Background: Few randomized trials have been conducted in children with relapsed/refractory neuroblastoma and data about outcomes including progression-free survival (PFS) in these patients are scarce. Procedure:A meta-analysis of three phase II studies of children with relapsed/refractory neuroblastoma conducted in Europe (temozolomide, topotecan-vincristine-doxorubicin and topotecantemozolomide) was performed. Individual patient data with extended follow-up were collected from the trial databases after publication to describe trial outcomes (response rate, clinical benefit ratio, duration of treatment, PFS, and overall survival [OS]). Characteristics of subjects with relapsed/refractory neuroblastoma were compared.Results: Data from 71 children and adolescents with relapsed/refractory neuroblastoma were collected. Response definitions were not homogeneous in the three trials. Patients were on study for a median of 3.5 months (interquartile range [IQR] 1.9-6.2). Of those, 35.2% achieved a complete or partial response, 26.3% experienced a response after more than two cycles, and 23.9% received more than six cycles. Median PFS from study entry for all, refractory, and relapsed patients was 6.4 ± 1.0, 12.5 ± 6.8, and 5.7 ± 1.0 months, respectively (P = 0.006). Median OS from study entry for all, refractory, and relapsed patients was 16.1 ± 4.3, 27.9 ± 20.2, and 11.0 ± 1.6 months, respectively (P = 0.03). Conclusions:Baseline data for response rate, clinical benefit ratio, duration of treatment, PFS, and OS were provided. Two subpopulations (relapsed/refractory) were clearly distinct and should be included in the interpretation of all trials. These results should help informing the design of forthcoming studies in relapsed/refractory neuroblastoma.

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PurposeMetastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([123I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate.Materials and MethodsPatients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m2/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m2, and doxorubicin, 45 mg/m2.ResultsSixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%).ConclusionTVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

The purpose of this study was to identify the plasma/serum biomarkers that are able to predict overall survival (OS) of neuroblastoma (NB) patients. Concentration of soluble (s) biomarkers was evaluated in plasma (sHLA-E, sHLA-F, chromogranin, and B7H3) or serum (calprotectin) samples from NB patients or healthy children. The levels of biomarkers that were significantly higher in NB patients were then analyzed considering localized or metastatic subsets. Finally, biomarkers that were significantly different in these two subsets were correlated with patient's outcome. With the exception of B7H3, levels of all molecules were significantly higher in NB patients than those in controls. However, only chromogranin, sHLA-E, and sHLA-F levels were different between patients with metastatic and localized tumors. sHLA-E and -F levels correlated with each other but not chromogranin. Chromogranin levels correlated with different event-free survival (EFS), whereas sHLA-E and -F levels also correlated with different OS. Association with OS was also detected considering only patients with metastatic disease. In conclusion, low levels of sHLA-E and -F significantly associated with worse EFS/OS in the whole cohort of NB patients and in patients with metastatic NB. Thus, these molecules deserve to be tested in prospective studies to evaluate their predictive power for high-risk NB patients.

Background Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Nucleolin (NCL) is a protein overexpressed and partially localized on the cell surface of tumor cells of adult cancers. Little is known about NCL and pediatric tumors and nothing is reported about cell surface NCL and NB. Methods NB cell lines, Schwannian stroma-poor NB tumors and bone marrow (BM)-infiltrating NB cells were evaluated for the expression of cell surface NCL by Flow Cytometry, Imaging Flow Cytometry and Immunohistochemistry analyses. The cytotoxic activity of doxorubicin (DXR)-loaded nanocarriers decorated with the NCL-recognizing F3 peptide (T-DXR) was evaluated in terms of inhibition of NB cell proliferation and induction of cell death in vitro, whereas metastatic and orthotopic animal models of NB were used to examine their in vivo anti-tumor potential. Results NB cell lines, NB tumor cells (including patient-derived and Patient-Derived Xenografts-PDX) and 70% of BM-infiltrating NB cells show cell surface NCL expression. NCL staining was evident on both tumor and endothelial tumor cells in NB xenografts. F3 peptide-targeted nanoparticles, co-localizing with cell surface NCL, strongly associates with NB cells showing selective tumor cell internalization. T-DXR result significantly more effective, in terms of inhibition of cell proliferation and reduction of cell viability in vitro, and in terms of delay of tumor growth in all NB animal model tested, when compared to both control mice and those treated with the untargeted formulation. Conclusions Our findings demonstrate that NCL could represent an innovative therapeutic cellular target for NB.