Factors influencing outcomes of older children with medulloblastoma over 15 years in Peru, a resource-limited setting.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-to-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru. METHODS: Between 1997 and 2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997-2008 and 2009-2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, whereas prognostic factors were determined by univariate analysis (log-rank test). RESULTS: Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The 5-year OS was 62% (95% CI: 53%-74%), while EFS was 57% (95% CI: 48%-69%). The variables adversely affecting survival were anaplastic histology (compared to desmoplastic; OS: HR = 3.4, p = .03), metastasis (OS: HR = 3.5, p = .01; EFS: HR = 4.3, p = .004), delay in radiation therapy of 31-60 days (compared to ≤30 days; EFS: HR = 2.1, p = .04), and treatment 2009-2013 cohort (OS: HR = 2.2, p = .02; EFS: HR = 2.0, p = .03). CONCLUSIONS: Outcomes for medulloblastoma at INEN were low compared with HIC. Anaplastic subtype, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009-2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment, and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.

Targetable Intercellular Signaling Pathways Facilitate Lung Colonization in Osteosarcoma.

Outcomes for young people diagnosed with osteosarcoma hinge almost exclusively on whether they develop lung metastasis. The striking predilection that osteosarcoma shows for metastatic spread to lung suggests properties and/or lung interactions that generate tissue-specific survival and proliferation advantages. While these mechanisms remain overall poorly defined, studies have begun to describe biological elements important to metastasis. Mechanisms described to date include both cell-autonomous adaptations that allow disseminated tumor cells to survive the stressors imposed by metastasis and intercellular signaling networks that tumor cells exploit to pirate needed signals from surrounding tissues or to recruit other cells that create a more favorable niche. Evidence suggests that cell-autonomous changes are largely driven by epigenetic reprogramming of disseminated tumor cells that facilitates resistance to late apoptosis, manages endoplasmic reticulum (ER) stressors, promotes translation of complex transcripts, and activates clotting pathways. Tumor-host signaling pathways important for lung colonization drive interactions with lung epithelium, mesenchymal stem cells, and mediators of innate and adaptive immunity. In this chapter, we highlight one particular pathway that integrates cell-autonomous adaptations with lung-specific tumor-host interactions. In this mechanism, aberrant ΔNp63 expression primes tumor cells to produce IL6 and CXCL8 upon interaction with lung epithelial cells. This tumor-derived IL6 and CXCL8 then initiates autocrine, osteosarcoma-lung paracrine, and osteosarcoma-immune paracrine interactions that facilitate metastasis. Importantly, many of these pathways appear targetable with clinically feasible therapeutics. Ongoing work to better understand metastasis is driving efforts to improve outcomes by targeting the most devastating complication of this disease.