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ObjectiveThis study intends to retrospectively analyze the data of patients with sacral metastases in our center, and analyze the treatment methods and therapeutic effects of sacral metastases.Methods73 patients with sacral metastases treated in our hospital from June 2013 to June 2019 were retrospectively analyzed. There were 54 cases of neurological symptoms, 42 cases of sacroiliac joint instability, 24 cases of lower limb muscle weakness and 19 cases of abnormal urination and defecation. Four patients with tumors below S3 underwent complete tumor resection, 23 patients with tumors above S3 and without sacroiliac joint instability underwent tumor curettage and nerve root lysis, 34 patients with tumors above S3 and sacroiliac joint instability underwent tumor curettage, nerve root release and screw rod reconstruction. 12 patients with multiple metastases underwent percutaneous radiofrequency ablation and sacroplasty. VAS was used to evaluate the preoperative and postoperative pain scores, and the postoperative pain relief, neurological function, bowel function, wound healing and complications were evaluated.ResultsThere were no perioperative death, 8 cases of poor wound healing, 5 cases of nerve injury, postoperative sensory and motor loss of lower limbs. Cerebrospinal fluid (CSF) leak in 7 cases. The patients were followed up for 6-25 months (mean 12 months). The VAS scores of patients with pain symptoms were 7 points before operation and 1.44 points after operation, In 19 patients with abnormal urination and defecation function, 12 patients recovered to normal 3-6 months after operation, 5 cases had no significant change compared with preoperative, and 2 cases had aggravated symptoms; 17 cases of patients with lower limb muscle strength were significantly recovered after operation, and the average muscle strength was increased by 2 grades; 30 cases of patients with unstable sacroiliac joint got internal fixation had significantly pain relief. Pain symptoms of 9 patients were significantly relieved after percutaneous radiofrequency ablation.Conclusionthe operation of sacral metastases mainly adopts a relatively conservative surgical method, which can effectively improve the quality of life of patients with sacral metastases by retaining the nerve function and relieving the pain of patients, combining with radiofrequency ablation, sacroplasty and targeted drugs.

ObjectiveTo compare the efficacy and prognosis of reverse total shoulder arthroplasty (rTSA) with shoulder hemiarthroplasty (SHA) using devitalized autograft or allograft composite reconstruction after proximal humeral tumor resection.MethodsWe retrospectively reviewed patients who underwent SHA (32) and rTSA (20) for tumor resections of the proximal humerus from January 2014 to July 2020. The clinical results included duration of the operation, intraoperative blood loss, bone union, visual analog scale (VAS) score, shoulder range of motion (ROM), American Shoulder and Elbow Surgeons (ASES) shoulder score, recurrence, and overall survival.ResultsFifty-two patients were followed up for a mean of 30 months. Thirty-two patients were SHA with allograft-prosthetic composite (APC) reconstructions, while other 20 were rTSA with devitalized autograft-prosthetic composite reconstructions. At the end of the follow-up, 2 recurrence, 3 postoperative infections, and 4 subluxations occurred among the SHA patients. Two patients in the rTSA group had postoperative anterior dislocation and underwent revision surgery with surgical mesh, and 2 (2/20) had grade II scapular notching. The mean VAS score of the shoulder was 1.5 ± 0.8 in the rTSA group and 2.3 ± 1.2 in the SHA group (p < 0.05). The mean active forward flexion of the shoulder joint was 50.6 ± 6.0 in the SHA group and 100 ± 7.6 in the rTSA group (p < 0.05). The ASES shoulder score was 78 ± 3.0 in the rTSA group and 52 ± 5.6 in the SHA group (p < 0.05). The overall 3-year survival rate of all patients was 60.0%, and patients in the rTSA group showed better survival in terms of the mean 3-year OS than patients in the SHA group (p = 0.04).ConclusionrTSA with devitalized autograft-prosthetic composite can offer a reasonable reconstruction of the shoulder joint after Malawer type I tumor resection. Compared with patients who underwent SHA, patients who underwent rTSA present good outcomes, a better range of motion, better bone union, and no increase in instability rate in the mid-term.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with highly aggressive behavior and early systemic metastasis. The survival rates for osteosarcoma remain unchanged over the past two decades. Studies aiming to find new or alternative therapies for patients with refractory osteosarcoma are urgently needed. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging clinical activity in NSLCC and soft tissue sarcoma, whereas its effect on osteosarcoma has not been studied. In our study, we investigated the anti-tumor activity and underlying mechanism of anlotinib in osteosarcoma. Various in vitro and in vivo models of human osteosarcoma were used to determine the anti-proliferative, anti-angiogenesis and anti-metastasis efficacy of anlotinib. Our results showed that anlotinib suppressed tumor growth and increased the chemo-sensitivity of osteosarcoma. In addition, anlotinib inhibited migration and invasion in osteosarcoma cells. Furthermore, in order to explore the anti-tumor mechanism of anlotinib, phospho-RTK antibody arrays were performed. These analyses confirmed that anlotinib suppressed the phosphorylation of MET, VEGFR2 and the downstream signaling pathway activation. Moreover, we demonstrated that anlotinib blocked hepatocyte growth factor (HGF)-induced cell migration, invasion and VEGF-induced angiogenesis. Notably, a 143B-Luc orthotopic osteosarcoma model further showed that anlotinib significantly inhibited growth and lung metastasis of implanted tumor cells. Our preclinical work indicates that anlotinib acts as a novel inhibitor of VEGFR2 and MET that blocks tumorigenesis in osteosarcoma, which could be translated into future clinical trials.

