The MR features described in this study are useful for distinguishing malignant peripheral nerve sheath tumors from neurofibromas. If a tumor has two or more of the four statistically significant features, it can be considered to be highly suspicious of malignancy and should be subjected to a biopsy for early diagnosis.

Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Previous studies demonstrated that inhibition of HA suppressed the tumorigenicity of various malignant tumors including breast cancer. 4-methylumbelliferone (MU) has been reported to inhibit HA synthesis in several cell types. However, few studies have focused on the effects of HA inhibition in breast cancer cells by MU, nor the effects on bone metastasis. We hypothesized that MU would suppress the progression of bone metastasis via inhibition of HA synthesis. Here, we investigated the effects of MU on HA expression in MDA-MB-231 breast cancer cell line in addition to their tumorigenicity in vitro and in vivo. HAS2 mRNA expression was downregulated after 6 and 24 hr treatment with MU. Quantitative analysis of HA revealed that MU significantly inhibited the intracellular and cell surface HA. MU significantly inhibited cell growth and induced apoptosis as determined by cell proliferation and TUNEL assays, respectively. Phosphorylation of Akt was suppressed after 12 and 24 hr treatment with MU. MU treatment also inhibited cell motility as well as cell invasiveness. MU also inhibited cell growth and motility in murine fibroblast cell line NIH3T3. In vivo, administration of MU inhibited the expansion of osteolytic lesions on soft X-rays in mouse breast cancer xenograft models. HA accumulation in bone metastatic lesions was perturbed peripherally. These data suggest that MU might be a therapeutic candidate for bone metastasis of breast cancer via suppression of HA synthesis and accumulation.Breast cancer is the most common cancer in women particularly in western countries. 1,2 Approximately 6% of breast cancer patients present to hospital with distant metastasis 2 and about 25% despite neoadjuvant or adjuvant systemic treatment develop distant metastasis. 3 In a retrospective study of patients with metastatic breast cancer, bone was the most common site of metastatic spread and 70% of these patients developed metastases in one or more bones before they died. 4 Bone metastases occasionally result in hypercalcemia, pathologic fractures and spinal cord compression, 5 and substantially reduce patients' quality of life. 6 Hyaluronan (HA) is a high molecular weight linear glycosaminoglycan, the structure of which is composed of repeating disaccharides of D-glucuronic acid and N-acetyl-Dglucosamine. HA is a ubiquitous extracellular and cell surface associated matrix component of connective, epithelial and neural tissues. 7 HA is abundant in surrounding migrating and proliferating cells during morphogenesis and wound healing. 8,9 Increased HA levels are also observed, both in stroma of malignant areas and in a part of tumor parenchyma in some malignant tumors including colorectal, ovarian and breast cancer and liposarcoma. [10][11][12][13][14] Not only the HA accumulation level in the stroma of malignancy 11,15,16 but also the HA level in tumor parenchyma 10,13 has been reported to associate with a poor clinical outcome. In in vitr...

Background:Hyaluronan (HA) plays crucial roles in the tumourigenicity of many types of malignant tumours. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis. Several studies have shown its inhibitory effects on malignant tumours; however, none have focused on its effects on osteosarcoma.Methods:We investigated the effects of MU on HA accumulation and tumourigenicity of highly metastatic murine osteosarcoma cells (LM8) that have HA-rich cell-associated matrix, and human osteosarcoma cell lines (MG-63 and HOS).Results:In vitro, MU inhibited HA retention, thereby reducing the formation of functional cell-associated matrices, and also inhibited cell proliferation, migration, and invasion. Akt phosphorylation was suppressed by MU (1.0 m). In vivo, although MU showed only a mild inhibitory effect on the growth of the primary tumour, it markedly inhibited (75% reduction) the development of lung metastasis. Hyaluronan retention in the periphery of the primary tumour was markedly suppressed by MU.Conclusion:These findings suggested that MU suppressed HA retention and cell-associated matrix formation in osteosarcoma cells, resulting in a reduction of tumourigenicity, including lung metastasis. 4-Methylumbelliferone is a promising therapeutic agent targeting both primary tumours and distant metastasis of osteosarcoma, possibly via suppression of HA retention.

The data suggest an adequate additional wide excision may improve the local control and survival in patients with an unplanned excision as well as the patients with a planned excision. While patients with unplanned excisions had superficial and smaller tumors, survival and postoperative function were similar to those with planned excisions.

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