Tao Ji

Endoprosthetic replacement for primary tumours around the knee: EXPERIENCE FROM PEKING UNIVERSITY

In developing countries locally-made low-cost prostheses are mainly used in limb-salvage surgery to alleviate the economic burden. We retrospectively collected data on 104 patients treated by limb-salvage surgery between July 1997 and July 2005. We used a locally-designed and fabricated stainless-steel endoprosthesis in each case. Oncological and functional outcomes were evaluated at a mean follow-up of 47 months (12 to 118). A total of 73 patients (70.2%) were free from disease, nine (8.7%) were alive with disease, 19 (18.2%) had died from their disease and three (2.9%) from unrelated causes. According to the Musculoskeletal Tumor Society scoring system, the mean functional score was 76.3% (SD 17.8). The five-year survival for the implant was 70.5%. There were nine cases (8.7%) of infection, seven early and two late, seven (6.7%) of breakage of the prosthesis, three (2.9%) of aseptic loosening and two (1.9%) of failure of the polyethylene bushing. Multivariate analysis showed that a proximal tibial prosthesis and a resection length of 14 cm or more were significant negative prognostic factors. Our survival rates and Musculoskeletal Tumor Society functional scores are similar to those reported in the literature. Although longer follow-up is needed to confirm our results, we believe that a low-cost custom-made endoprosthesis is a cost-effective and reliable reconstructive option for limb salvage in developing countries.

Flavokawain B, a kava chalcone, inhibits growth of human osteosarcoma cells through G2/M cell cycle arrest and apoptosis

BackgroundOsteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Limited by the severe toxicity of conventional agents, the therapeutic bottleneck of osteosarcoma still remains unconquered. Flavokawain B (FKB), a kava extract, has been reported to have significant anti-tumor effects on several carcinoma cell lines both in vitro and in vivo. Its efficacy and low toxicity profile make FKB a promising agent for use as a novel chemotherapeutic agent.ResultsIn the current study, we investigated the anti-proliferative and apoptotic effects of FKB against human osteosarcomas. Exposure of OS cells to FKB resulted in apoptosis, evidenced by loss of cell viability, morphological changes and the externalization of phosphatidylserine. Apoptosis induced by FKB resulted in activation of Caspase-3/7, -8 and −9 in OS cell lines, 143B and Saos-2. FKB also down-regulated inhibitory apoptotic markers, including Bcl-2 and Survivin and led to concomitant increases in apoptotic proteins, Bax, Puma and Fas. Therefore, the induction of apoptosis by FKB involved both extrinsic and intrinsic pathways. FKB also caused G2/M phase cell cycle arrest, which was observed through reductions in the levels of cyclin B1, cdc2 and cdc25c and increases in Myt1 levels. Furthermore, migration and invasion ability was decreased by FKB in a dose-dependent manner. The cytotoxicity profile showed FKB had significant lower side effects on bone marrow cells and small intestinal epithelial cells compared with Adriamycin.ConclusionsTaken together, our evidence of apoptosis and cell cycle arrest by FKB treatment with less toxicity than the standard treatments provides an innovative argument for the use of FKB as a chemotherapeutic and chemopreventive compound. In vivo experiments utilizing FKB to reduce tumorigenesis and metastatic potential will be crucial to further justify clinical application.

Inhibition of enhancer of zeste homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration, and invasion in endometrial cancer cell lines.

Objective To investigate the impact of enhancer of zeste homolog 2 (EZH2) expression on endometrial cancer cell line behavior. Materials and Methods Enhancer of zeste homolog 2 expression levels were compared between the nonmalignant endometrial cell line T-HESC and 3 endometrial cancer cell lines, ECC-1, RL95-2, and HEC1-A. Stable EZH2 knockdown cell lines were created, and the impact on cellular proliferation, migration, and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. Enhancer of zeste homolog 2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and short-hairpin EZH2 cell lines was performed using the Student t test and the Fischer exact test. Results Enhancer of zeste homolog 2 protein expression was increased in all 3 cancer cell lines and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration, and invasion. Down-regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in the G2/M phase. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3 and a concomitant decrease in &bgr;-catenin. Enhancer of zeste homolog 2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion, and nodal metastasis. Conclusions Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation, migration, and invasion in 3 endometrial cancer cell lines as well as with increased stage, grade, depth of invasion, and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted.

Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Using in vivo and in vitro studies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector. In vitro experiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.

