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Minerva Pediatrica 2019 Jan 02

DOI: 10.23736/S0026-4946.18.05444-0


language: English

Evaluation of Ki-67 as prognostic factor for pediatric neuroblastoma and the possibility of molecular-targeted drugs with vascular endothelial growth factor and platelet-derived growth factor receptor

Shunsuke WATANABE , Tatsuya SUZUKI, Yasuhiro KONDO, Atsuki NAOE, Naoko UGA, Toshihiro YASUI, Fujio HARA, Tomonori TSUCHIYA

Department of Pediatric Surgery, Fujita Medical University,Toyoake, Japan


BACKGROUND: Neuroblastoma (NB) is a pediatric malignant solid tumor characterized as refractory cancer with poor prognosis. Mitosis-karyorrhexis index (MKI) is a prognostic factor but is prone to observer bias. The usefulness of MKI with Ki-67, as a marker of malignancy, was investigated. The efficacy of molecular-targeted therapeutic agents with fewer side effects in tumors has been studied. Molecular-targeted therapy targets include vascular endothelial growth factor (VEGF), involved in tumor angiogenesis; c-Kit, receptor of Kit/stem cells involved in tumor growth, vasculature, and lymphangiogenesis; platelet-derived growth factor receptor (PDGFR); and B-Raf proto-oncogene, serine/threonine kinase (BRAF), involved in the RAS protein-mediated mitogen-activated protein kinase pathway. Therefore, expression profiles of these factors and growth inhibitory effects of molecular-targeted drugs against NB were investigated.
METHODS: Ten frozen NB tissue samples collected during January 1993-December 2017 were evaluated immunohistochemically for Ki-67 and VEGF. c-Kit, PDGFR, and BRAF expression levels were evaluated using enzyme-linked immunosorbent assays; relationships between these factors and clinicopathological parameters of NB were analyzed.
RESULTS: Eight patients with NB showed no amplification of MYCN (MYCN proto- oncogene, bHLH transcription factor). There were two cases of ganglioneuroblastoma (GNB). More NB cells were positive for Ki-67 than for GNB cells. VEGF expression was observed in all NB specimens and was stronger in stage IIB and higher. No BRAF or c-Kit activity was observed; PDGFR activity was greater in NB than in GNB (p = 0.02).
CONCLUSIONS: Thus, Ki-67 may help evaluate NB malignancy. As the first therapy for NB prevents amplification of MYCN, agents targeting PDGFR as well as VGFG can inhibit NB cell proliferation.

KEY WORDS: Neuroblastoma - Vascular endothelial growth factor - C-Kit - Platelet-derived growth factor receptor - B-Raf proto-oncogene - Serine/threonine kinase

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