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Hendriksz C.J.,Salford Royal Foundation NHS Trust | Parini R.,Fondazione MBBM | AlSayed M.D.,King Faisal Specialist Hospital And Research Center | Raiman J.,Hospital for Sick Children | And 13 more authors.
Molecular Genetics and Metabolism | Year: 2016

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96 weeks (reaching 120 weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0 mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0 mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120 weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N = 173), analyses were also performed for a modified per-protocol (MPP) population (N = 124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥ 20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3) m and 39.9 (10.1) m for patients receiving elosulfase alfa at 2.0 mg/kg/week throughout the study (N = 56) and 15.1 (7.1) m and 31.7 (6.8) m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0) stairs/min for patients receiving elosulfase alfa at 2.0 mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3) stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was − 59.4 (1.8)% and − 62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P < 0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified. © 2016 The Authors


Hjorth L.,Skåne University Hospital | Haupt R.,Instituto Giannina Gaslini | Skinner R.,Newcastle University | Grabow D.,University Medical Center Mainz | And 20 more authors.
European Journal of Cancer | Year: 2015

Survival after childhood cancer has improved substantially over recent decades. Although cancer in childhood is rare increasingly effective treatments have led to a growing number of long-term survivors. It is estimated that there are between 300,000 and 500,000 childhood cancer survivors in Europe. Such good survival prospects raise important questions relating to late effects of treatment for cancer. Research has shown that the majority will suffer adverse health outcomes and premature mortality compared with the general population. While chronic health conditions are common among childhood cancer survivors, each specific type of late effect is very rare. Long-term effects must be considered particularly when addressing complex multimodality treatments, and taking into account the interaction between aspects of treatment and genotype. The PanCare Network was set up across Europe in order to effectively answer many of these questions and thereby improve the care and quality of life of survivors. The need for a structured long-term follow-up system after childhood cancer has been recognised for some time and strategies for implementation have been developed, first nationally and then trans-nationally, across Europe. Since its first meeting in Lund in 2008, the goal of the PanCare Network has been to coordinate and implement these strategies to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. This paper will outline the structure and work of the PanCare Network, including the results of several European surveys, the start of two EU-funded projects and interactions with relevant stakeholders and related projects. © 2015 Elsevier Ltd.


Terenziani M.,Fondazione IRCCS Instituto Nazionale dei Tumori | Spinelli M.,Fondazione MBBM | Jankovic M.,Fondazione MBBM | Bardi E.,Markusovszky Hospital | And 5 more authors.
Pediatric Blood and Cancer | Year: 2014

Background: Fertility is impaired in many survivors of childhood cancer following treatment. Preservation of fertility after cancer has become a central survivorship concern. Nevertheless, several doctors, patients, and families do not discuss fertility and recommendations for fertility preservation in pediatrics are still lacking. Recommendations based on scientific evidence are needed and before their development we wanted to assess the practice patterns of fertility preservation in Europe. Procedures: On behalf of the PanCare network, we sent a questionnaire to pediatric onco-hematology institutions across Europe. The survey consisted of 21 questions assessing their usual practices around fertility preservation. Results: One hundred ninety-eight institutional representatives across Europe received the survey and 68 (response rate 34.3%) responded. Pre-treatment fertility counseling was offered by 64 institutions. Counseling was done by a pediatric onco-hematologist in 52% (33/64) and in 32% (20/64) by a team. The majority of institutions (53%) lacked recommendations for fertility preservation. All 64 centers offered sperm banking; eight offered testicular tissue cryopreservation for pre-pubertal males. For females, the possibility of preserving ovarian tissue was offered by 40 institutions. Conclusions: There is a high level of interest in fertility preservation among European centers responding to our survey. However, while most recommended sperm cryopreservation, many also recommended technologies whose efficacy has not been shown. There is an urgent need for evidence-based European recommendations for fertility preservation to help survivors deal with the stressful topic of fertility. © 2014 Wiley Periodicals, Inc.


Cappelletti G.,Fondazione MBBM | Nespoli A.,University of Milan Bicocca | Fumagalli S.,Fondazione MBBM | Borrelli S.E.,University of Nottingham
Midwifery | Year: 2016