Wnt Signaling in Osteosarcoma

Osteosarcoma (OS) is the most common primary bone malignancy diagnosed in children and adolescents with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the last two decades. With current treatments, 60-70 % of patients with localized disease survive. Given a propensity of Wnt signaling to control multiple cellular processes, including proliferation, cell fate determination, and differentiation, it is a critical pathway in OS disease progression. At the same time, this pathway is extremely complex with vast arrays of cross-talk. Even though decades of research have linked the role of Wnt to tumorigenesis, there are still outstanding areas that remain poorly understood and even controversial. The canonical Wnt pathway functions to regulate the levels of the transcriptional co-activator β-catenin, which ultimately controls key developmental gene expressions. Given the central role of this mediator, inhibition of Wnt/β-catenin signaling has been investigated as a potential strategy for cancer control. In OS, several secreted protein families modulate the Wnt/β-catenin signaling, including secreted Frizzled-related proteins (sFRPs), Wnt inhibitory protein (WIF), Dickkopf proteins (DKK-1,2,3), sclerostin, and small molecules. This chapter focuses on our current understanding of Wnt/β-catenin signaling in OS, based on recent in vitro and in vivo data. Wnt activates noncanonical signaling pathways as well that are independent of β-catenin which will be discussed. In addition, stem cells and their association with Wnt/β-catenin are important factors to consider. Ultimately, the multiple canonical and noncanonical Wnt/β-catenin agonists and antagonists need to be further explored for potential targeted therapies.

Modular hemipelvic endoprosthesis reconstruction--experience in 100 patients with mid-term follow-up results.

INTRODUCTION Pelvic endoprostheses are becoming more commonly used in recent years. In 2007, we reported the early results of modular hemipelvic endoprosthesis. In order to provide longer follow-up results, we conducted the current study. OBJECTIVE To explore overall survival, local recurrence rate, metastasis rate, function score and survivorship of the prosthesis and related complications. METHODS We retrospectively reviewed one hundred consecutive patients who received reconstruction with modular hemipelvic endoprostheses from June 2001 to March 2010. The living patients were followed for an average of 52.9 (range, 24-103) months. There were 85 primary tumors and 15 isolated metastases. RESULTS At the time of last follow-up, fifty-eight patients were alive with no evidence of disease and thirty-six patients died of disease. Twenty patients experienced a local recurrence and twenty-eight patients developed distant metastasis. Patients with wide surgical margins had a significantly lower local recurrence rate than those with inadequate margins (p = 0.03). The mean MSTS (Musculoskeletal Tumor Society) 93 score was 57.2% (range, 16.7-86.7%). The mean Karnofsky Performance Score (KPS) was 64.4 (range, 30-90). Postoperative complications occurred in 45% of the patients. Wound healing disturbance (18%) and deep infection (15%) were the most predominant. Less frequent complications included dislocation, which occurred in nine patients and mechanical complications including 5 breakages and 2 aseptic loosening. CONCLUSION The modular hemipelvic endoprosthesis can provide a versatile reconstruction option for a variety of pelvic defects with an acceptable rate of complication. Wide margins whenever possible should be the goal for these complex patients.

Neuropilin-2 expression is inhibited by secreted Wnt antagonists and its down-regulation is associated with reduced tumor growth and metastasis in osteosarcoma.

BackgroundNeuropilin 2 (NRP2) isa multi-functional co-receptor to many receptors, including VEGF receptor, c-Met and others. NRP2 has recently been implicated in tumor angiogenesis, growth, and metastasis of many other cancers. However, its role in osteosarcoma remains poorly understood.ResultsNRP2 was overexpressed in osteosarcoma cell lines and tissues, and associated with poor survival of osteosarcoma patients. Knockdown of NRP2 expression by short-hairpin (Sh) RNA resulted in reduced tumor growth, metastasis, and blood vessel formation of osteosarcoma. Knockdown of NRP2 expression by ShRNA also inhibited the recruitment of HUVEC cells to osteosarcoma cells. Inhibition of Wnt signaling by overexpression of secreted Wnt antagonists soluble LRP5, Frzb, and WIF1 markedly down-regulated mRNA and protein expression of NRP2 in osteosarcoma cell lines.ConclusionsRegulation of NRP2 receptor expression may represent a novel approach for treatment of osteosarcoma through retarding osteosarcoma growth, metastasis and blood vessel formation. In addition, down-regulation of NRP2 expression can be achieved by expression of secreted Wnt antagonists.

