Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma.

Neuroblastoma accounts for approximately 15% of pediatric cancer-related deaths despite intensive multimodal therapy. This is due, in part, to high rates of metastatic disease at diagnosis and disease relapse. A better understanding of tumor biology of aggressive, pro-metastatic phenotypes is necessary to develop novel, more effective therapeutics against neuroblastoma. Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) has been found to stimulate migration, invasion, and metastasis in several adult malignancies. However, its role in neuroblastoma is currently unknown. In the present study, we found that P-Rex1 is upregulated in pro-metastatic murine models of neuroblastoma, as well as human neuroblastoma metastases. Correspondingly, silencing of P-Rex1 was associated with decreased migration and invasion in vitro. This was associated with decreased AKT-mTOR and ERK2 activity, dysregulation of Rac, and diminished secretion of matrix metalloproteinases. Furthermore, increased P-Rex1 expression was associated with inferior relapse-free and overall survival via tissue microarray and Kaplan-Meier survival analysis of a publicly available clinical database. Together, these findings suggest that P-Rex1 may be a novel therapeutic target and potential prognostic factor in neuroblastoma.

Social Determinants of Outcomes Disparity among Pediatric Patients with Solid Tumor.

BACKGROUND: Socioeconomic factors have a significant impact on healthcare outcomes. Metrics such as area deprivation index (ADI) are used to quantify the anticipated influence of these factors. Here, we sought to assess the impact of socioeconomic factors on clinical outcomes among pediatric patients with solid tumor in our region. STUDY DESIGN: We identified 3,863 pediatric patients who were diagnosed with a malignant solid tumor in the Texas Cancer Registry between 1995 and 2019. ADI was used to quantify socioeconomic determinants of health. These outcome variables were determined: stage of disease at diagnosis, time between diagnosis and treatment initiation, and overall mortality. Statistical analysis was performed using logistic regression, linear regression, Cox proportional hazards regression, and Kaplan-Meier survival curves. RESULTS: A total of 53.5% of patients were male and the average age at diagnosis was 4.5 years. Forty-seven percent of patients were White, 13.3% were Black, 36.2% were Hispanic, 1.7% were Asian, and other rare minority groups made up 1.8%. On multivariable analysis, increased risk of death was associated with Black race, rare minority race, residence in a border county, and increasing ADI score, with the risk of death at 5 years rising 4% with each increasing ADI point. CONCLUSIONS: Social determinants of health are associated with disparate outcomes among pediatric patients with solid tumor. Our results suggest that patients who are part of racial minority groups and those who reside in socioeconomically disadvantaged neighborhoods or regions near the Texas-Mexico border are at an increased risk of death. This information may be useful in strategizing outreach and expanding resources to improve outcomes in at-risk communities.

The in-utero diagnosis of choledochal cyst: can postnatal imaging predict benefit from early surgical intervention?

BACKGROUND: Infants prenatally suspected of having a choledochal cyst (CDC) typically undergo ultrasound imaging shortly after birth. This study sought to evaluate features on the initial postnatal ultrasound (IPU) that could identify newborns at risk for early complications. METHODS: Following IRB approval, patients from four US fetal centers with prenatal suspicion for CDC and postnatal imaging from 2000 to 2017 were reviewed. Imaging and clinical courses were assessed. RESULTS: Forty-two patients had prenatal ultrasounds suspicious for CDC. Nineteen (45.2%) were excluded due to diagnostic revision (n = 9), cyst resolution (n = 5), lack of IPU measurements (n = 3), or lack of follow-up (n = 2). The 23 remaining patients were included in the study. Of these, five (21.7%) developed symptoms at a median age of 16.5 days (IQR 16-19 days), and 18 (78.3%) remained asymptomatic throughout the first year after birth. Five patients (21.7%) had cysts ≥ 4.5 cm on IPU (Symptomatic: n = 3; Asymptomatic: n = 2). Eighteen patients (78.3%) had cysts < 4.5 cm on IPU (Symptomatic: n = 2; Asymptomatic: n = 16). An IPU cyst size ≥ 4.5 cm was associated with neonatal symptom manifestation (p = 0.048), with 88.9% specificity (95% CI 65.3-98.6%) and 60% sensitivity (95% CI 14.7-94.7%). CONCLUSIONS: In newborns with prenatally diagnosed CDC, a cyst size ≥ 4.5 cm on IPU is associated with symptom development during the first month after birth and therefore early cyst excision is recommended.