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Objective. To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA). Methods. Data from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively). Results. Three hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment. Conclusion. The results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time. © 2022 The Journal of Rheumatology.

OBJECTIVE: To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: Data from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively). RESULTS: Three hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment. CONCLUSION: The results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time. [ClinicalTrials.gov: NCT01399281 and NCT03932344].

To evaluate if a different morphology of the implant-abutment connection (internal vs. external hexagon) is able to condition the behaviour of hard and soft peri-implant tissues.Twenty patients with significantly unfavourable prognoses for their residual maxillary or mandibular dentitions were selected and rehabilitated with immediately loaded fixed full-arch rehabilitations in two different centres. Four to six implants with identical macro- and micro-topography were inserted in each arch: external hexagon implants (EHC) in one randomly selected side of the dental arch and internal hexagon implants (IHC) in the other side. Primary outcome measures were the success rates of the implants and prostheses. Any technical and biological complication was recorded. Secondary outcome measures were: peri-implant marginal bone level (MBL) changes, Plaque Index (PI), probing depth (PD) and bleeding on probing (BoP), evaluated at implant insertion and at 3, 6 and 12 months post-loading.Forty-three EHC and 40 IHC implants were inserted in 20 patients. No patients dropped out. Two implants failed; one IHC after 3 months and one EHC after 6 months in two different patients (difference IHC vs. EHC at patient level: 0.06%; 95% CI: -1.9 to 2.1; P = 0.99). No prosthesis failed. No biological complications were identified and three loose prosthetic abutment screws were identified in three different patients (two EHC and one IHC); difference at patient level IHC vs. EHC: 2.1% (95% CI: -0.8 to 5; P = 0.43). Overall marginal bone loss was not significantly different between the two treatment groups (EHC vs. IHC) at any time point. The mean difference of bone levels between EHC and IHC was 0.25 mm (95% CI: -0.18 to 0.69) at implant placement. Mean difference between IHC and EHC was -0.01 mm (95% CI: -0.34 to 0.36) at 3 months, 0.13 mm (95% CI: -0.48 to 0.22) at 6 months and 0.11 mm (95% CI: -0.45 to 0.25) at 12 months. All the implants showed good periodontal health at the 1-year-in-function visit, with no statistically significant differences between groups. At 12 months mean (± standard deviation) PI was 2 (± 1.5) for the EHC and 1.85 (± 1.58) for the IHC group (P = 0.57) with a mean difference between the two groups of 0.15 (95% CI: -0.56 to 0.85). Mean PD was 2.23 mm (± 0.52) for the EHC and 2.10 mm (± 0.39) for the IHC group (P = 0.39), with a mean difference between the two groups of 0.12 mm (95% CI: -0.08 to 0.33). At 12 months 41.4% of EHC and 43.6% of IHC implants presented no BoP (mean difference: -2.2%, 95% CI: -24.0 to 19.3; P = 0.51). No significant effect of centres over all outcomes was identified (P = 0.71 for MBL, P = 0.14 for PI, P = 0.14 for PD and P = 0.20 for BoP).On the basis of the present trial the two types of implant connections were clinically reliable. After 12 months in function, both implants provided good clinical outcomes, without statistically significant differences between the two groups.

To evaluate the self-reported prevalence of poor adherence to recombinant human growth hormone (rhGH) therapy in a large, representative sample of Italian children and adolescents and to assess treatment and patient level correlates of poor adherence.The study was conducted in 46 pediatric centers throughout Italy. A questionnaire was administered to consecutive children/adolescents treated with rhGH or their parents. Eligible patients were represented by subjects aged between 6 and 16 years, of both sexes, on rhGH treatment for at least 6 months. The questionnaire was administered to the person in charge of preparing the injection. Multivariable logistic regression analysis was performed to identify factors independently associated with adherence.Overall, 1,007 children/adolescents were involved, of whom 24.4% missed 1 or more injections during a typical week and were thus considered as nonadherent. The most frequently reported reasons for missing a dose were being away from home (33.3%), forgetfulness (24.7%), not feeling well (12.9%), and pain (10.3%). Multivariable analysis indicated association between poor adherence and adolescence, low level of parent education, longer duration of treatment, need to convince the child to inject, and low level of awareness of the consequences of not properly following treatment. The likelihood of adherence markedly increased with higher levels of perceived device convenience.Poor adherence is still a major problem in the treatment of growth disorders. Increasing awareness and reassessment of treatment adherence on an annual basis should be part of clinical practice of pediatric endocrinologists involved with rhGH treatment.CI = confidence interval GH = growth hormone rhGH = recombinant human growth hormone.

