Exploiting Gangliosides for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline Glioma.

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood-brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher's disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

Benefits of Exercise Training for Children and Adolescents Undergoing Cancer Treatment: Results From the Randomized Controlled MUCKI Trial.

Objective: In cancer patients, the impairment in muscle function is a frequently observed phenomenon. However, comprehensive evaluation of the effect of exercise training on muscle function in childhood cancer patients (CCPs) is sparse and therefore investigated in the MUCKI trial. Study Design: In the randomized controlled MUCKI trial, CCPs during intensive cancer treatment and aged 4-18 years were recruited. Eligible patients were enrolled soon after diagnosis as long as they were physically and mentally able to participate in exercise testing and training. Patients of the exercise group (n = 16) participated in average 2.7 ± 1.2 times per week in a combined resistance and endurance training with moderate exercise intensity, for a time period of 8.0 ± 2.1 weeks, while patients of the control group (n = 17) received usual care. Leg strength was evaluated as the primary endpoint. Secondary endpoints were 6-min walk performance, arm strength, body composition, fatigue, and health-related quality of life. Results: Comparisons of pre- and post-intervention results were evaluated by baseline and stratification criteria adjusted analysis and showed positive effects for the exercise group regarding leg strength [F (1, 20) = 5.733; p = 0.027*; η p 2 = 0.223], walking performance [F (1, 25) = 4.270; p = 0.049*; η p 2 = 0.146], fatigue [F (1, 13) = 8.353; p = 0.013*; η p 2 = 0.391], self-esteem [F (1, 6) = 6.823; p = 0.040*; η p 2 = 0.532], and self-reported strength and endurance capacity [F (1, 6) = 6.273; p = 0.046*; η p 2 = 0.511]. No significant differences were found for the other parameters. Conclusion: Within one of the first randomized controlled trials, the present study provides evidence for a positive effect of combined training in CCPs during intensive cancer treatment. Further research is needed to confirm these results and to evaluate their clinical impact. Clinical Trial Registration Number: NCT02612025.

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma.

Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient's liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.

Maternal hypothalamus-pituitary-adrenal (HPA) system activity and stress during pregnancy: Effects on gestational age and infant's anthropometric measures at birth.

BACKGROUND: Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome. METHODS: In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 ±â€¯1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth. RESULTS: Maternal prenatal distress during late gestation was associated with significant reduction in birth weight (-217 g; p = .005), birth length (-1.2 cm; p = .005) and head circumference (-0.8 cm; p = .001). Prenatal stress was modestly but significantly associated with altered diurnal cortisol pattern (flattened cortisol decline and higher evening cortisol), which in turn was significantly related to reduced length of gestation. No evidence for a profound interaction between maternal cortisol level in late pregnancy and infant's anthropometric measures at birth (i.e., birth weight, length, head circumference) was found. CONCLUSION: Prenatal stress is associated with flattened circadian saliva cortisol profiles and reduced infant's anthropometric measures at birth. HPA system activity during pregnancy may be related to low gestational age. The effect of prenatal stress might be partly mediated by maternal-placental-fetal neuroendocrine mechanisms especially the dysregulation of diurnal cortisol profile.

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy.

High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.

[Implants with 32P-foils for LDR-brachytherapy of benign stenosis in urology and gastroenterology]. / (32)P-haltige Folien als Implantate für die LDR-Brachytherapie gutartiger Stenosen in der Urologie und Gastroenterologie.

For LDR-brachytherapy, a limited number of implant geometries and materials are available. To avoid wound healing related hyper-proliferation (stenosis, keloids) a novel radioactive foil system was developed based on beta emitting (32)P, which can be easily integrated in existing implants such as urethral catheters or bile duct stents. As substrate material for these foils PEEK (polyetherethercetone) was chosen because of its radiation hardness during neutron activation of (32)P. The activity was determined by liquid scintillation counting and gamma spectroscopy, dose distributions were measured with scintillation detectors and radiochromic films. The correlation between activity and dose was checked by Monte-Carlo-simulations (Geant4). Prototypes of the (32)P-implants have shown in wash-out tests the required tightness for sealed radioactive sources. In animal tests on urethra and bile duct, the uncomplicated and save application of (32)P-foils mounted on standard implants has been demonstrated, which is almost unchanged due to the simple radiation protection with plexiglass. This concept of radioactive implants with integrated (32)P-foils could extend essentially the application possibilities of LDR-brachytherapy.