Strontium ranelate retards disc degradation and improves endplate and bone micro-architecture in ovariectomized rats with lumbar fusion induced - Adjacent segment disc degeneration.

Objectives: Adjacent segment disc degeneration (ASDD) is one of the long-term sequelae of spinal fusion, which is more susceptible with osteoporosis. As an anti-osteoporosis drug, strontium ranelate (SR) has been reported to not only regulate bone metabolism but also cartilage matrix formation. However, it is not yet clear whether SR has a reversal or delaying effect on fusion-induced ASDD in a model of osteoporosis. Materials and methods: Fifth three-month-old female Sprague-Dawley rats that underwent L4-L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after bilateral ovariectomy (OVX) surgery. Animals were administered vehicle (V) or SR (900 mg/kg/d) orally for 12 weeks post-PLF as follows: Sham+V, OVX + V, PLF + V, OVX + PLF + V, and OVX + PLF + SR. Manual palpation and X-ray were used to evaluate the state of lumbar fusion. Adjacent-segment disc was assessed by histological (VG staining and Scoring), histomorphometry (Disc Height, MVD, Calcification rate and Vascular Bud rate), immunohistochemical (Col-II, Aggrecan, MMP-13, ADAMTS-4 and Caspase-3), and mRNA analysis (Col-I, Col-II, Aggrecan, MMP-13 and ADAMTS-4). Adjacent L6 vertebrae microstructures were evaluated by microcomputed tomography. Results: Manual palpation and radiographs showed clear evidence of the fused segment's immobility. After 12 weeks of PLF surgery, a fusion-induced ASDD model was established. Low bone mass caused by ovariectomy can significantly exacerbate ASDD progression. SR exerted a protective effect on adjacent segment intervertebral disc with the underlying mechanism possibly being associated with preserving bone mass to prevent spinal instability, maintaining the functional integrity of endplate vascular microstructure, and regulating matrix metabolism in the nucleus pulposus and annulus fibrosus. Discussion: Anti-osteoporosis medication SR treatments not only maintain bone mass and prevent fractures, but early intervention could also potentially delay degenerative conditions linked to osteoporosis. Taken together, our results suggested that SR might be a promising approach for the intervention of fusion-induced ASDD with osteoporosis.

CacyBP/SIP promotes tumor progression by regulating apoptosis and arresting the cell cycle in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric and adolescent patients. The calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) performs an essential function in cell proliferation and apoptosis. The present study investigated the effect of CacyBP/SIP in OS cell proliferation and apoptosis. CacyBP/SIP mRNA expression levels were evaluated in four OS cell lines by quantitative PCR. CacyBP/SIP expression was downregulated in Saos-2 cells using a lentivirus transfection system and the transfection efficiency was analyzed. The effects of CacyBP/SIP downregulation on Saos-2 cell proliferation and colony-formation ability were evaluated by MTT and colony-formation assays. The effect of CacyBP/SIP knockdown on Saos-2 cell cycle and apoptosis was analyzed by flow cytometry cell sorting. The Cancer Genome Atlas (TCGA) data was analyzed for validation. Human OS cell lines Saos-2, MG-63, HOS and U20S expressed CacyBP/SIP mRNA. CacyBP/SIP knockdown significantly inhibited cell proliferation and colony-formation ability. G1/S phase arrest was induced by CacyBP/SIP downregulation, which also resulted in the downregulation of CDK and cyclins and the upregulation of p21. In addition, CacyBP/SIP downregulation induced Saos-2 cell apoptosis mediated by Bax and Bcl-2. High expression of CacyBP/SIP was significantly associated with poor prognosis in TCGA sarcoma database. Thus, CacyBP/SIP performs important functions in the proliferation and apoptosis of human OS cells.

Short-term Preoperative Denosumab With Surgery in Unresectable or Recurrent Giant Cell Tumor of Bone.

