Clinical value of serum bone resorption markers for predicting clinical outcomes after use of bone modifying agents in metastatic bone tumors: A prospective cohort study.

Bone modifying agents (BMAs) have become a standard treatment to prevent skeletal-related events (SREs) in bone metastases (BMs). The aim of our study is to determine the clinical value of serum bone resorption markers for predicting clinical outcomes after using BMAs in patients with BM. Patients were enrolled between May 2013 and October 2017 at the Nagoya University Hospital, Japan. We prospectively observed changes in pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) during treatment with BMAs. The relationship between serum markers before and after treatment and clinical outcomes such as progression of bone disease (BD), SREs and overall survival (OS) were evaluated. Pearson chi-square test and Kaplan-Meier product limit methods were used for analysis. Sixty-seven patients were analyzed. The primary tumor sites were 21 lung, 16 breast and 30 others. Forty and 27 patients were treated with Denosumab and Zoledronic acid, respectively. Progression of BDs, SREs and death were observed in 10, 16 and 31 cases, respectively. The median follow-up period after using BMAs was 12.3 (range 0.3-66.3) months. ICTP at 3-4 weeks was significantly correlated with increasing BD progression, SREs and death after treatment in both the whole and lung cancer cohorts. Base line ICTP and TRACP-5b were also associated with increasing BD progression in the whole cohort. Our study showed that early posttreatment ICTP is useful for predicting BD progression, SREs and OS after use of BMAs in patients with BM and even in patients with lung cancer BM.

Predictors of complications in heat-treated autograft reconstruction after intercalary resection for malignant musculoskeletal tumors of the extremity.

BACKGROUND: Biological reconstruction with recycled heat-treated autografts has been an option for a segmental skeletal defect after intercalary resection for malignant musculoskeletal tumors in the extremity. This study was undertaken to evaluate the clinical outcomes in patients treated with this procedure and identify factors affecting the incidence of complications. METHODS: We retrospectively reviewed 24 patients treated with heat-treated autografts after intercalary resection at our institution between 1992 and 2015. RESULTS: The survival rate of the heat-treated autografts was 70.1% at 10 years. Of the 48 host-graft junctions in the 24 patients, nonunion occurred in 18 junctions (38%). In the univariate analysis, location in the upper extremity, intercalary grafts without vascularized fibula autografts (VFG), and junction at the diaphysis significantly increased the rate of nonunion (P = 0.003, P = 0.003, and P = 0.031, respectively). Location in the upper extremity was an independent factor associated with nonunion in the multivariate analysis (P = 0.006). Upper extremity location and intercalary grafts without VFG were also significant factors for bone absorption (P = 0.042 and P < 0.001, respectively). CONCLUSIONS: Our results can provide useful information to devise possibly novel clinical approaches to patients requiring intercalary reconstruction of the extremity.

Single metastasis of myxoid liposarcoma from the thigh to thyroid gland: a case report.

BACKGROUND: Thyroid metastasis of soft tissue sarcoma is very rare, and the diagnosis is especially difficult when only a single lesion is present. CASE PRESENTATION: A 50-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two and a half years after the surgery, a growing low-density area was incidentally observed in the right lobe of his thyroid gland on follow-up chest computed tomography. Fine needle aspiration biopsy was performed twice, and the thyroid mass was suspected of being a sarcoma metastasis. He was treated by hemithyroidectomy, and the lesion was pathologically confirmed as a metastasis of myxoid liposarcoma. CONCLUSION: We experienced single thyroid gland metastasis in patients with myxoid liposarcoma in whom a growing mass is observed in the thyroid gland after radical surgery of the primary site.

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium.

Accumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging and retinal disorders such as Stargardt disease and age-related macular degeneration. These aberrant fluorescent condensation products, including di-retinoid-pyridinium-ethanolamine (A2E), are thought to be transferred to RPE cells primarily through phagocytosis of the photoreceptor outer segments. However, we observed by two-photon microscopy that mouse retinas incapable of phagocytosis due to a deficiency of the c-Mer proto-oncogene tyrosine kinase (Mertk) nonetheless contained fluorescent retinoid condensation material in their RPE. Primary RPE cells from Mertk-/- mice also accumulated fluorescent products in vitro Finally, quantification of A2E demonstrated the acquisition of retinal condensation products in Mertk-/- mouse RPE prior to retinal degeneration. In these mice, we identified activated microglial cells that likely were recruited to transport A2E-like condensation products to the RPE and dispose of the dying photoreceptor cells. These observations demonstrate a novel transport mechanism between photoreceptor cells and RPE that does not involve canonical Mertk-dependent phagocytosis.

New Treatments for Stargardt Disease and Related Retinal Degenerative Diseases.

Stargardt disease is a progressive hereditary retinal disease which is currently incurable. Although ABCA4 has been identified as a major causative gene, patients with genetic mutations in other genes (PRPH2, ELOVL4, and PROM1) display similar clinical phenotypes as Stargardt disease. Recent advances in genetic and molecular studies have greatly enhanced our understanding of the disease and have led to identification of targetable pathophysiological progresses and new molecular clinical applications. Here we summarize the current understanding of the pathophysiology and potential therapies for Stargardt disease and other related retinal degenerative diseases.

Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium.

Autophagy is an evolutionarily conserved catabolic mechanism that relieves cellular stress by removing/recycling damaged organelles and debris through the action of lysosomes. Compromised autophagy has been implicated in many neurodegenerative diseases, including retinal degeneration. Here we examined retinal phenotypes resulting from RPE-specific deletion of the autophagy regulatory gene Atg7 by generating Atg7(flox/flox);VMD2-rtTA-cre+ mice to determine whether autophagy is essential for RPE functions including retinoid recycling. Atg7-deficient RPE displayed abnormal morphology with increased RPE thickness, cellular debris and vacuole formation indicating that autophagy is important in maintaining RPE homeostasis. In contrast, 11-cis-retinal content, ERGs and retinal histology were normal in mice with Atg7-deficient RPE in both fasted and fed states. Because A2E accumulation in the RPE is associated with pathogenesis of both Stargardt disease and age-related macular degeneration (AMD) in humans, deletion of Abca4 was introduced into Atg7(flox/flox);VMD2-rtTA-cre+ mice to investigate the role of autophagy during A2E accumulation. Comparable A2E concentrations were detected in the eyes of 6-month-old mice with and without Atg7 from both Abca4(-/-) and Abca4(+/+) backgrounds. To identify other autophagy-related molecules involved in A2E accumulation, we performed gene expression array analysis on A2E-treated human RPE cells and found up-regulation of four autophagy related genes; DRAM1, NPC1, CASP3, and EIF2AK3/PERK. These observations indicate that Atg7-mediated autophagy is dispensable for retinoid recycling and A2E deposition; however, autophagy plays a role in coping with stress caused by A2E accumulation.

Inhibition of hyaluronan synthesis alters sulfated glycosaminoglycans deposition during chondrogenic differentiation in ATDC5 cells.