Cytokine expression assessed by flow cytometry in 53 acquired aplastic anemia patients before and after combined immunosuppression (EBMT WPSAA protocols) showed that CD3(+) marrow cells containing TNF-alpha, IFN-gamma and IL4 were similar in subjects with disease at onset (DO) and responsive to treatment who had more CD3(+)/TNF-alpha(+) and CD 3(+)/IFN-gamma(+) cells than normal controls. In vitro block of TNF-alpha and/or IFN-gamma significantly increased BFU-e over baseline in 28 patients. In responsive to treatment patients only TNF-alpha block significantly incremented colonies over normal controls. Absolute marrow CD3(+)/TNF-alpha(+) and CD3(+)/IFN-gamma(+) cells prospectively tested in a group of 21 subjects declined significantly more in Responders than in Non Responders to immunosuppression at Response Evaluation Time respect to Diagnosis. Both in Responders and in Non Responders these cells remained higher than in normal controls. This study suggests that immunosuppression does not fully clear excess TNF-alpha and IFN-gamma from marrow of patients with good outcome and raises the hypothesis that additional cytokine blockade might be useful in immunosuppression for acquired aplastic anemia.

Objective. To validate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile dermatomyositis (DM). Methods. In 2001, a preliminary consensus-derived core set for evaluating response to therapy in juvenile DM was established. In the present study, the core set was validated through an evidence-based, large-scale data collection that led to the enrollment of 294 patients from 36 countries. Consecutive patients with active disease were assessed at baseline and after 6 months. The validation procedures included assessment of feasibility, responsiveness, discriminant and construct ability, concordance in the evaluation of response to therapy between physicians and parents, redundancy, internal consistency, and ability to predict a therapeutic response. Results. The following clinical measures were found to be feasible, and to have good construct validity, discriminative ability, and internal consistency; furthermore, they were not redundant, proved responsive to clinically important changes in disease activity, and were associated strongly with treatment outcome and thus were included in the final core set: 1) physician's global assessment of disease activity, 2) muscle strength, 3) global disease activity measure, 4) parent's global assessment of patient's well-being, 5) functional ability, and 6) health-related quality of life. Conclusion. The members of the Paediatric Rheumatology International Trials Organisation, with the endorsement of the American College of Rheumatology and the European League Against Rheumatism, propose a core set of criteria for the evaluation of response to therapy that is scientifically and clinically relevant and statistically validated. The core set will help standardize the conduct and reporting of clinical trials and assist practitioners in deciding whether a child with juvenile DM has responded adequately to therapy. © 2008, American College of Rheumatology.

Low birth weight and length for gestational age are associated with a high risk of short stature and metabolic syndrome in adulthood. The mechanisms that link prenatal growth to adult stature and metabolic syndrome have not yet been entirely clarified. The aim of our study was to evaluate the relationship between standardized anthropometric measures at birth and insulin-like growth factor (IGF)-I, IGF-II, insulin, adiponectin, and non-esterified fatty acid (NEFA) cord blood levels in the general population. One hundred fifty-eight random newborn subjects (77F, 81M) from Genoa, Italy, were analyzed. Anthropometric parameters were measured and standardized according to standard Italian tables. Insulin values were treated as categorical, since in several cases the results fell below detection cut-off. Mean birth weight was 3,214.23#x2213;488.99 gr and mean length was 49.82#x2213;2.17 cm. Females had higher mean IGF-I (p=0.04), and were more likely to have insulin values either2#956;U/ml or4.5#956;U/ml (p= 0.04) compared to males. Weight and length SD scores (SDS) were higher in subjects with elevated insulin levels (p=0.002). A moderate correlation was found between weight and IGF-II (r=0.354). Multivariable analysis demonstrated that standardized birth weight was associated with IGFII and insulin values. Our data highlight the importance of IGF-II in fetal growth and suggest that gender differences should be taken into consideration when evaluating prenatal growth.

Introduction Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. Materials and methods CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). Results Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86–88) and at 45 years was 81% (95% CI: 77–84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7–12), corresponding to an AER of 48 (95% CI: 45–51). Mortality decreased by 60% for survivors treated most recently (1990–1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. Conclusions This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

Background: Febrile neutropenia (FN) is a possible complication of antineoplastic chemotherapy. Aim of the study was to estimate the risk of developing fever at the beginning of any neutropenic period based on the previous history of FN. Procedure: The conditional frailty model was used to estimate the risk of developing fever during neutropenia separately for children with acute leukaemia/non-Hodgkin lymphoma (AL/NHL), or solid tumour (ST). The total number of previous FN episodes (PFNE), age, gender, type of tumour, calendar year of granulocytopenic period, phase of treatment, and granulocyte count were included in the model. Results: A total of 901 granulocytopenic periods was observed in 223 children: 306 in 66 AL/NHL and 595 in 157 ST. Fever developed in 328 cases: 125 in 53 AL/NHL and 203 in 92 ST. The PFNE variable was not significantly associated to the risk of fever [hazard ratio (HR) of 0.87, 95% confidence interval (CI) of 0.62-1.22 in children with AL/NHL, and HR of 0.98, 95% CI of 0.70-1.37 in those with ST]. The hazard of FN was significantly affected by the phase of treatment in AL/NHL (P