in any cycle was: mucositis 9% and diarrhea 11% for the infusional 5-FU part, nausea/vomiting 3%, diarrhea 14%, and neutropenia 43% for the CPT-11 part of regimen. Conclusions: Our alternating schedule of 5-FU/LV and CPT-11 is a well-tolerated outpatient treatment as front-line therapy for MCRC with comparable efficacy to regimens with both drugs given together.

An association between obesity and migraine has been observed in recent studies and it is supported by plausible biological mechanisms. The objective of this study is to evaluate the efficacy of frovatriptan and other triptans in the acute treatment of migraine, in patients enrolled in three randomized, double-blind, crossover, Italian studies and classified according to body mass index (BMI) levels, as normal weight or non-obese (NO, BMI 18.5-24.9 kg/m(2)) and overweight or obese subjects (O, BMI ≥ 25 kg/m(2)). 414 migraineurs with or without aura were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). After treating up to three episodes of migraine in 3 months with the first treatment, patients switched to the alternate treatment for the next 3 months. The present analysis assessed triptan efficacy in 220 N and in 109 O subjects of the 346 individuals of the intention-to-treat population. The proportion of pain free at 2 h did not significantly differ between frovatriptan and the comparators in either NO (30 vs. 34 %) or O (24 vs. 27 %). However, the rate of pain free at 2 h was significantly (p < 0.05) larger in NO than in O, irrespective of the type of triptan. Pain relief at 2 h was also similar between drug treatments for either subgroup. Pain relapse occurred at 48 h in significantly (p < 0.05) fewer episodes treated with frovatriptan in both NO (26 vs. 36 %) and O (27 vs. 49 %). The rate of 48-h relapse was similar in NO and O with frovatriptan, while it was significantly (p < 0.05) higher in O with the comparators. Frovatriptan, in contrast to other triptans, retains a sustained antimigraine effect in NO and even more so in O subjects.

Background: the SMILE studies proved the prognostic benefit of zofenopril vs. placebo or other ACE-inhibitors (ACEIs) in post-acute myocardial infarction (AMI). In this retrospective pooled analysis of these studies we assessed whether the zofenopril effect is influenced by gender. Methods the four double-blind, randomized, parallel-group SMILE studies, compared the efficacy and safety of 6–48 week treatment with zofenopril 60 mg/day with that of placebo, lisinopril 10 mg/day or ramipril 10 mg/day in 3630 AMI patients. This pooled analysis compared treatment efficacy (1-year combined occurrence of death or hospitalization for CV causes) in 2733 men and 897 women. Results women were older than men, had a higher prevalence of diabetes and of other major CV risk factors. The risk of a major CV event was significantly larger for women (23% vs. 17% men, pConclusions post-AMI women are at higher risk of CV complications than men, particularly when living in Mediterranean countries. Their response to ACE-inhibition varies according to the type of drug and is usually better in men.

Background An in vitro procedure based on a microarray containing many different allergen components has recently been introduced for use in allergy diagnosis. Recombinant and highly purified allergens belonging to different allergenic sources (inhalants, food, latex and hymenoptera) are present in the array. These components can either be genuine or cross-reactive, resistant or susceptible to heat and low pH, and innocuous or potentially dangerous. A large number of complex and heterogeneous relationships among these components has emerged, such that sometimes these interactions cannot be effectively managed by the allergist. In the 1960s, specialized languages and environments were developed to support the replacement of human experts with dedicated decision-making information systems. Currently, expert systems (ES) are advanced informatics tools that are widely used in medicine, engineering, finance and trading.Methods We developed an ES, named Allergenius ®, to support the interpretation of allergy tests based on microarray technology (ImmunoCAP ISAC ®). The ES was implemented using Flex, a LPA Win-Prolog shell. Rules representing the knowledge base (KB) were derived from the literature and specialized databases. The input data included the patient’s ID and disease(s), the results of either a skin prick test or specific IgE assays and ISAC results. The output was a medical report.Results The ES was first validated using artificial and real life cases and passed all in silico validations. Then, the opinions of allergists with experience in molecular diagnostics were compared with the ES reports. The Allergenius reports included all of the allergists’ opinions and considerations, as well as any additional information.Conclusions Allergenius is a trustable ES dedicated to molecular tests for allergy. In the present version, it provides a powerful method to understand ISAC results and to obtain a comprehensive interpretation of the patient’s IgE profiling. Keywords: 3 TO 10 DIFFERENT ImmunoCAP ISAC, Allergen microarray, Artificial intelligence, Expert system, ISAC interpretation, Genuine component, Cross-reactive component, Computer supported diagnosis

Background A historical cohort mortality study was conducted among 3984 shipyard workers assigned to ship repair, refitting, and construction in the harbor of Genoa, Italy, between 1960 and 1981. These workers were exposed to asbestos fibers, welding fumes and gases, silica dust, polycyclic aromatic hydrocarbons, and solvents. Methods Workers were classified in 20 different job-titles depending upon the type of activity. Standardized mortality ratios (SMRs) were computed using male residents of the Province of Genoa as the referent population. Results and Conclusions For the whole cohort significantly increased SMRs were detected for all causes, all cancers, liver, larynx, lung, pleural and bladder cancers, respiratory tract diseases, and cirrhosis of the liver. The analysis by job-title showed increased SMRs not only for pleural cancer, but also for lung, laryngeal cancers and respiratory tract diseases in occupations entailing heavy asbestos exposure. Bladder and liver cancers and liver cirrhosis mortality also appeared to be related to occupational exposure.