OBJECTIVE: The purpose of this retrospective study was to evaluate the clinical and oncological results of combination treatment of short-term preoperative denosumab (the receptor activator of nuclear factor kappa-B ligand inhibitor) with surgery in unresectable or recurrent cases of giant cell tumor of the bone (GCTB). METHODS: Between 2016 and 2018, 11 eligible patients (1 man, 10 women, mean age 38.1 years) with grade 3 GCTB were treated with a combination of short-term (six doses) preoperative denosumab and surgery in a single institution. The clinical, radiological, and pathological alteration after the denosumab treatment were compared. The oncological results of the combination therapy were also recorded. Meanwhile, adverse effects or complications of denosumab, if any, were reported. RESULTS: The median follow-up time after surgical procedure was 30 months (range 13-45 months). After 3-4 denosumab injections, pain relief was observed in all patients. In two spine patients, the neurological status improved after four doses of treatment. Intraoperatively, the margin of the tumor became clear and the intensity of the tumor increased while the blood supply around and within the lesion decreased. Within the lesion, the typically soft and loose tissue were replaced by the tough and dense fibro-osseous tissue. The mean diameter of the lesion before and after treatment was 61.55 ± 22.49 mm and 51.81 ± 21.12 mm, respectively, and the T-score was 1.02 (P = 0.32). Variable calcification was observed at the periphery and within the lesion. A total of three patients experienced local recurrence in this study. In the resection group, only one extremity patient had soft tissue recurrence that was treated with en-bloc excision. In the curettage group, two of three sacral tumor patients had local occurrence. Both refused re-operation and restarted the monthly denosumab injection thereafter, and the lesions remained stable at the final follow up. Finally, no adverse effects or complications related to denosumab treatment were found. CONCLUSION: For the unresectable or recurrent GCTB cases, short-term (six doses) preoperative use of denosumab improved clinical symptoms, decreased the tumor size, and increased the tumor density. The changes in tumors, in turn, simplified the tumor removal manipulation and, subsequently, decreased the local recurrence for the resection surgery. For the curettage, the denosumab-induced changes had mixed impacts, and shorter term (fewer than six doses) usage may be more appropriate. Our six-dose regime was deemed safe, while the safety of long-term use remains unknown.

Diagnostic yield of percutaneous core needle biopsy in suspected soft tissue lesions of extremities.

OBJECTIVE: This retrospective study was performed to investigate the diagnostic yield of percutaneous core needle biopsy (CNB) for suspected soft tissue lesions of the extremities. METHODS: The medical records of 139 consecutive patients who underwent percutaneous CNB for suspected soft tissue lesions of the extremities from January 2014 to December 2016 at a single institution were reviewed. The pathologic findings or clinical follow-ups were used to evaluate the performance of CNB. Alterations in the treatment regimen from pre- to post-biopsy were also analyzed. Complications, when present, were documented. RESULTS: In total, 141 biopsy procedures were performed in 139 patients. In total, 136 (96%) biopsies were successful, among which 5 were false-negative and 131 were diagnosed accurately. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CNB in the differentiation of malignant from benign lesions were 94%, 100%, 96%, 100%, and 90%, respectively. The treatment regimen was altered based on the biopsy findings in 25 cases. Two patients developed mild nerve injury but fully recovered during follow-up. CONCLUSIONS: CNB is effective and safe, with high sensitivity, specificity, and accuracy for the diagnosis of soft tissue lesions, especially for differentiating malignant from benign lesions.

S100A4 promotes lung tumor development through ß-catenin pathway-mediated autophagy inhibition.

