Efficacy of denosumab treatment for lung metastasis secondary to proximal humerus chondroblastoma.

Chondroblastoma is a rare benign cartilaginous tumor that accounts for approximately 1% of bone tumors, but it can be associated with lung metastasis in extremely rare cases, leading to a poor prognosis and death. Herein, we report the case of a 19-year-old male patient who presented with an aggressive chondroblastoma of the proximal humerus and bilateral lung metastasis. The patient was treated with wide local resection, partial metastasectomy, and denosumab. Denosumab treatment was effective in controlling metastatic progression and preventing local recurrence.

Treatment of Chondroblastoma with Denosumab: A Case Report with a Correlative Analysis of Effect on the RANK Signaling Pathway.

CASE: A 15-year-old boy with chondroblastoma of the right hemipelvis presented with significant periacetabular bone destruction. Neoadjuvant denosumab treatment facilitated initial joint preserving surgery. Unfortunately, he experienced 2 local recurrences and underwent wide surgical resection 2 years after his initial diagnosis. CONCLUSION: Inhibition of the receptor activator of NF-κB (RANK)/RANK ligand (RANK-L) pathway with denosumab has been used neoadjuvantly for the treatment of giant cell tumor of bone, but its role in the treatment of chondroblastoma is less understood. This patient's clinical response and effect on cellular RANK/RANK-L activity support the consideration of denosumab in the treatment algorithm for other osteolytic bone tumors such as chondroblastoma.

Chondroblastoma Expresses RANKL by RNA In Situ Hybridization and May Respond to Denosumab Therapy.

Lesions of bone featuring osteoclast-like giant cells comprise a diverse group of entities, including giant cell tumor (GCT) of bone, chondroblastoma, and aneurysmal bone cyst, among others. The receptor activator of nuclear factor-κB ligand (RANKL) has been implicated in the pathogenesis of GCT of bone and may play a role in the pathogenesis of other giant cell-rich lesions as well. In addition, RANKL inhibitors (denosumab) have also been shown to have some efficacy in treating some giant cell-rich lesions. Herein, we examine RANKL expression by RNA in situ hybridization in a total of 84 osseous lesions with a focus on chondroblastoma, GCT, fibrous dysplasia, and aneurysmal bone cyst. The lesions were tested for RANKL expression using a chromogenic RNA in situ hybridization assay. RANKL expression was identified in 24/25 (96%) GCT, 24/26 (92%) chondroblastomas, 6/7 (86%) aneurysmal bone cysts, and 3/16 (19%) patients with fibrous dysplasia. RANKL expression was statistically lower in chondroblastoma and aneurysmal bone cyst compared with GCT. RANKL reactivity in fibrous dysplasia was exclusively seen in the 3 cases with osteoclast-type giant cells. Our results indicate a high proportion of chondroblastomas, GCTs, and aneurysmal bone cysts express RANKL while reactivity in fibrous dysplasia is dependent on the presence of osteoclast-type giant cells. On the basis of the success of denosumab therapy for GCTs, our results indicate that it may be a potential therapeutic option in other primary osseous tumors.

Inhibition of mTOR and HIF pathways diminishes chondro-osteogenesis and cell proliferation in chondroblastoma.

Chondroblastoma (CBL) is a benign bone tumor occurring mostly in teenagers. Despite this, CBL can recur and metastasize after curettage, which may impede normal epiphysis. In search of a novel targeted therapy for CBL, we aimed at BMP-2, a factor critical for chondro-osteogenesis and chondrocyte proliferation. Two pathways upstream of BMP-2, the mTOR and HIF, were targeted with rapamycin (Rapa) and FM19G11 (FM), respectively. Using immunohistochemistry, we found BMP-2 was highly expressed in CBL tissues. CBL cells explanted and confirmed with higher BMP-2 level than normal cartilage. Protumorigenic effect of Rapa and FM on CBL cells were transduced via BMP-2. Combination of Rapa and FM conferred stronger inhibition of cell proliferation than either monotherapy and inhibited levels of chondro-osteogenic markers (Sox9, aggrecan, and type II collagen). To minimize the adverse effect of Rapa, we performed screening in essential amino acids and found leucine deprivation-sensitized CBL cells to Rapa. Combination treatment of low dose Rapa, FM, and leucine deprivation conferred compatible inhibitory effects on CBL cell proliferation, chondro-osteogenic potential, and tumorigenic capacity. We conclude that targeting BMP-2 using mTOR/HIF inhibition could potently curb the disease. Addition of low-leucine diet could lower the dose of rapamycin in chase for less toxicity.

