No abstract

Summary:We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR Ͻ70 ml/min/1.73 m 2 ). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.

No abstract

After SCT in childhood, survivors may develop disorders of glucose metabolism. The role of obesity is controversial. We measured insulin sensitivity using the homeostasis model assessment (HOMA) and the frequently sampled i.v. glucose tolerance test (FSIVGTT), as well as body composition using dual-energy X-ray absorptiometry in 18 young adults median 18.2 years after SCT and compared them with matched controls. We also measured growth hormone (GH) secretion, and levels of leptin and adiponectin. HOMA showed insulin resistance in eight patients (44%), as opposed to none of the controls (P=0.008) and FSIVGTT showed a decreased sensitivity index in the patients (2.98 vs 4.54 mU/L/min, P=0.042). Dual energy X-ray absorptiometry showed a higher percentage fat mass in the patients (34.9 vs 24.3%, P=0.011), which correlated inversely with the sensitivity index (r=-0.52, P=0.032). The patients had a lower peak value of GH (GH(max) 9 vs 20.7 mU/L, P=0.002). Time post SCT correlated with percentage fat mass and inversely with GH(max). The patients had higher levels of leptin and lower levels of adiponectin, even after adjustment for fat mass. We propose that the decreased insulin sensitivity may primarily be explained by the adverse body composition, which may owe to long-standing GH deficiency.

B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.

Summary:We performed serial pulmonary function tests (PFTs) consisting of spirometry and diffusing capacity in 26 children after BMT. The median follow-up was 10 years. The influence of total body irradiation (TBI) on long-term pulmonary function was of particular interest. In the 20 children who had received TBI, after an initial decrease the PFTs showed recovery, but the mean lung volumes were still significantly decreased 5 years after BMT at 10% below baseline. The proportions of children with restrictive impairment 5 and 10 years after BMT were 20 and 21%, respectively. Only one child was diagnosed with obstructive impairment. The proportions of children with isolated diffusing impairment at 5 and 10 years were 7/20 (35%) and 7/13 (54%), respectively. Six children had received chemotherapy only and showed isolated diffusing impairment as the only long-term sequela in 4/5 and 1/3 at 5 and 10 years. Our main finding was that there was little change in PFTs 1-10 years after BMT. TBI was associated with persistently decreased lung volumes in a proportion of patients, whereas chemotherapy also might have been of importance for the development of impaired gas exchange.

Introduction Pilocytic astrocytoma is the most common brain tumour in childhood but knowledge concerning its long-term outcome is sparse. The aim of the study was to investigate if children treated for low-grade pilocytic astrocytoma in the posterior fossa had complications affecting physical and psychological health, cognitive functions, learning difficulties and HRQoL. Methods A descriptive single-centre study, where 22 children and young adults out of 27 eligible patients (81%) treated for pilocytic astrocytoma, with a mean follow-up time of 12.4 years (5–19 years) participated (14 adults, two by telephone interviews and eight children). The study included a review of medical records, an interview, neurological investigation, screening tools for psychiatric symptoms (Beck Depression and Anxiety Inventories and Beck Youth Inventory Scales) and HRQoL measures (RAND-36). Results Motor complications were most common, reported in 12 patients and mainly affecting fine-motor skills. Seven patients reported cognitive difficulties affecting performance in school. Educational support was given in the period immediately after treatment but not after primary school. None had elevated levels of psychiatric symptoms and the level of HRQoL as well as their psychosocial and educational situation was in correspondence with Swedish norms. The HRQoL score for vitality (VT) almost reached statistical significance. Conclusions The long-term functional outcome for children treated for low-grade astrocytoma is favourable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programmes including interventions in school.

Background Children and adolescents with leukemia are potentially at high risk of vitamin D inadequacy, which may have clinical relevance for skeletal morbidity, infections, and cancer outcome. This study aimed to evaluate vitamin D status at the time of diagnosis to investigate its predictors and association with overall survival in children with leukemia. Procedure We included all 295 children and adolescents diagnosed with leukemia at our institution between 1990 and 2016 who had available serum sample from the time of diagnosis. We analyzed serum 25‐hydroxyvitamin D and parathyroid hormone levels and correlated them with clinical data. Results The 25‐hydroxyvitamin D level was deficient (< 25 nmol/L), insufficient (25‐50 nmol/L), sufficient (50‐75 nmol/L), and optimal (> 75 nmol/L) in 6.4%, 26.8%, 39.7%, and 27.1% of the children, respectively. Older age and a more recent time of sampling (calendar year) predicted lower 25‐hydroxyvitamin D level. In preschool children (age ≤6 years), lower 25‐hydroxyvitamin D level was also associated with acute myeloid leukemia, and a 25‐hydroxyvitamin D level < 50 nmol/L was associated with inferior overall survival. In school‐aged children (age > 6 years), the 25‐hydroxyvitamin D level showed significant seasonal variation. Conclusion It remains unclear whether vitamin D supplementation in pediatric leukemia patients will improve outcome.