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Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a wellestablished model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, A-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described watersoluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumormicroenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma. [Cancer Res 2007;67(19):9435-42]

OBJECTIVE An assessment of the transcranial approach (TCA) and the endoscopic endonasal approach (EEA) for craniopharyngiomas (CPs) according to tumor types has not been reported. The aim of this study was to evaluate both surgical approaches for different types of CPs. METHODS A retrospective review of primary resected CPs was performed. A QST classification system based on tumor origin was used to classify tumors into 3 types as follows: infrasellar/subdiaphragmatic CPs (Q-CPs), subarachnoidal CPs (S-CPs), and pars tuberalis CPs (T-CPs). Within each tumor type, patients were further arranged into two groups: those treated via the TCA and those treated via the EEA. Patient and tumor characteristics, surgical outcomes, and postoperative complications were obtained. All variables were statistically analyzed between surgical groups for each tumor type. RESULTS A total of 315 patients were included in this series, of whom 87 were identified with Q-CPs (49 treated via TCA and 38 via EEA); 56 with S-CPs (36 treated via TCA and 20 via EEA); and 172 with T-CPs (105 treated via TCA and 67 via EEA). Patient and tumor characteristics were equivalent between both surgical groups in each tumor type. The overall gross-total resection rate (90.5% TCA vs 91.2% EEA, p = 0.85) and recurrence rate (8.9% TCA vs 6.4% EEA, p = 0.35) were similar between surgical groups. The EEA group had a greater chance of visual improvement (61.6% vs 35.8%, p = 0.01) and a decreased risk of visual deterioration (1.6% vs 11.0%, p < 0.001). Of the patients with T-CPs, postoperative hypothalamic status was better in the TCA group than in the EEA group (p = 0.016). Postoperative CSF leaks and nasal complication rates occurred more frequently in the EEA group (12.0% vs 0.5%, and 9.6% vs 0.5%; both p < 0.001). For Q-CPs, EEA was associated with an increased gross-total resection rate (97.4% vs 85.7%, p = 0.017), decreased recurrence rate (2.6% vs 12.2%, p = 0.001), and lower new hypopituitarism rate (28.9% vs 57.1%, p = 0.008). The recurrence-free survival in patients with Q-CPs was also significantly different between surgical groups (log-rank test, p = 0.037). The EEA required longer surgical time for T-CPs (p = 0.01). CONCLUSIONS CPs could be effectively treated by radical surgery with favorable results. Both TCA and EEA have their advantages and limitations when used to manage different types of tumors. Individualized surgical strategies based on tumor growth patterns are mandatory to achieve optimal outcomes.

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The aim of this study was to clarify pathological and anatomical relationships between adamantinomatous craniopharyngiomas (ACP) and their surrounding structures. We previously established a QST classification scheme based on the apparent anatomic origin of the tumors. According to this classification, 13 type Q tumors, 6 type S tumors, and 42 type T ACPs were analyzed. Type Q tumors, which are most likely to involve the pituitary gland, did not invade the area of contact with the adenohypophysis. Instead, tumor invasion was observed in areas where the tumor contacted the neurohypophysis. Type S tumors primarily involved the pituitary stalk; the arachnoid remained present between these tumors and normal structures. Type T tumors were located beneath the basal arachnoid membrane and outside the pia mater. The pia mater was disrupted and finger-like invasions were found in the neural layer of the third ventricle floor along the invasive front. Tumors were never observed to break through the ependymal layer of the third ventricle. The QST classification has important implications for understanding the growth pattern of tumors and can be used to guide surgical procedures.

Purpose Epirubicin is one of the most effective drugs against osteosarcoma. miR-1301 is involved in the occurrence and development of osteosarcoma. Whether miR-1301 is responsible for the chemosensitivity of osteosarcoma cells to epirubicin remains largely unknown. Materials and Methods U2OS and SAOS-2 cells were treated with various concentrations of epirubicin. Flow cytometry was employed to evaluate cell apoptotic rate. Cell proliferation was measured by Cell Counting Kit-8 assay. Western blot and quantitative real-time polymerase chain reaction were utilized to detect the expressions of B-cell lymphoma-2 (Bcl-2), Bcl-2 assaciated X protein (Bax), cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerases (PARP1), TP53-regulated inhibitor of apoptosis 1 (TRIAP1), and microRNA-1301 (miR-1301). The relationship between miR-1301 and TRIAP1 was determined by luciferase reporter assay. Results Epirubicin inhibited proliferation in a dose-dependent manner, induced apoptosis, decreased the expression of Bcl-2, and increased the expressions of Bax, cleaved-caspase-3, and cleaved-PARP1 in osteosarcoma cells. miR-1301 was downregulated in U2OS and SAOS-2 cells. Importantly, epirubicin significantly increased the levels of miR-1301. Overexpression of miR-1301 suppressed proliferation and promoted apoptosis. Interestingly, those effects were enhanced by epirubicin. In contrast, miR-1301 depletion attenuated the epirubicin-mediated anti-osteosarcoma effect. miR-1301 negatively regulated the expression of TRIAP1 in U2OS and SAOS-2 cells. Furthermore, epirubicin inhibited the mRNA and protein levels of TRIAP1 by upregulating miR-1301 levels. Epirubicin suppressed cell proliferation by downregulating TRIAP1. Conclusion miR-1301 was implicated in the chemosensitivity of osteosarcoma to epirubicin by modulating TRIAP1.

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