Purpose Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed. Design In this study, a sarcoma-targeting peptide-decorated disulfide-crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity. Results The targeted, loaded nanogel, STP-NG/SHK, killed osteosarcoma cells by inducing RIP1- and RIP3-dependent necroptosis in vitro. Necroptosis is a novel cell death form that could be well adapted as an efficient antitumor strategy, the main obstacle of which is its high toxicity. After intravenous injection, STP-NG/SHK efficiently suppressed tumor growth and reduced pulmonary metastasis, offering greater tumor necrosis and higher RIP1 and RIP3 upregulation compared to free SHK or untargeted NG/SHK in vivo. Additionally, the treatment with NG/SHK or STP-NG/SHK showed minimal toxicity to normal organs, suggesting low systemic toxicity compared to free SHK. Conclusion The STP-guided intracellular drug delivery system using the necroptosis mechanism showed profound anti-osteosarcoma activity, especially eliminated lung metastasis in vivo. This drug formulation may have great potential for treatment of osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (As2S2), the main active ingredient of the traditional Chinese medicine realgar, has been proved to have antitumor efficacy in several tumor types including acute promyelocytic leukemia, gastric cancer and colon cancer. Here, we investigated the efficacy and mechanism of As2S2 in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that As2S2 potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As2S2 induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. As2S2 was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As2S2-induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As2S2 inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As2S2-induced apoptosis and autophagy. Finally, As2S2in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As2S2 induced G2/M phase arrest, apoptosis, and autophagy via activing ROS/JNK and blocking Akt/mTOR signaling pathway in human osteosarcoma cells. Arsenic sulfide may be a potential clinical antitumor drugs targeting osteosarcoma.

Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti‐tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti‐tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase‐dependent apoptosis, G2/M cell cycle arrest in a dose and time‐dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription‐3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3‐dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino‐terminal kinases (JNK), extracellular signal‐regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol‐induced cell death was significantly restored in the presence of the ROS scavenger, N‐acetyl‐l‐cysteine (NAC) or a caspase inhibitor Z‐VAD‐FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen‐activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down‐regulation of phosph‐STAT3 Tyr705 and up‐regulation of cleaved caspase‐3 and phosph‐SAPK (Stress‐activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS‐dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti‐tumour drugs target OS.