In chondrogenic differentiation, expression and collaboration of specific molecules, such as aggrecan and type II collagen, in extracellular matrix (ECM) are crucial. However, few studies have clarified the roles of hyaluronan (HA) in proteoglycan aggregation during chondrogenic differentiation. We assessed the roles of HA in sulfated glycosaminoglycans deposition during chondrogenic differentiation by means of 4-methylumbelliferone (4-MU), an HA synthase inhibitor, using ATDC5 cells. ATDC5 cells were treated with 0.5 mM 4-MU for 7 or 21 days after induction of chondrogenic differentiation with insulin. Depositions of sulfated glycosaminoglycans were evaluated with Alcian blue staining. mRNA expression of ECM molecules was determined using real-time RT-PCR. The deposition of aggrecan and versican was investigated with immunohistochemical staining using specific antibodies. Effects of 4-MU on HA concentrations were analyzed by HA binding assay. 4-MU suppressed the positivity of Alcian blue staining, although this delay was reversible. Interestingly, stronger positivity of Alcian blue staining was observed at day 21 in cultures with 4-MU discontinuation than in the control. 4-MU significantly increased the mRNA expression of aggrecan, versican, and type II collagen, which was consistent with increased deposition of aggrecan and versican. The HA concentration in ECM and cell-associated region was significantly suppressed with 4-MU treatment. We conclude that the inhibition of HA synthesis slows sulfated glycosaminoglycans deposition during chondrogenic differentiation despite the increased deposition of other ECM molecules. Transient starvation of HA with 4-MU accelerates chondrogenic ECM formation, suggesting its potential to stimulate chondrogenic differentiation with adequate use.

Ablation of Kcnj10 expression in retinal explants revealed pivotal roles for Kcnj10 in the proliferation and development of Müller glia.

PURPOSE: We previously found that Kcnj10, an inwardly-rectifying potassium channel, is a gene expressed in c-kit-positive retinal progenitor cells on P1. The shRNA-mediated screening of the functions of the genes for retinal development in retinal explant culture suggested a role for Kcnj10 in the differentiation of 23Müller glia. In the present study, we extended the work and focused on analyzing the role of Kcnj10 in retinal development. METHODS: shRNA-mediated downregulation of Kcnj10 in retinal explants and the in vivo mouse retina at the P1 stage was performed. Differentiation and proliferation of the retina were examined with immunohistochemistry. The effect of barium (Ba(2+)) treatment, which inhibits potassium currents by blocking potassium channels, on retinal development was examined. RESULTS: When Kcnj10 was downregulated at E18, cellular proliferation and morphological differentiation were perturbed; in particular, a decreased number of Müller glial cells with abnormal morphological maturation was observed. The overexpression of Kcnj10 in retinal progenitors did not result in gross abnormality during retinal development, but rescued the abnormal differentiation induced with sh-Kcnj10. The presence of Ba(2+) in the retinal explant medium led to a phenotype similar to that seen with sh-Kcnj10. Ba(2+) exerts an effect mainly during late retinal development, and sh-Kcnj10 in the P1 retina affected Müller glia maturation, suggesting that Kcnj10 plays a pivotal role in the maturation of retinal cell subsets. A previous study of Kcnj10-knockout mice showed no obvious abnormality in retinal differentiation, especially of Müller glia. We examined the effects of the downregulation of Kcnj10 with in vivo electroporation of sh-Kcnj10 in the P1 retina. Retinal differentiation was perturbed, as seen following the in vitro downregulation of Kcnj10, suggesting that compensatory gene expression and/or signaling occurred in the Kcnj10-knockout mice in the retina, leading to normal eye development. CONCLUSION: Kcnj10 plays a role in Müller glia maturation during retinal development probably through ionic channel activities.

Residual tumor after unplanned excision reflects clinical aggressiveness for soft tissue sarcomas.

The aims of this study are to investigate clinical and pathological factors associated with the existence of residual tumor in reexcised specimens (RTRS) following unplanned excisions for soft tissue sarcomas and to determine whether RTRS has an impact on the oncologic outcome. A total of 113 patients with soft tissue sarcoma who received unplanned excision at the prereferral hospital were treated with additional reexcision at our institutions from 1986 to 2010. Clinical and pathological variables were analyzed as possible factors correlated with the existence of RTRS. These factors in addition to surgical margin in reexcisions were analyzed as factors possibly correlated with the oncological outcome. RTRS was observed in 58 cases (51 %). Histological subtype tended to associate with the presence of RTRS (P = 0.063), particularly in patients with dermatofibrosarcoma protuberances (DFSP) (83 %) and myxofibrosarcoma (100 %), whereas the other factors did not. Five-year local recurrence-free, metastasis-free, and overall survival (LRFS, MFS, and OS) were 93, 96, and 97 %, respectively. Patients with RTRS tended to have lower LRFS (89 %) than those without (97 %, P = 0.067) and had significantly lower MFS (92 %) than those without (100 %, P = 0.043). Other factors had no impact on prognosis. Patients receiving unplanned excision particularly for myxofibrosarcoma and DFSP require reexcision with an adequate surgical margin. Although patients with unplanned excision have a favorable clinical outcome following additional wide reexcision, those with RTRS require careful follow-up.

