Wenxi Yu

Analysis of prognostic factors in 333 Chinese patients with high-grade osteosarcoma treated by multidisciplinary combined therapy

To investigate prognostic factors for long‐term outcomes in Chinese patients with high‐grade osteosarcoma of the extremities or trunk treated by multidisciplinary combined therapy.

Stereotactic radiosurgery, a potential alternative treatment for pulmonary metastases from osteosarcoma

Stereotactic radiosurgery (SRS), such as body gamma knife, was reported to achieve excellent rates of local disease control with limited toxicity in many cases of primary or secondary pulmonary tumor, except osteosarcoma. To confirm the value of SRS in pulmonary metastases from osteosarcoma, we reviewed the experience from our institution (Department of Oncology, Affiliated Sixth People’s Hospital, Shanghai) and compared the efficiency of SRS with that of surgical resection. From January 2005 to December 2012, we carried out a retrospective investigation of 58 patients (age, 8–59 years; mean, 25.2 years) who were diagnosed with non-metastatic osteosarcoma of the extremity and later developed pulmonary metastasis during the period of adjuvant chemotherapy or follow-up. Among them, 27 patients were treated by SRS using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 31 patients were treated by surgical resection. Two-year progression-free survival rate, two-year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. All 27 patients tolerated gamma knife radiosurgery well while only 9 patients had grades 1–2 pneumonitis. We believe SRS, compared with surgical resection, is effective and safe in treating pulmonary metastasis from osteosarcoma, especially for those patients who were medically unfit for a resection or who refused surgery.

Heterogeneous expression and biological function of ubiquitin carboxy-terminal hydrolase-L1 in osteosarcoma

Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a member of the UCH class of DUBs, has been reported as either an oncogene or a tumor suppressor. However, the molecular mechanism underlying the biological function of UCHL1 in osteosarcoma is still unclear. This study was aimed at elucidating the roles of UCHL1 in regulating the biological behavior of osteosarcoma cells. In this study, we found that UCHL1 was elevated in osteosarcoma compared with normal bone tissue. Moreover, UCHL1 expression level was correlated with tumor maximum diameter, high rate of lung metastases and short survival time. Then, we found that knockdown of UCHL1 in osteosarcoma cell MG63 inhibited cell proliferation and significantly increased cell population in the G1 phase. Several cyclins promoting G1/S phase transition were reduced after UCHL1 knockdown, including cell cycle regulator cyclin D1, cyclin E1 and CDK6. Moreover, inhibition of UCHL1 in MG63 cells dramatically induced cell apoptosis. We also found that down-regulation of UCHL1 in MG63 significantly inhibited cell invasion. Then, we found that there was a positive correlation between UCHL1 expression level and the Akt and ERK phosphorylation status. Finally, in vivo data showed that knockdown of UCHL1 inhibited osteosarcoma growth in nude mice. These results indicate that UCHL1 could work as an oncogene and may serve as a promising therapeutic strategy for osteosarcoma.

Mediator of RNA polymerase II transcription subunit 19 promotes osteosarcoma growth and metastasis and associates with prognosis

Osteosarcoma (OS) is the most common primary malignant tumour of bone. Nearly 30-40% of OS patients have a poor prognosis despite multimodal treatments. Because the carcinogenesis of OS remains unclear, the identification of new oncogenes that control the tumourigenesis and progression of OS is crucial for developing new therapies. Here, we found that the expression of Mediator of RNA polymerase II transcription subunit 19 (Med19) was increased in OS samples from patients compared to normal bone tissues. Cyclin D1 and cyclin B1 are upregulated in Med19 positive OS tissues. Importantly, among 97 OS patients of Enneking stage IIB or IIIB, Med19 expression was correlated with metastasis (P<0.05) and poor prognosis (P<0.01). Med19 knockdown significantly induced growth inhibition, reduced colony-forming ability and suppressed migration in the OS cell lines Saos-2 and U2OS, along with the downregulated expression of cyclin D1 and cyclin B1. Med19 knockdown also induced apoptosis in Saos-2 cells via induction of caspase-3 and poly ADP-ribose polymerase (PARP). In addition, Med19 knockdown significantly suppressed tumour growth in an OS xenograft nude mouse model via suppression of cyclin D1 and cyclin B1. Simultaneously, Med19 downregulation decreased the expression of Ki67 and proliferating cell nuclear antigen (PCNA) in tumour samples from OS xenograft nude mice. Med19 depletion remarkably reduced tumour metastasis in a model of OS metastatic spreading. Taken together, our data suggest that Med19 acts as an oncogene in OS via a possible cyclin D1/cyclin B1 modulation pathway.

