Assessment of a new home-based care pathway for children newly diagnosed with type 1 diabetes.

AIM: To compare the outcomes of home-based and conventional hospital-based care for children newly diagnosed with type 1 diabetes mellitus. METHODS: A descriptive study was conducted of all children newly diagnosed with diabetes mellitus at the Timone Hospital in Marseille, France, between November 2017 and July 2019. The patients received either home-based or in-patient hospital care. The primary outcome was the length of initial hospital stay. The secondary outcome measures were glycemic control in the first year of treatment, families' diabetes knowledge, the effect of diabetes on quality of life, and overall quality of care. RESULTS: A total of 85 patients were included, 37 in the home-based care group and 48 in the in-patient care group. The initial length of hospital stay was 6 days in the home-based care group versus 9 days in the in-patient care group. Levels of glycemic control, diabetes knowledge and quality of care were comparable in the two groups despite a higher rate of socioeconomic deprivation in the home-based care group. CONCLUSION: Home-based care for children with diabetes is safe and effective. This new healthcare pathway provides good overall social care, especially for socioeconomically deprived families.

Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: A French real-life observational study.

BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

Children's Drawings of Coronavirus.

OBJECTIVES: To understand how children perceive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in relation to public representations and to evaluate their interpretations. METHODS: Children's perceptions of SARS-CoV-2 were evaluated by asking 103 French children, aged 5 to 17 years old, first to draw a coronavirus and then to identify SARS-CoV-2 in a series of 16 images during summer 2020. RESULTS: One hundred three children were included in the study, either during outpatient visits at the hospital (in Marseille and Paris) or through the authors' social network, and were grouped in terms of age, parents' occupation, mode of recruitment, and recollection of having previously seen a representation of a coronavirus. Half of the children drew the coronavirus as circular in shape, and almost all included a crownlike feature. One-third of the drawings had anthropomorphic features. Although the pictorial representations of the virus were fairly accurate overall, the children's interpretations of the crownlike structure were imaginative. The explanations the children gave for their drawings were in some cases surprising. Among the 16 pictures they were shown, the children correctly identified those of SARS-CoV-2, other than the electron micrograph, in more than two-thirds of cases. CONCLUSIONS: Children of all ages, even the youngest, and both sexes had a relatively accurate perception of SARS-CoV-2, as evaluated through their drawings and their ability to recognize it among other pictures. The children's drawings of the coronavirus were colorful and had a less frightening tone than expected in the light of media coverage, suggesting that they had developed coping mechanisms.

Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination-Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. RESULTS: Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. CONCLUSION: Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.

Assessment of mineral and bone biomarkers highlights a high frequency of hypercalciuria in asymptomatic healthy teenagers.

AIM: Assessment of mineral metabolism is complex in paediatrics. METHODS: We assessed the evolution of the main mineral and bone biomarkers (total/bone alkaline phosphatase ALP/BAP, ß-crosslaps, osteocalcin, sclerostin, C-terminal and intact FGF23) in 100 healthy teenagers (10-18 years, 50 boys). RESULTS: At a mean age of 13.7 ± 2.2 years, phosphatemia, tubular phosphate reabsorption, ALP and BAP significantly decreased along puberty in both genders, whilst parathyroid hormone (PTH), 25-vitamin D (25D), FGF23, plasma calcium and urinary calcium were not modified. In girls, osteocalcin, ß-crosslaps and sclerostin significantly decreased at the end of puberty. Calciuria above the crystallisation threshold (>3.8 mmol/L) and urinary calcium/creatinine ratio >0.7 mmol/mmol were found in 39% and 6% of subjects, respectively. Multivariable analyses showed that renal function and PTH were significant predictors of calciuria and urinary calcium/creatinine, whilst 25D remained a predictor only of urinary calcium/creatinine ratio. CONCLUSION: Using the most recent assays, this study provides data for mineral/bone biomarkers across puberty and highlights the risk of hyper-calciuria in apparent asymptomatic healthy teenagers, not related to calcium intake but rather to 25D. Future studies are required to dissect the underlying mechanisms increasing calciuria and prevent nephrolithiasis as early as during childhood.

Growth curves for congenital adrenal hyperplasia from a national retrospective cohort.

BACKGROUND: In congenital adrenal hyperplasia (CAH), adjusting hydrocortisone dose during childhood avoids reduced adult height. However, there are currently no CAH-specific charts to monitor growth during treatment. Our objective was to elaborate growth reference charts and bone maturation data for CAH patients. METHODS: We conducted a retrospective observational cohort study, in 34 French CAH centers. Patients were 496 children born 1970-1991 with genetically proven 21-hydroxylase deficiency. Their growth and bone maturation data were collected until age 18 together with adult height, puberty onset, parental height, and treatment. The mean (SD) heights were modeled from birth to adulthood. The median±1 SD and ±2 SDs model-generated curves were compared with the French references. A linear model for bone maturation and a logistic regression model for the probability of short adult height were built. RESULTS: Growth charts were built by sex for salt wasting (SW) and simple virilizing (SV) children treated before 1 year of age. In girls and boys, growth was close to that of the general French population up to puberty onset. There was almost no pubertal spurt and the mean adult height was shorter than that of the general population in girls (-1.2 SD, 156.7 cm) and boys (-1.0 SD, 168.8 cm). Advanced bone age at 8 years had a strong impact on the risk of short adult height (OR: 4.5 per year advance). CONCLUSIONS: The 8-year bone age is a strong predictor of adult height. It will help monitoring the growth of CAH-affected children.

Management of adolescents with very poorly controlled type 1 diabetes by nurses: a parallel group randomized controlled trial.