Extraskeletal osteosarcoma of the breast in an adolescent girl.

Extraskeletal osteosarcoma (ESOS) is a rare malignancy, usually arising in older adults. We were unable to find reports of children or adolescents affected by an ESOS of the breast. Here, we present the case of a high-grade osteosarcoma arising in the breast of a 16-year-old girl. The tumor was treated with breast-conserving resections and adjuvant multiagent chemotherapy, based on a regimen of doxorubicin, high-dose methotrexate, cisplatin, and ifosfamide. At last follow-up, the patient was in first complete remission, 29 months after initial diagnosis.

Osteogenic progenitor cell potency after high-dose chemotherapy (COSS-96).

BACKGROUND: Since the first trial of chemotherapy in patients with osteosarcoma the survival rate has gradually improved. For more than two decades, most osteosarcoma patients from Germany, Austria and Switzerland have been treated according to the protocols of the Cooperative Osteosarcoma Study Group (COSS). The uniform treatment concept of a high-dose polychemotherapy pre- and postoperatively improved the survival rate of these patients significantly. One severe side-effect of COSS chemotherapy is multiple osteonecrosis. PATIENTS AND METHODS: In this study the osteogenic stem cell potency of three different tissue types was elucidated after COSS-96 chemotherapy (high-risk arm). Mononuclear cells were obtained from the periosteum, cartilage and bone marrow of a 17-year-old female with a chondroblastic osteosarcoma. The cells were cultivated for 4 weeks in standard medium and stimulated for osteogenic differentiation after the second passage with dexamethasone, glycerolphosphate and ascorbine acid. Two weeks later, the cell cultures were analysed with respect to cell morphology and immunochemical stainings. RESULTS: All cells cultures showed an osteoblastic regeneration potential measured by osteocalcin (OC), osteopontin (OP) and alkaline phosphatase (ALP) expression. Compared to other donor tissues and localizations, the fibula periosteum showed significantly higher osteoblast rates in vitro, whereas collagen II, CD34 and CD45 were not expressed in any culture. CONCLUSION: The results of this study demonstrate the survival of mesenchymal progenitor cells in bone marrow during COSS-96 polychemotherapy, which allows for an osteogenic regeneration in vitro and potentially in vivo.

Expression of P-glycoprotein in high grade osteosarcomas with special emphasis on chondroblastic subtype.

The development of chemoresistance is one of the major clinical problems in the therapy of malignant bone tumors in childhood. The expression of membrane-bound P-glycoprotein turned out to be an essential factor in the evidence of resistant tumor cells. To investigate the significance of multidrug resistance in the prognosis of highly malignant osteosarcomas, the immunohistologic expression of P-glycoprotein was investigated in the tumor tissue of 52 patients under special consideration of the histologic subtype. The data were compared with the histologic regression grade in the resection specimen and correlated with clinical data. Formalin-fixed, paraffin-embedded tissue and, additionally, fresh frozen material taken from the primary biopsy were stained using monoclonal antibody JSB1. 29 (55%) of the tumors investigated were P-glycoprotein positive. Considering the response to chemotherapy, no conclusion could be drawn regarding P-glycoprotein expression, regression grade in the resection specimens, and the clinical follow-up. P-glycoprotein was detected in only 52% of the non-responders. A positive reaction was also evidenced in 59% of the patients with high chemosensitivity. A comparison of the histologic subtypes yielded a significant result in the chondroblastic osteosarcomas. 11 of 12 cases showed a strong expression of P-glycoprotein. Most of the cases were non-responders, and using Kaplan-Meier live tables, an unfavorable clinical outcome could be demonstrated. Possibly, chondroblastic tumors have a special position among osteosarcomas because of their differentiation.

Final results obtained in the treatment of bone cysts with methylprednisolone acetate (depo-medrol) and a discussion of results achieved in other bone lesions.

Extremely favorable results are obtained with the use of microcrystals of methylprednisolone acetate for treatment of bone cysts. These results have led to a complete suspension of surgical treatment of bone cysts since 1974. On the basis of these results with corticosteroids, a surgical procedure that involves an incision at the fracture location and bone graft inserted is not indicated. Results following surgery indicate a recurrence rate of approximately 25% to 30%. Since we are as yet unable to explain the mechanism by which the local injection of MPA promotes bone replacement of the cyst, the present observations only reaffirm the hypothesis (presented in our early publications) that the corticosteroid exerts a destructive action on the pathological tissue of the lesion, thus favoring a progressive process of repair. We consider this explanation valid even for lesions, e.g., eosinophilic granulomas and nonossifying fibromas, in which this method of treatment has had varying degrees of success.