Revisiting Neuroblastoma: Nrf2, NF-κB and Phox2B as a Promising Network in Neuroblastoma.

Neuroblastoma is the most common solid extracranial tumor during childhood; it displays extraordinary heterogeneous clinical courses, from spontaneous regression to poor outcome in high-risk patients due to aggressive growth, metastasizing, and treatment resistance. Therefore, the identification and detailed analysis of promising tumorigenic molecular mechanisms are inevitable. This review highlights the abnormal regulation of NF-κB, Nrf2, and Phox2B as well as their interactions among each other in neuroblastoma. NF-κB and Nrf2 play a key role in antioxidant responses, anti-inflammatory regulation and tumor chemoresistance. Recent studies revealed a regulation of NF-κB by means of the Nrf2/antioxidant response element (ARE) system. On the other hand, Phox2B contributes to the differentiation of immature sympathetic nervous system stem cells: this transcription factor regulates the expression of RET, thereby facilitating cell survival and proliferation. As observed in other tumors, we presume striking interactions between NF-κB, Nrf2, and Phox2B, which might constitute an important crosstalk triangle, whose decompensation may trigger a more aggressive phenotype. Consequently, these transcription factors could be a promising target for novel therapeutic approaches and hence, further investigation on their regulation in neuroblastoma shall be reinforced.

High prevalence of multidrug-resistant Gram-negative bacteria carriage in children screened prospectively for multidrug resistant organisms at admission to a paediatric hospital, Hamburg, Germany, September 2018 to May 2019.

BackgroundIncreasing resistance to antibiotics poses medical challenges worldwide. Prospective data on carriage prevalence of multidrug resistant organisms (MDRO) in children at hospital admission are limited and associated risk factors are poorly defined.AimTo determine prevalence of MDRO carriage in children at admission to our paediatric hospital in Hamburg and to identify MDRO carriage risk factors.MethodsWe prospectively obtained and cultured nasal/throat and inguinal/anal swabs from children (≤ 18 years) at admission between September 2018 and May 2019 to determine prevalence of meticillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Gram-negative bacteria (MRGN) and vancomycin-resistant enterococcus (VRE) and associated species. We collected medical histories using a questionnaire and evaluated 31 risk factors using logistic regression models.ResultsMDRO carriage prevalence of 3,964 children was 4.31% (95% confidence interval (CI): 3.69-5.00). MRSA carriage prevalence was 0.68% (95% CI: 0.44-0.99), MRGN prevalence was 3.64% (95% CI: 3.07-4.28) and VRE prevalence 0.08% (95% CI: 0.02-0.22). MDRO carriage was associated with MRGN history (odds ratio (OR): 6.53; 95% CI: 2.58-16.13), chronic condition requiring permanent care (OR: 2.67; 95% CI: 1.07-6.13), antibiotic therapy (OR: 1.92, 95% CI: 1.24-2.94), living in a care facility (OR: 3.34; 95% CI: 0.72-12.44) and refugee status in previous 12 months (OR: 1.91; 95% CI: 0.27-8.02). Compared to established practice, screening using risk-factors had better diagnostic sensitivity (86.13%; 95% CI: 80.89-91.40) and specificity (73.54%; 95% CI: 72.12-74.97).ConclusionMRGN carriage was higher than MRSA and VRE. Extended risk-factor-based admission screening system seems warranted.

NovoSorb® Biodegradable Temporizing Matrix: a novel approach for treatment of extremity avulsion injuries in children.

PURPOSE: In pediatric population, large soft tissue defects occur in avulsion injuries. In addition to the challenges of primary surgical therapy, elasticity, appearance and function of the scar in children are of crucial importance, especially in the context of body growth. So far various flaps, plasties, skin grafts and dermal substitutes have become established, although infections and skin shrinkage remain challenging. In 2020, a new skin substitute material-NovoSorb® Biodegradable Temporizing Matrix (BTM)-was introduced in Europe for temporary wound closure and tissue regeneration. The aim of this study was to evaluate the value of BTM in pediatric patients. METHODS: The study included all children treated with BTM after traumatic soft tissue defects following limb avulsion injuries between June 2021 and June 2023 at a university hospital. RESULTS: 7 patients with limb avulsion injuries were treated with BTM, 4 boys, 3 girls. Mean age was 6.5 years (2-11 years) at the time of BTM placement. 4/7 had concomitant fractures. BTM was used successfully in all cases, infection did not occur, skin shrinkage was seen in one case. Split thickness skin graft (STSG) after BTM application was performed in average after 33 days (26 to 39 days). Limitations of this study were highlighted. CONCLUSION: BTM is a promising alternative for reconstruction of complex trauma extremity wounds in children following avulsion injuries, even in cases of concomitant bone injuries. Interpretation may be limited by sample size.

Health-Related Quality of Life and Mental Health of Children with Embryonal Abdominal Tumors.

(1) Background: Embryonal abdominal tumors are one of the most common entities of solid childhood cancer. The present study investigates the Health-Related Quality of Life (HRQoL) and the mental health of children to obtain a comprehensive picture of their health status and uncover a possible gap in healthcare. (2) Methods: The sample consisted of 54 children who were treated for embryonal abdominal tumors and a control group of 46 children who received uncomplicated outpatient surgery. The HRQoL and the mental health were assessed by the parent proxy reports of the questionnaires Pediatric Quality of Life Inventory (PedsQL) and Strengths and Difficulties Questionnaire (SDQ). (3) Results: Children with embryonal abdominal tumors showed significantly lower HRQoL and mental health values compared to the norm data. The index group showed lower values in the social subscales of HRQoL and mental health compared to the control group. (4) Conclusions: Embryonal abdominal tumors affect the well-being of children. There is still a gap in healthcare due to children's HRQoL and mental health, especially regarding social development. It is essential to further advance the psychological care of children and improve their chances to develop social relationships.

Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L.

Neuroblastoma is the most common extracranial solid tumor during infancy and childhood.Outcome of high-risk and late-stage disease remains poor despite intensive treatment regimens.Suppressing inhibitor of apoptosis proteins (IAPs) using Smac mimetics (SM) significantly sensitizes neuroblastoma (NB) cells for chemotherapy, however strongly dependent on the cytotoxic drug combined with SM.Therefore, a systematic analysis of the impact of SM in combination with different classes of chemotherapeutics was of crucial importance. Treatment of NB cell lines with SM LCL161 and vinca alkaloids revealed a strong synergistic inhibition of proliferation and significant induction of apoptosis in virtually all established and de novo NB cell lines (n=8).In contrast, combination of anthracyclines or topoisomerase inhibitors with LCL161 showed a synergism for single drugs and/or cell lines only.Furthermore, we could show that insensibility to LCL161-mediated sensitization for chemotherapeutics is associated with aberrant activation of anaplastic lymphoma kinase (ALK) by common mutation F1174L. Inhibition of ALK using TAE684 is able to overcome this resistance in a synergistic fashion, a finding that could be highly relevant for improvement of neuroblastoma therapy.