Suppression of hyaluronan synthesis alleviates inflammatory responses in murine arthritis and in human rheumatoid synovial fibroblasts.

OBJECTIVE: To clarify the roles of hyaluronan (HA) in joint inflammation and the process of joint destruction, using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, in a mouse model of collagen-induced arthritis (CIA) and in a monolayer culture of fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis. METHODS: DAB/1J mice were immunized with type II collagen. The effects of 4-MU were evaluated by the physiologic arthritis score, paw swelling, the histologic arthritis score, and expression of matrix metalloproteinase 3 (MMP-3) and MMP-13 in chondrocytes and synovial tissue. In vitro, the effect of 4-MU on messenger RNA and protein expression of MMP-1 and MMP-3 was determined. The effects of 4-MU on HA deposition and on serum/medium concentrations of HA were analyzed using biotinylated HA binding protein staining and an HA binding assay, respectively. RESULTS: Treatment with 4-MU in mice with CIA dramatically decreased the severity of arthritis (based on the arthritis score), paw thickness, and histopathologic changes. MMP-3 and MMP-13 expression in chondrocytes and synovial cells was significantly inhibited by 4-MU in vivo. Treatment with 4-MU also inhibited MMP-1 and MMP-3 expression in tumor necrosis factor α-stimulated FLS, in a dose-dependent manner. The 4-MU-induced decreases in the serum HA concentration in mice with CIA and in "medium" and "pericellular" HA concentrations in cultured FLS support the contention that the inhibitory mechanism of 4-MU is mediated by HA suppression. CONCLUSION: Reduced disease activity induced by 4-MU in mice with CIA revealed HA to be a crucial regulator in the course of arthritis. Therefore, 4-MU is a potential therapeutic agent in arthritis, and its inhibitory mechanism is possibly mediated by suppression of HA synthesis.

Lower leg compartment syndrome in neurofibromatosis 1 patient with plexiform neurofibrom: a case report of aneurysm rupture.

A 37-year-old woman with neurofibromatosis type 1 was referred for a rapidly growing plexiform neurofibroma of the left lower leg, acute serious pain, and leg palsy because of concern for malignant transformation of the tumor. Contrast-enhanced computed tomography confirmed a rupture of anterior tibial artery aneurysm, resulting in both anterior and posterior compartment syndrome in her left leg. Arterial involvement in neurofibromatosis is a well known; however, rupture of peripheral arteries is exceptional. Moreover, coexistence with plexiform neurofibroma occasionally delays the diagnosis with suspicion of malignant transformation without awareness of a vascular rupture.

Multiple primary malignancies in elderly patients with high-grade soft tissue sarcoma.

BACKGROUND: Several previous reports have described multiple cancers with regard to epithelial tumors, but few reports have focused on multiple primary malignancies including soft tissue sarcomas (STS). METHODS: The purpose of this study was to analyze the clinical features of patients with high-grade STS with multiple malignancies and possible clinical problems, compared with those with STS as a single malignancy, focusing on elderly patients. This study enrolled 107 patients aged 65 years or over with high-grade STS. RESULTS: Eighty-four patients (79 %) had sarcomas only (S group), and 23 (21 %) had multiple primary malignancies (M group). STS preceded carcinoma in 10 patients, and carcinoma preceded STS in 13. In 7 patients (30 %), the interval between the first and second malignancy was less than a year. Of 7 patients who received treatment for sarcoma and carcinoma at the same time, the presence of other malignancies had an impact on determination of the treatment modality in 5 patients. The overall survival rate at 5 years was higher in M group (79 %) than in S group (69 %), although this difference was not significant (P = 0.095). CONCLUSIONS: This study demonstrates that the presence of multiple malignancies was not correlated with a poor prognosis, and was actually associated with a better prognosis in elderly patients with STS. Physicians should be aware of the possible occurrence of a second malignancy, and on occasion the treatment modalities and their logistical aspects need to be well organized and carefully selected for patients with ongoing multiple malignancies.