Objective: The aim of this study is to explore first-time mothers' experiences of early labour in Italian maternity care services when admitted to hospital or advised to return home after maternity triage assessment. Setting: The study was conducted in a second-level maternity hospital in northern Italy with an obstetric unit for both low- and high-risk women. Participants: The participants included 15 first-time mothers in good general health with spontaneous labour at term of a low-risk pregnancy who accessed maternity triage during early labour, and were either admitted to hospital or advised to return home. Design: A qualitative interpretive phenomenological study was conducted. A face-to-face recorded semi-structured interview was conducted with each participant 48-72 h after birth. Findings: Four key themes emerged from the interviews: (a) recognising signs of early labour; (b) coping with pain at home; (c) seeking reassurance from healthcare professionals; and (d) being admitted to hospital versus returning home. Uncertainty about the progression of labour and the need for reassurance were cited by women as the main reasons for hospital visit in early labour. An ambivalent feeling was reported by the participants when admitted to hospital in early labour. In fact, while the women felt reassured in the first instance, some women subsequently felt dissatisfied due to the absence of one-to-one dedicated care during early labour. When advised to return home, a number of women reported feelings of disappointment, anger, fear, discouragement and anxiety about not being admitted to hospital; however, some of these women reported a subsequent feeling of comfort due to being at home and putting in place the suggestions made by the midwives during the maternity triage assessment. The guidance provided by midwives during triage assessment seemed to be the key factor influencing women[U+05F3]s satisfaction when advised either to return home or to stay at the hospital during early labour. Conclusions and implications for practice: During antenatal classes and clinics, midwives should provide clear information and advice about early labour in order to increase women[U+05F3]s confidence and self-efficacy, and decrease their anxiety and fear. During early labour, appropriate maternity care services should be offered according to individual needs. When home visits are not provided by midwives, a telephone triage run by midwives should be considered as a routine service for the first point of contact with women during early labour. © 2015 Elsevier Ltd.


Russo F.M.,University of Milan Bicocca | Pozzi E.,University of Milan Bicocca | Verderio M.,University of Milan Bicocca | Bernasconi D.P.,University of Milan Bicocca | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2016

Data on the outcome of trisomy T18 (T18) when diagnosed during pregnancy are lacking. We performed a retrospective study of pregnancies complicated by T18 diagnosed at our center and a literature search for publications on the topic, with pooled estimates of survival rates at different gestational and post-natal ages. In our series, all the 60 patients included in the analysis had prenatally detected ultrasound anomalies, which were evidenced in the first trimester or at the second trimester scan in 73% of cases. In the continued pregnancies, ultrasound findings did not correlate with prenatal or post-natal outcome. A meta-analysis of available literature and our data showed that 48% [37-60%] of fetuses were live born, and among these 39% [11-72%] survived beyond 48hr and 11% [3-21%] beyond 1 month. Our results confirm that prenatal ultrasound has high sensitivity in detection of T18 but is not predictive of the outcome of the continued pregnancies. The data on survival support that T18, even when antenatally diagnosed, cannot be considered as a uniformly lethal syndrome. © 2016 Wiley Periodicals, Inc.


Buoli Comani G.,University of Milan Bicocca | Panceri R.,Fondazione MBBM | Dinelli M.,Unita Endoscopia Digestiva | Biondi A.,University of Milan Bicocca | And 3 more authors.
Genes and Nutrition | Year: 2015

Celiac disease is an intestinal disease which shows different symptoms and clinical manifestations among pediatric and adult patients. These variations could be imputable to age-related changes in gut architecture and intestinal immune system, which could be characterized by gene expression differences possibly regulated by miRNAs. We analyzed a panel of miRNAs and their target genes in duodenal biopsies of Marsh 3AB and 3C pediatric celiac patients, compared to controls. Moreover, to assess variation of expression in plasma samples, we evaluated circulating miRNA levels in controls and patients at diagnosis or on gluten-free diet. We detected a decreased miR-192-5p expression in celiac patients, but no variations in NOD2 and CXCL2, targets previously identified in adults. Conversely, we detected a significant increase in mRNA and protein levels of another target, MAD2L1, protein related to cell cycle control. miR-31-5p and miR-338-3p were down-regulated and their respective targets, FOXP3 and RUNX1, involved in Treg function, resulted up-regulated in celiac patients. Finally, we detected, in celiac patients, an increased expression of miR-21-5p, possibly caused by a regulatory loop with its putative target STAT3, which showed an increased activation in Marsh 3C patients. The analysis of plasma revealed a trend similar to that observed in biopsies, but in presence of gluten-free diet we could not detect circulating miRNAs values comparable to controls. miRNAs and their gene targets showed an altered expression in duodenal mucosa and plasma of celiac disease pediatric patients, and these alterations could be different from adult ones. © 2015, Springer-Verlag Berlin Heidelberg.


PubMed | Fondazione MBBM and University of Milan Bicocca
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

Data on the outcome of trisomy T18 (T18) when diagnosed during pregnancy are lacking. We performed a retrospective study of pregnancies complicated by T18 diagnosed at our center and a literature search for publications on the topic, with pooled estimates of survival rates at different gestational and post-natal ages. In our series, all the 60 patients included in the analysis had prenatally detected ultrasound anomalies, which were evidenced in the first trimester or at the second trimester scan in 73% of cases. In the continued pregnancies, ultrasound findings did not correlate with prenatal or post-natal outcome. A meta-analysis of available literature and our data showed that 48% [37-60%] of fetuses were live born, and among these 39% [11-72%] survived beyond 48hr and 11% [3-21%] beyond 1 month. Our results confirm that prenatal ultrasound has high sensitivity in detection of T18 but is not predictive of the outcome of the continued pregnancies. The data on survival support that T18, even when antenatally diagnosed, cannot be considered as a uniformly lethal syndrome.

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