Stage IIIb non-small-cell lung cancer (NSCLC) has a poor prognosis. The median survival is approximately 6 months, and only 30% of patients are alive 1 year after diagnosis. The need for effective treatment is evident. The aim of this study was to evaluate whether the infusion of tumor-infiltrating lymphocytes (TILs), isolated from resected tumor, expanded in vitro and injected together with recombinant Interleukin-2, is feasible and may at least partially modify the poor prognosis in these patients. The infusion of TILs, derived from surgically resected NSCLC and expanded in vitro, together with subcutaneous (s.c.) injections of recombinant interleukin-2 (rIL-2) was attempted in a group of 11 patients. Treated patients were infused i.v. with in vitro expanded TILs (from 4 to 70 x 10(9) cells), and rIL-2 was injected s.c. at doses varying from 61 to 378 x 10(6) IU. Toxic side effects (fever and, in some cases, hypotension) were observed and limited the dose of rIL-2 infused. Follow-up was continued for 40 months. The mean survival time was 13.8 months. Three of five TIL-treated patients with residual disease have no evident disease after 1 year, and two of them are still alive and have no evidence of disease after 40 months. This pilot study suggests that the infusion of in vitro expanded TILs, derived from surgical samples, is feasible and seems to prolong overall survival and to control the residual disease in patients with advanced NSCLC.

The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) in patients with metastatic colorectal cancer (CRC). An increased risk of arterial thromboembolic events has been observed in some trials in older patients, and the potential benefit of a maintenance therapy with bevacizumab alone has not been clearly demonstrated. This phase II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab followed by bevacizumab alone in elderly patients with advanced CRC.Treatment consisted of bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) on day 1, plus capecitabine 1,000 mg/m(2) twice daily on days 1-14, every 3 weeks up to a maximum of 8 cycles. Patients then received maintenance therapy consisting of bevacizumab alone (7.5 mg/kg) once every 3 weeks up to disease progression. The primary study end-points were safety and response rate.A total of 44 patients were recruited. In an intention-to-treat analysis, the overall response rate was 52% [95% confidence interval (CI) 37 to 68%], with 86% of patients achieving disease control. Median PFS and overall survival were 11.5 months (95% CI 10.0-12.9 months) and 19.3 months (95% CI 16.5-22.1 months), respectively. In all, 10 patients (23%) had grade 3/4 adverse events (AEs), the most common being diarrhea (9%), neutropenia (7%), peripheral neuropathy (7%), and stomatitis (7%). No patients died because of treatment-related AEs. The rate of bevacizumab-related AEs (hypertension, thromboembolic events, and gastrointestinal perforation) was consistent with that reported earlier in the general CRC population.The combination of XELOX and bevacizumab is effective and has a manageable tolerability profile when administered to elderly patients with advanced CRC. Maintenance therapy with single-agent bevacizumab may be considered to extend PFS in this setting of patients.

Objective Plasma total Adiponectin (tAN) is a novel biomarker with interesting potentialities in pediatrics. Age-related intervals are needed for the correct interpretation of results. In this study, we calculated the reference values for tAN using a large number of results derived from pediatric patients. Design and methods tAN was determined by ELISA in more than 4000 samples and the results collected in the Laboratory Information System were used for the calculation of reference intervals. Results tAN reference values for the different age intervals were obtained and age related tAN reference intervals were calculated. Some differences were observed in males and females. In obese children, no correlation between age and tAN could be observed. On the contrary, significant relations were observed in the total group of patients and in healthy control subjects. For this reason, the parameters of the equations to calculate tAN reference values using age as a continuous variable were defined. Conclusion The use of continuous tAN reference intervals, calculated on age, should be considered a useful laboratory tool, at least in the pediatric population, for those biomarkers whose reference values have been shown to change from birth to the late adolescence.

Heart failure (HF) is a leading cause of morbidity and mortality. The detection of patients at high risk for death is a major challenge in HF management. The authors compared the prognostic value of 23 clinical Doppler echocardiography and cardiopulmonary exercise indexes in a stable, moderately symptomatic, systolic HF outpatient population receiving optimal medical therapy. The end point was the incidence of overall mortality. Between January 2002 and December 2008, a total of 146 patients with left ventricular (LV) ejection fraction 0.31±0.8 and New York Heart Association functional class II or III were enrolled. The prognostic power of single variables was assessed using chi-square test for categoric variables and t test for continuous variables. Variables associated with the prespecified end point were included as predictors in a binary logistic regression multivariate model. At multivariate analysis, "restrictive" LV filling pattern (P=.004), ischemic etiology (P=.022), pulmonary artery systolic pressure (PASP) ≥50 mm Hg (P=.027), and peak oxygen uptake (VO(2) )15.9 mL/kg/min (P=.046) resulted independent predictors of the outcome. A simple risk score was then obtained using these significant independent variables, excluding peak VO(2) because of only borderline significance. Patients with ischemic etiology, restrictive LV filling pattern, and PASP ≥50 mm Hg have a very high risk of death (odds ratio, 33.77; 95% confidence interval, 5.74-198.8; P.001, compared with patients with no risk factors). In this high-risk group, evaluation of peak VO(2) could be superfluous. A very simple clinical echocardiographic model based on etiology-LV filling and pulmonary pressure is a powerful tool for risk stratification of systolic HF in ambulatory patients.