Background: Neuroblastoma (NB) is the most common tumour in children younger than 5 years old and notable for highly heterogeneous. Our aim was to quantify the intra-tumoural metabolic heterogeneity of primary tumour lesions by using¹⁸F-FDG PET/CT and evaluate the prognostic value of intra-tumoural metabolic heterogeneity in NB patients.Methods: We retrospectively enrolled 38 pretreatment NB patients in our study.¹⁸F-FDG PET/CT images were reviewed and analyzed using 3D slicer software. The semi-quantitative metabolic parameters of primary tumour were measured, including the maximum standard uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG). The areas under the curve of cumulative SUV-volume histogram index (AUC-CSH index) was used to quantify intra-tumoural metabolic heterogeneity. The median follow-up was 21.3 months (range 3.6 - 33.4 months). The outcome endpoint was event-free survival (EFS), including progression-free survival and overall survival. Survival analysis was performed using Cox regression models and Kaplan Meier survival plots.Results: In all 38 newly diagnosed NB patients, 2 patients died, and 17 patients experienced a relapse. The AUC-CSH_total(r=0.630, P<0.001) showed moderate correlation with the AUC-CSH_40%. In univariate analysis, chromosome 11q deletion (P=0.033), Children's Oncology Group (COG) risk grouping (P=0.009), bone marrow involvement (BMI, P=0.015), and AUC-CSH_total(P=0.007) were associated with EFS. The AUC-CSH_total(P=0.036) and BMI (P=0.045) remained significant in multivariate analysis. The Kaplan Meier survival analyses demonstrated that patients with higher intra-tumoural metabolic heterogeneity and BMI had worse outcomes (log-rank P=0.002).Conclusion: The intra-tumoural metabolic heterogeneity of primary lesions in NB was an independent prognostic factor for EFS. The combined predictive effect of intra-tumoural metabolic heterogeneity and BMI provided prognostic survival information in NB patients.

Gemcitabine (Gem) is currently used as the first-line therapy for liver and pancreatic cancer but has limited efficacy in most cases. Dexamethasone (Dex) have been applied as a chemoprotectant and chemosensitizer in cancer chemotherapy. This study further explored the potential of combination of Gem and Dex and tested the hypothesis that glucocorticoid receptor signaling is essential for the synergistic antitumor activity. In the HepG2 and AsPC-1 xenograft models, the combination treatment showed a significantly synergistic antitumor activity. Immunohistochemistry of post-treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. Dex alone and the combination with Gem inhibited the expression of glucocorticoid receptor. The combination of Dex and Gem showed synergistic cytotoxicity in cell lines in vitro. The antiproliferative synergism is prevented by used glucocorticoid receptor (GR) small interfering RNA, demonstrating that the glucocorticoid receptor is required for the antiproliferative synergism of Gem and Dex. The inhibition of glucocorticoid receptor signaling pathway and induction of apoptosis via activation of caspases 3, 8 and 9, PARP, contributed to the synergistic effect of this combination therapy. These results demonstrate that Dex could potentiate the antitumor efficacy of Gem. The synergistic antitumor activity of the combination of Dex and Gem was through glucocorticoid receptor signaling. Taken together, a combination of Dex and Gem shows a significant synergistic antitumor activity and lesser toxicity both in vitro and in vivo and could be a combination chemotherapy for the treatment of highly expression of glucocorticoid receptor patients.