// Zhuoying Wang 1, * , Chongren Wang 1, * , Zifei Zhou 1, * , Mengxiong Sun 1 , Chenghao Zhou 2 , Jian Chen 2 , Fei Yin 2 , Hongsheng Wang 2 , Binhui Lin 1 , Dongqing Zuo 2 , Suoyuan Li 2 , Lijin Feng 3 , Zhenfeng Duan 4 , Zhengdong Cai 1, 2 , Yingqi Hua 1, 2 1 Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China 2 Shanghai Bone Tumor Institution, Shanghai, 201620, China 3 Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China 4 Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA * These authors have contributed equally to this work Correspondence to: Zhengdong Cai, email: czd856@vip.163.com Yingqi Hua, email: hua_yingqi@163.com Keywords: osteosarcoma, tetraspanin, CD151, metastasis, adhesion Received: December 25, 2015 Accepted: July 26, 2016 Published: August 19, 2016 ABSTRACT CD151, a tetraspanin family protein involved in cell-cell and cell-extracellular matrix interaction, is differentially expressed in osteosarcoma cell membranes. Thus, this study aimed to investigate the role of CD151 in osteosarcoma metastasis. We analyzed CD151 expression in patient tissue samples using immunohistochemistry. CD151 expression was also silenced with shRNA in osteosarcoma cells of high metastatic potential, and cell adhesion, migration and invasion were evaluated in vitro and pulmonary metastasis was investigated in vivo . Mediators of cell signaling pathways were also examined following suppression of CD151 expression. Overall survival for patients with low versus high CD151 expression level was 94 vs. 41 months ( p =0.0451). CD151 expression in osteosarcoma cells with high metastatic potential was significantly higher than in those with low metastatic potential ( p

In this study, we evaluated the photodynamic efficacy of a new photosensitizer, benzochloroporphyrin derivative 18 (BCPD-18), in Ewing sarcoma. We found that BCPD-18 decreased the viability of TC-71 cells irradiated by 670 nm laser in a concentration dependent manner. We also observed cells undergoing apoptosis as well as cell cycle arrest at the G2M phase after BCPD–18-mediated photodynamic therapy (BCPD-PDT). In addition, in vivo study (subcutaneous and orthotopic models) showed that BCPD-PDT reduced tumor size, tumor weight and tumor-bearing leg weight. After PDT, apoptosis was shown in vivo. Bax expression was increased, and Bcl-2 expression was decreased. This study provides evidence that BCPD-18 could probably be a useful photosensitizer in PDT for Ewing sarcoma.

Osteosarcoma (OS) is ranked as the most common primary bone malignancy in children and adolescents worldwide, and the 5-year overall survival rate of OS is not optimistic. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been implicated in tumor cell growth, proliferation, and anti-apoptosis in OS. Therefore, the discovery of novel molecular compounds that can effectively block STAT3 activation, is essential for the treatment of OS and improving prognosis. Here, we investigate whether Glaucocalyxin A (GLA), derived from Rabdosia japonica, exhibit the potential anticancer effects in OS. First of all, we identify that GLA potently suppressed cell proliferation, induced G2/M phase arrest and promoted substantial apoptosis in OS. Next, we conclude that GLA could induce Reactive oxygen species (ROS)-mediated oxidative stress via an imbalance of GSH and GSSG. Then, we elucidate for the first time that GLA could significantly inhibit both constitutive and IL-6-inducible activation of STAT3 (Tyr705) and JAK2, the upstream regulator of STAT3. Furthermore, we elucidate that the inhibition of STAT3 is mainly induced by ROS-mediated oxidative stress. Overall, our findings demonstrate that GLA could exhibit potent anticancer effects through effectively blocking the STAT3 signaling pathway, which was induced by ROS-mediated oxidative stress in OS in vitro and in vivo.