Clinical factors affecting pathological fracture and healing of unicameral bone cysts.

BACKGROUND: Unicameral bone cyst (UBC) is the most common benign lytic bone lesion seen in children. The aim of this study is to investigate clinical factors affecting pathological fracture and healing of UBC. METHODS: We retrospectively reviewed 155 UBC patients who consulted Nagoya musculoskeletal oncology group hospitals in Japan. Sixty of the 155 patients had pathological fracture at presentation. Of 141 patients with follow-up periods exceeding 6 months, 77 were followed conservatively and 64 treated by surgery. RESULTS: The fracture risk was significantly higher in the humerus than other bones. In multivariate analysis, ballooning of bone, cyst in long bone, male sex, thin cortical thickness and multilocular cyst were significant adverse prognostic factors for pathological fractures at presentation. The healing rates were 30% and 83% with observation and surgery, respectively. Multivariate analysis revealed that fracture at presentation and history of biopsy were good prognostic factors for healing of UBC in patients under observation. CONCLUSION: The present results suggest that mechanical disruption of UBC such as fracture and biopsy promotes healing, and thus watchful waiting is indicated in these patients, whereas patients with poor prognostic factors for fractures should be considered for surgery.

Osteoarthritic change is delayed in a Ctsk-knockout mouse model of osteoarthritis.

OBJECTIVE: Several studies have shown that cathepsin K (CTK) is overexpressed in osteoarthritic (OA) cartilage and subchondral bone. However, it has not been well established whether CTK expression is harmful or beneficial. We undertook this study to investigate the direct involvement of CTK in OA development using Ctsk-knockout (Ctsk(-/-)) mice in a joint instability-induced model of OA. METHODS: We analyzed the natural course of the phenotype of 25-week-old Ctsk(-/-) mice. OA development was evaluated with a modified Mankin histologic score up to 8 weeks after surgery was performed to destabilize the knee in Ctsk(-/-) and Ctsk(+/+) mice. Histologic analysis was used to evaluate expression of CTK, matrix metalloproteinase 13 (MMP-13), ADAMTS-5, and tartrate-resistant acid phosphatase (TRAP) proteins in chondrocytes, synovial cells, and osteoclasts. Bone architecture was analyzed by histomorphometry. RESULTS: Bone mineral content and bone volume were higher in Ctsk(-/-) mice at 25 weeks, whereas OA did not develop spontaneously in either Ctsk(-/-) or Ctsk(+/+) mice. In a model of destabilization-induced OA, OA progression was significantly delayed in Ctsk(-/-) mice. CTK was overexpressed in chondrocytes and synovial cells of knee joints developing OA in Ctsk(+/+) mice. MMP-13 and ADAMTS-5 were less strongly expressed in chondrocytes of Ctsk(-/-) mice, and MMP-13 was less strongly expressed in synovial cells. TRAP-positive osteoclasts were overexpressed in Ctsk(-/-) mice. CONCLUSION: These results indicate that CTK plays crucial direct roles in the early to intermediate stage of OA development. CTK-positive chondrocytes and synovial cells may be a possible target to prevent disease progression in OA.

Metastasis of osteosarcoma to stomach made clinically evident by hematemesis: a case report.