Reconstruction with 3D-printed pelvic endoprostheses after resection of a pelvic tumour

AIMS The aims of this retrospective study were to report the feasibility of using 3D-printing technology for patients with a pelvic tumour who underwent reconstruction. PATIENTS AND METHODS A total of 35 patients underwent resection of a pelvic tumour and reconstruction using 3D-printed endoprostheses between September 2013 and December 2015. According to Ennekings classification of bone defects, there were three Type I lesions, 12 Type II+III lesions, five Type I+II lesions, two Type I+II+III lesions, ten type I+II+IV lesions and three type I+II+III+IV lesions. A total of three patients underwent reconstruction using an iliac prosthesis, 12 using a standard hemipelvic prosthesis and 20 using a screw-rod connected hemipelvic prosthesis. RESULTS All patients had an en bloc resection. Margins were wide in 15 patients, marginal in 14 and intralesional in six. After a mean follow-up of 20.5 months (6 to 30), 25 patients survived without evidence of disease, five were alive with disease and five had died from metastatic disease. Complications included seven patients with delayed wound healing and two with a dislocation of the hip. None had a deep infection. For the 30 surviving patients, the mean Musculoskeletal Society 93 score was 22.7 (20 to 25) for patients with an iliac prosthesis, 19.8 (15 to 26) for those with a standard prosthesis, and 17.7 (9 to 25) for those with a screw-rod connected prosthesis. CONCLUSION The application of 3D-printing technology can facilitate the precise matching and osseointegration between implants and the host bone. We found that the use of 3D-printed pelvic prostheses for reconstruction of the bony defect after resection of a pelvic tumour was safe, without additional complications, and gave good short-term functional results. Cite this article: Bone Joint J 2017;99-B:267-75.

Dietary feeding of flavokawain A, a Kava chalcone, exhibits a satisfactory safety profile and its association with enhancement of phase II enzymes in mice

Flavokawain A (FKA), a major chalcone in the Kava plant, has recently demonstrated promising anti-cancer activities. A systematic evaluation of FKAs safety profile has not been reported before. In this study, male FVB/N mice were fed with an AIN-76A diet or AIN-76A diet supplemented with 0.6% (6 g/kg food) FKA or 0.6% commercial kava root extract (KRE) for three weeks. Dietary feeding of FKA did not affect food consumption and body weight. Histopathological examination of liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of FKA-induced toxicity. Biochemical serum analysis and histological examination confirmed normal organ function in FKA-treated mice. The cytotoxicity profile showed FKA had minimal side effects on bone marrow and small intestinal epithelial cells compared with Adriamycin. In addition, oral feeding of FKA increased activities of both glutathione S-transferase and quinone reductase in the liver, lung, prostate and bladder tissues of mice. In comparison, dietary feeding of 0.6% KRE increased liver/body weight ratio and decreased spleen, thymus, and testis/body weight ratios, as well as induced nodular proliferation in liver tissues. Therefore, dietary feeding FKA showed no adverse effects on major organ function and homeostasis in mice, suggesting the potential of FKA for chemoprevention study of human cancers.

Robotic guidance for en bloc sacrectomy: a case report.

Study Design. Case report of a patient with primary osteosarcoma of the sacrum who underwent en bloc sacrectomy. Objective. To describe a novel approach using robotic guidance for sacral tumor resection. Summary of Background Data. En bloc sacrectomy for aggressive primary malignancies or metastatic tumors of the sacrum can be technically challenging. Although imaging can delineate appropriately planned resection margins, the complex anatomy of the spinopelvic junction poses a challenge for the exact intraoperative execution of the preoperative plan. Methods. The patient was a 22-year-old male who was diagnosed with a primary sacral osteosarcoma. The mass extended to the left sacroiliac joint requiring a transiliac osteotomy. Preoperative robotic-guidance software was used allowing for virtual planning of the transiliac osteotomy. Results. During surgery, the robot was attached and synchronized with the preoperative imaging. Pilot holes were drilled along the planned iliac resection margin. With rigid tubes placed in the left iliac pilot holes, we passed a series of osteotomes parallel to the tubes to the same depth as our drillings and completed our left iliac osteotomy. Negative tumor margins were achieved and the postoperative course was uneventful. Conclusion. We report the first case of robotic-guided en bloc transiliac resection of a primary sacral osteosarcoma with extension to the sacroiliac joint. Robotic guidance for tumor resection can be a useful tool in such challenging surgical procedures to fully resect the tumor, while minimizing disruption of the surrounding healthy anatomy. Level of Evidence: 5