BACKGROUNDS: Fluctuation in glycemia due to hormonal changes, growth periods, physical activity, and emotions make diabetes management difficult during adolescence. Our objective was to show that a close control of patients' self-management of diabetes by nurse-counseling could probably improve metabolic control in adolescents with type 1 diabetes. METHODS: We designed a multicenter, randomized controlled, parallel group, clinical trial. Seventy seven adolescents aged 12-17 years with A1C >8% were assigned to either an intervention group (pediatrician visit every 3 months + nurse visit and phone calls) or to the control group (pediatrician visit every 3 months). The primary outcome was the evolution of the rate of A1C during the 12 months of follow-up. Secondary outcomes include patient's acceptance of the disease (evaluated by visual analog scale), the number of hypoglycemic or ketoacidosis episodes requiring hospitalization, and evaluation of A1C rate over time in each group. RESULTS: Seventy-seven patients were enrolled by 10 clinical centers. Seventy (89.6%) completed the study, the evolution of A1C and participants satisfaction over the follow-up period was not significantly influenced by the nurse intervention. CONCLUSION: Nurse-led intervention to improve A1C did not show a significant benefit in adolescents with type 1 diabetes because of lack of power. Only psychological management and continuous glucose monitoring have shown, so far, a slight but significant benefit on A1C. We did not show improvements in A1C control in teenagers by nurse-led intervention. TRIAL REGISTRATION: Clinical Trials.gov registration number: NCT00308256, 28 March 2006.

Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition.

BACKGROUND: Currently, Atypical Teratoid Rhabdoid Tumor (AT/RT) constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines. RESULTS: AT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination. CONCLUSIONS: In addition to previously described involvement of insulin like growth factor (IGF) family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

Cytotoxicity, drug combinability, and biological correlates of ABT-737 against acute lymphoblastic leukemia cells with MLL rearrangement.

BACKGROUND: ABT-737 is a BH3 mimetic small-molecule inhibitor that binds with high affinity to Bcl-2 to induce apoptosis in malignant cells and has shown promise as an effective anti-leukemic agent in pediatric preclinical tests. This study focuses on the effects of ABT-737 on leukemia cells with MLL rearrangement and identifies some of the biological correlates of its activity. PROCEDURE: Cells were cultured in the presence of increasing concentrations of ABT-737 alone or in combination with other agents. After 4 days in culture, cell growth inhibition was measured by Alamar blue assay. The expression and activation of potential intracellular targets of ABT-737 activity were determined by Western blot analysis. RESULTS: Significant Bcl-2 expression was detected in all infant leukemia cells investigated. ABT-737 induced cell death in all cell lines studied although the IC(50) values differed somewhat between cell lines. Western blot analysis identified the effects of ABT-737 on survival and apoptosis-regulatory proteins PARP, caspase-8, and cytochrome-c. Drug combination studies indicated synergy with distinct anti-neoplastic agents, including the multi-tyrosine kinase inhibitor sunitinib. This effective drug synergy appears to be mediated by the combined inhibition of Bcl-2 and intracellular signaling pathways. CONCLUSIONS: We describe the in vitro studies to demonstrate the activity and drug combinability of ABT-737 against MLL rearranged leukemia cells. In addition, identification of the molecular changes that occur in the presence of ABT-737 provides information regarding effective target validation and target modulation analyses in future clinical trials.

Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children.

We report the post-transplant lymphocyte subset recovery of 226 children treated with Unrelated Cord Blood transplant (UCBT) (n = 112) or Unrelated Bone Marrow Transplant (UBMT) (n = 114) for malignant or non-malignant diseases. Absolute numbers of natural killer (NK), B and T cells were monitored by flow cytometry up to 5 years post-transplant. Immunological endpoints were: time to achieve a CD3(+) cell count > 0·5 and 1·5 × 109/l, CD4(+) > 0·2 and 0·5 × 109/l, CD8(+) > 0·25 ×109/l, CD19(+) > 0·2 × 109/l, NK > 0·1 × 109/l. These endpoints were analysed through the use of cumulative incidence curves in the context of competing risks. CD8(+) T cell recovery was delayed after UCBT with a median time to reach CD8(+) T cells > 0·25 × 109/l of 7·7 months whereas it was 2·8 months in UBMT (P < 0·001). B cell recovery was better in UCBT, with a median time to reach CD19(+) cells > 0·2 × 109/l of 3·2 months in UCBT and 6·4 months in UBMT (P = 0·03). Median time for CD4(+) T cell and NK cell recovery was similar in UCBT and UBMT. CD4(+) T cells recovery was negatively correlated to age (better reconstitution in younger patients, P = 0·002). CD8(+) T cells recovery was shorter in recipients with a positive cytomegalovirus serology (P =0·001).

Establishment of atypical-teratoid/rhabdoid tumor (AT/RT) cell cultures from disseminated CSF cells: a model to elucidate biology and potential targeted therapeutics.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects infants and young children. In this report, we describe culture conditions that enabled the sustained growth of tumor cells obtained from the cerebrospinal fluid (CSF) of an infant with AT/RT. These cells retained the morphological and biomarker characteristics of the original tumor. A screening of receptor tyrosine kinases identified the presence of phosphorylated ErbB4, Insulin-R, PDGFR and IGF-IR, which appear to depend on Hsp90 to maintain their active form. IGF-IR activity is consistent with data from other established AT/RT cell lines. Inhibition of IGF-IR by the small molecular weight inhibitor AEW541 led to growth suppression of cultured AT/RT cells. In addition, neutralizing antibodies to IGF-II also inhibited the growth of these cells suggesting a potential autocrine function for this cytokine. We also compared cultured AT/RT cells to established cell lines to identify consistent drug sensitivity patterns among these cells. In addition to previously described cell lines and xenograft models, continuous culture of CSF derived cells may also provide an effective way to study the biology of AT/RT and to identify potential targets for future therapeutics for this tumor.