BACKGROUND: Gastric metastasis from osteosarcoma is very rare and its clinical features are not well recognized. CASE PRESENTATION: A 73-year-old man was diagnosed with osteosarcoma and treated with four cycles of preoperative chemotherapy with ifosfamide and doxorubicin followed by wide resection. Two cycles of postoperative chemotherapy with ifosfamide and doxorubicin and ten cycles of chemotherapy with carboplatin and etoposide were administered. Eleven months after the surgery, he vomited fresh blood. Unusual progression of anemia was observed with the hematemesis. A biopsy was performed by gastrointestinal endoscopy, and the stomach tumor was diagnosed as metastasis of osteosarcoma. CONCLUSIONS: Even though gastric metastasis from osteosarcoma is very rare, all three previous reports and our case showed the presence of ulcer on the surface of the gastric lesion. We should consider the possibility of gastric metastasis in patients with osteosarcoma in whom progression of anemia or gastric hemorrhage is observed.

Planned preservation surgery for soft tissue sarcomas adjacent to critical structures.

BACKGROUND: Whether to preserve or sacrifice critical structures (bone, major vessels and major nerves) adjacent to soft tissue sarcomas is still controversial. Referring to characteristic imaging and intraoperative findings, we perform planned preservation surgery for these critical structures. The aim of this study was to investigate the clinical outcome of soft tissue sarcomas adjacent to critical structures and to validate this procedure. METHODS: Of 202 cases of soft tissue sarcomas surgically treated at our department of orthopedic surgery from 2004 to 2010, 57 cases (28 %) whose tumors were adjacent to the critical structures were studied. There were 36 men and 21 women. In 32 cases critical structures were preserved, and in 25 resected together with the tumor. The oncological outcome and histological surgical margin were analyzed. RESULTS: The overall survival and local recurrence-free survival rates at 5 years were 75.9 and 83.2 %. In 26 of the 32 (81 %) preserved cases histologically the surgical margin was negative, and in 17 (53 %) radiotherapy could be avoided. Neither overall survival (p = 0.9669) nor local recurrence-free survival (p = 0.7819) differed significantly between two groups. CONCLUSIONS: When soft tissue sarcomas are located adjacent to bone or major vessels, by meticulously detaching the periosteum or neurovascular sheath referring to characteristic imaging and intraoperative findings, a histologically negative surgical margin can be achieved in the majority, allowing avoidance of postoperative radiotherapy. Planned preservation surgery provided no significant adverse effect on survival or local recurrence rates, validating this procedure.

Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo.

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.

Versican V1 isoform regulates cell-associated matrix formation and cell behavior differentially from aggrecan in Swarm rat chondrosarcoma cells.

Versican, a large chondroitin sulfate proteoglycan that binds hyaluronan and is composed of large extracellular matrix aggregates, has been shown to correlate with tumor progression. No studies have examined the roles of versican in chondrosarcoma nor compared them to those of aggrecan. In clinical specimens of human chondromatous tumors, versican expression was significantly increased in malignant tumors, moreover, as the tumor grade increased. To clarify the roles of versican in chondrosarcoma, versican splicing variant 1, variant 3 or only GFP was stably transfected to Swarm rat chondrosarcoma cells with Trap-In System. Forced expression of versican V1 isoform in Swarm rat chondrosarcoma cells induced a marked increase of cell-associated matrix compared to V3-, GFP- transfected or RCS cells. Versican was immunolocalized in a fashion similar to that of hyaluronan and more diffusively than aggrecan. Anchor-dependent and -independent growth was not affected by versican isoform expression, whereas cell motility and migration were significantly enhanced by V1 isoform transfection. Tumors formed in vivo with V1-transfected cells exhibited more myxomatous area and included more spindle shaped cells. These results support the concept that versican has the capacity to form more extensive cell-associated matrix than aggrecan, and the prominent matrix formation alters the cell behavior of chondrosarcoma more aggressively. These observations suggest that versican expression may serve as a marker of tumor grade determination in chondrosarcoma and possibly help to decide on therapeutic targets in higher grades of chondrosarcoma.