High-intensity focused ultrasound: Noninvasive treatment for local unresectable recurrence of osteosarcoma

OBJECTIVE Local unresectable recurrence of osteosarcoma is one of the most challenging tumors to treat. High-intensity focused ultrasound (HIFU) is a new, noninvasive technique with potential to ablate and inactivate tumors. Treatment of solid tumors with HIFU has been reported. In this study, we assessed safety and efficacy of HIFU in treating local unresectable recurrence of osteosarcoma. METHODS We performed a retrospective analysis of 27 patients who had local unresectable recurrence of osteosarcoma from 2006 to 2010. Changes of biochemical markers and pain rating, response rate, disease control rate, local disease progression-free survival, progression-free survival (PFS) and overall survival (OS) were used to evaluate efficacy of HIFU treatment. RESULTS HIFU resulted in a significant change in alkaline phosphatase and lactic acid dehydrogenase and a remarkably relief in pain rating, without severe side effects. According to MRI examination 4-6 weeks after HIFU treatment, 2 (7.4%) patients had complete response (CR), 12 (44.4%) had partial response (PR), 9 (33.3%) had stable disease (SD) and 4 (14.8%) had progression disease (PD). The response rate was 51.8% and the local disease control rate was 85.2%. The 1-, 2-, and 3-year local disease control rates were 59.2%, 40.7% and 33.1%, respectively. The median local disease progression-free time was 14 months, the median progression-free time was 13 months and the median over-all survival time was 21 months. Patients without pulmonary metastasis had a better local disease control rate at 1-,2-,3-year and a longer local disease progression-free time, progression-free time, over-all survival time than patients with pulmonary metastasis. CONCLUSION HIFU is a safe and noninvasive treatment for local unresectable recurrence of osteosarcoma, with good local control and without severe complications.

Comparison of pemetrexed plus cisplatin with gemcitabine plus docetaxel in refractory/metastatic osteosarcoma: Clinical outcomes from a retrospective database monitored in a single institute

The prognosis for patients with relapsed/metastatic osteosarcoma is poor and the optimal treatment strategy remains to be refined. Whilst gemcitabine plus docetaxel combination treatment has already been demonstrated to have certain promising results in the treatment of osteosarcoma, the use of pemetrexed, a multi-targeted antifolate, remains controversial. In the present study, a retrospective investigation was conducted to evaluate the toxicity and efficacy of the pemetrexed plus cisplatin combination in relapsed/metastatic osteosarcoma. Comparison of this treatment with that of the gemcitabine plus docetaxel combination was also conducted. Clinical data from 39 patients suffering from refractory/metastatic osteosarcoma between January 2005 and May 2011 were reviewed retrospectively. Of these patients, 21 were administered the gemcitabine plus docetaxel combination, and 18 were provided the pemetrexed plus cisplatin combination. Treatment was continued until the occurrence of disease progression or unacceptable toxicity. In the gemcitabine plus docetaxel group, the overall response rate and disease control rate were found to be 9.5 and 28.5% respectively, compared with 5.5 and 33.3% respectively in the pemetrexed plus cisplatin group. The median progression-free survival (PFS) time was found to be 1.8 months for both the gemcitabine plus docetaxel and pemetrexed plus cisplatin groups. The median overall survival (OS) time was 6 months in the gemcitabine plus docetaxel group and 7 months in the pemetrexed plus cisplatin group. No statistically significant differences were recognized between the overall response rates, disease control rates, PFS times and OS times in the two groups. The two combinations appeared to be well tolerated. However, the incidence of grade 3/4 thrombocytopenia and leucopenia was higher in the gemcitabine plus docetaxel group than in the pemetrexed plus cisplatin group. The present study clearly demonstrated that both chemo-combinations were well-tolerated and exerted antitumor activity in patients with refractory/metastatic osteosarcoma. However, with regard to grade 3/4 toxicity, the pemetrexed plus cisplatin chemotherapy appears to be better tolerated.

Efficacy and safety of stereotactic radiosurgery for pulmonary metastases from osteosarcoma: Experience in 73 patients

Osteosarcoma pulmonary metastases are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic radiosurgery (SRS) can be an alternative to surgery that can achieve high rates of local control with limited toxicity. From January 2005 to December 2013, 73 patients who developed pulmonary metastasis during period of adjuvant chemotherapy or follow-up were analyzed. 33 patients were treated by stereotactic radiosurgery using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 40 patients were treated by surgical resection. Four-year progression-free survival rate, four-year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. Patients tolerated gamma knife radiosurgery well. Our study demonstrates that SRS is well-tolerated with excellent local control and less complications. SRS should be considered as a potential option in patients with pulmonary metastases from osteosarcoma, especially in those who are medically inoperable, refuse surgery.