The gelsolin (GSN) has been involved in the regulation of tumor formation and development, but the biological role of GSN in the pathogenesis of osteosarcoma (OS) has not been well characterized. In this study, we show that high expression of GSN was observed in OS tissues and correlated with tumor size, advanced Enneking stage, and poor patient prognosis. Knockdown of GSN significantly inhibited cell proliferation and invasiveness in the OS cell lines. Furthermore, stable overexpression of GSN in OS cells resulted in a significant increase in cell growth and motility with the downregulation of p-AKT and p-P38 pathway. Finally, overexpression of GSN promoted growth of OS tumors in SCID mice. Taken together, these results provided the first evidence that GSN might contribute to OS cancer development and could be an attractive therapeutic target for patients with OS.

Objective To reveal the alterations in quality of life (QOL) in bone metastases patients after magnetic resonance guided focused ultrasound (MRgFUS). Methods This retrospective study enrolled 26 patients diagnosed with bone metastases. Patients had various primary malignant tumors and tumor lesions in different locations. All patients received MRgFUS for bone metastasis. Each focal spot sonication pulse that was applied to create energy deposition lasted 20 s and was performed at a frequency of 1.05 MHz. The visual analog scale (VAS) was used to measure pain level and the EORTC QLQ-BM22 was applied to evaluate QOL for 12 months. The lower the QLQ-BM22 score, the better the QOL of patients. Results The painful site subscale of the EORTC QLQ-BM22 was observed without significant change. Significant reductions in the functional subscales were observed after therapy compared with the baseline. The functional interference was reduced significantly during the first 12 months. From the 2-month time point onwards, the pain characteristics subscale also decreased significantly. VAS scores had decreased by 40.8% 1 month after the operation and had decreased 10.9% compared with VAS scores preoperation. Scores for pain characteristics decreased by 28.8% after the operation and the scores were still down by 10.8% 1 year after the treatment. VAS scores indicated a significant reduction in pain over the course of the research until the 12-month time point follow-up compared with the baseline. Conclusion MRgFUS therapy improved the QOL of patients with bone metastasis by relieving bone pain.

Two-color stimulated Raman scattering (SRS) microscopy with label-free mapping of lipid/protein distributions has shown promise in virtual histology. Despite previous demonstrations of SRS in tumor delineation and diagnosis, the speed and efficiency of the current technique requires further improvements for practical use. Here, we integrate parallel dual-phase SRS detection with strip mosaicing, which reduces the imaging time of a whole mouse brain section from 70 to 8 minutes. We further verified our method in imaging fresh human surgical tissues, showing its great potential for rapid SRS histology, especially for large scale, large quantity imaging tasks.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.

Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells. Meanwhile, CA-4 or CQ could increase the expression of NDRG1 independently. We further performed mechanistic study to explore how CA-4 and CQ regulate the expression of NDRG1. Using luciferase reporter assay, we found that CA-4 transcriptionally upregulated NDRG1 expression, whereas CQ triggered colocalization of NDRG1 and lysosome, which subsequently prevented lysosome-dependent degradation of NDRG1. Further, we showed that knockdown of NDRG1 caused the defect of lysosomal function, which accumulated LC3-positive autophagosomes by decreasing their fusion with lysosomes. Moreover, NDRG1 inhibition increased apoptosis in response to combination treatment with CA-4 and CQ. Taken together, our study revealed abrogation of NDRG1 expression sensitizes OS cells to CA-4 by suppression of autophagosome–lysosome fusion. These results provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors.

Correction to: Cell Death and Disease (2017) 8 (9):e3048. doi: 10.1038/cddis.2017.438; published online 14 September 2017 Since the publication of this paper, the authors have noted that there was an error in Figure 1d, in that, the GAPDH for combination treatment with CA-4 and CQ in SJSA cells by mistake duplicated for CQ alone treatment (Figure 3e).