In Vivo Modeling of Chemoresistant Neuroblastoma Provides New Insights into Chemorefractory Disease and Metastasis.

Neuroblastoma is a pediatric cancer that is frequently metastatic and resistant to conventional treatment. In part, a lack of natively metastatic, chemoresistant in vivo models has limited our insight into the development of aggressive disease. The Th-MYCN genetically engineered mouse model develops rapidly progressive chemosensitive neuroblastoma and lacks clinically relevant metastases. To study tumor progression in a context more reflective of clinical therapy, we delivered multicycle treatment with cyclophosphamide to Th-MYCN mice, individualizing therapy using MRI, to generate the Th-MYCN CPM32 model. These mice developed chemoresistance and spontaneous bone marrow metastases. Tumors exhibited an altered immune microenvironment with increased stroma and tumor-associated fibroblasts. Analysis of copy number aberrations revealed genomic changes characteristic of human MYCN-amplified neuroblastoma, specifically copy number gains at mouse chromosome 11, syntenic with gains on human chromosome 17q. RNA sequencing revealed enriched expression of genes associated with 17q gain and upregulation of genes associated with high-risk neuroblastoma, such as the cell-cycle regulator cyclin B1-interacting protein 1 (Ccnb1ip1) and thymidine kinase (TK1). The antiapoptotic, prometastatic JAK-STAT3 pathway was activated in chemoresistant tumors, and treatment with the JAK1/JAK2 inhibitor CYT387 reduced progression of chemoresistant tumors and increased survival. Our results highlight that under treatment conditions that mimic chemotherapy in human patients, Th-MYCN mice develop genomic, microenvironmental, and clinical features reminiscent of human chemorefractory disease. The Th-MYCN CPM32 model therefore is a useful tool to dissect in detail mechanisms that drive metastasis and chemoresistance, and highlights dysregulation of signaling pathways such as JAK-STAT3 that could be targeted to improve treatment of aggressive disease. SIGNIFICANCE: An in vivo mouse model of high-risk treatment-resistant neuroblastoma exhibits changes in the tumor microenvironment, widespread metastases, and sensitivity to JAK1/2 inhibition.

Invasive bacterial and fungal infections in paediatric patients with cancer: incidence, risk factors, aetiology and outcomes in a UK regional cohort 2009-2011.

BACKGROUND: Cancer is the second most common cause of childhood deaths in the United Kingdom and infection contributes to a quarter of all cancer-related deaths. This study aimed to estimate the risk, aetiology and outcome of bloodstream bacterial and fungal infections in children with cancer within a geographically defined region in South-West London over a 3-year period. METHODS: Web-based questionnaires were completed using case records of children with positive blood cultures admitted to five London hospitals during 2009-2011. RESULTS: A total of 112 children with a median age of 5.4 (IQR 3.6-11.2) years had 266 significant blood cultures during 149 infection episodes. Haematological malignancy affected 68 patients (60.7%) and solid tumours 44 (39.3%). The overall bloodstream infection rate was 1.5 episodes per 1,000 days-at-risk (95% CI, 1.2-1.8) and was similar for those with haematological malignancies and solid tumours. Most episodes were attributed to central venous catheter infection (120/149, 80.5%). Coagulase-negative staphylococci were isolated in almost half the bloodstream infections (127/266; 47.7%), while Gram-negative organisms accounted for a further quarter (64/266; 24.1%). Fungal isolates from blood were uncommon (8/112 children, 7.1%) but significantly associated with neutropenia (18/149 [12.1%] vs. 1/114 [0.9%], P = 0.0004). Six children (5.4%) died, including three (2.7%; 95% CI, 0.6-7.6%) whose deaths were infection-related. CONCLUSIONS: This study provides an updated risk estimate for bloodstream infections in children with cancer and adds to the framework for developing evidence-based guidance for management of suspected infections in this highly vulnerable group.

Hepatoblastoma in a child with a paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p causing focal congenital hyperinsulinism.

Hepatoblastoma is a tumour of early childhood occurring in association with genetic syndromes including Beckwith-Wiedemann Syndrome (BWS) which results from dominance of paternally-inherited genes on chromosome 11p15. We report a child without clinical BWS, neonatally diagnosed with focal congenital hyperinsulinism resulting from a paternally-inherited recessively-acting mutation of ABCC8 and pancreatic paternal uniparental disomy (UPD) for chromosome 11p15, who subsequently developed hepatoblastoma. Genetic testing showed UPD 11p15 in the pancreas and liver but not systemically, allowing the expression of mutated ABCC8 in both tissues. Infants with large or multifocal forms of focal congenital hyperinsulinism may be at risk of BWS-like tumours due to mosaic UPD despite negative whole-blood and buccal DNA testing and tumour surveillance should be considered for this minority.