Autophagy has emerged as a critical pathway in tumor development. S100A4 plays important roles in tumor metastasis, but its role in regulating autophagy has not been well characterized. In this study, we found that S100A4 was significantly upregulated in lung adenocarcinoma tissues. Clinical investigation demonstrated that high expression level of S100A4 was associated with tumor size and advanced tumor grades of lung adenocarcinoma patients. Moreover, our results revealed that extracellular S100A4 or overexpression of S100A4 inhibited starvation-induced autophagy and promoted cell proliferation in lung cancer cells in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 increased autophagy and reduced cell viability in both A549 and LLC cells. Additionally, S100A4 inhibited starvation-induced autophagy to promote tumor cell viability via the Wnt pathway. Increased expression of ß-catenin consistently led to a decreased LC3-II protein abundance. Further, the inhibitory effect of S100A4 on autophagy and its promotion role in cell proliferation was abolished in A549 and LLC cells using the receptor for advanced glycation end products (RAGE)-specific inhibitor (FPS-ZM1). S100A4-deficient mice showed retarded tumor development. This effect was well correlated with increased expression of autophagy markers. Our findings demonstrate that S100A4 promotes lung tumor development through inhibiting autophagy in a ß-catenin signaling and S100A4 receptor RAGE-dependent manner, which provides a novel mechanism of S100A4-associated promotion of tumor development.

Clinical and Radiographic Results of Reconstruction with Fibular Autograft for Distal Radius Giant Cell Tumor.

OBJECTIVE: To evaluate the result of en bloc resection and reconstruction of the distal radius with a non-vascularized fibular autograft for giant cell tumor (GCT) of bone. METHODS: Between 2005 and 2015, 12 eligible patients (seven males, five females, mean age 31.3 years) with grade III GCT of the distal radius were treated by en bloc resection and reconstruction with non-vascularized proximal fibular autografts in four Chinese institutions (members of Giant Cell Tumor Team of China). The patients had a clinical and radiographic review every 6 months for the first 2 years then annually thereafter. The functional, oncologic and radiological outcomes of the patients were analyzed. RESULTS: The mean duration of follow-up was 39.6 months. Bony union was achieved in all cases. None of the patients were dissatisfied with the shape and appearance of the wrist. The mean MSTS score was 25.23 ± 2.38 (range, 22-29). The mean DASH score was 13.0 (range, 6.7-33.3). The average range of motion of the wrist was: 35.8° ± 14.5° of extension, 14.0° ± 8.4° of flexion, 15.5° ± 6.7° of radial deviation, 19.4° ± 10.1° of ulnar deviation, 57.2° ±18.9° of pronation and 44.0° ± 24.8° of supination. The average percentage of grip strength was 55.2% ± 29.0% compared with that of the contralateral side. One localized soft tissue recurrence occurred; it was successfully managed by excision. Lung metastases developed postoperatively in one case and were treated by gamma knife radiotherapy. There was radiographic evidence of radiocarpal arthritis in eleven patients, bone resorption in ten, distal radioulnar joint diastasis in six, ulnar deviation of the wrist in seven, subluxation of the carpal bone in three and dislocation of the carpal bone in one patient. CONCLUSIONS: Reconstruction with a non-vascularized proximal fibular autograft is a reasonable option after en bloc resection of the distal radius for giant cell tumor of bone.

Evaluation of the use of fluoroscopy guided needle biopsies for diagnosing cases of suspected pathological fractures.

AIM: Establishing an early and accurate diagnosis in cases of suspected pathological fractures is crucial to initiate optimal treatment without delay. The use of percutaneous biopsy has become popular over the past few years. However, there is a paucity of information regarding the efficacy and safety of percutaneous biopsy procedures guided by fluoroscopy. METHODS: A total of 137 percutaneous C-arm fluoroscopy-guided core needle biopsy (CNB) procedures were performed in 135 patients with suspected pathological fractures. The sensitivity, specificity, accuracy, and overall prognostic value of these procedures were evaluated. Complications, if any, were documented for all cases. RESULTS: The overall sensitivity, specificity, and accuracy were 82.0%, 100%, and 83.2%, respectively. The positive and negative predictive value was 100% and 28.1%, respectively. There were 23 "false negative" cases in our study, of which 15 were benign lesions and eight were malignant tumors. No "false-positives" were found. Major procedure-related complications occurred in three patients (2.2%). These complications, however, did not alter the prognosis of these patients. CONCLUSION: Percutaneous C-arm fluoroscopy-guided biopsy procedures are both effective and safe for diagnosis of suspected pathological fractures in the appendicular skeleton.

High nuclear expression of Twist1 in the skeletal extramedullary disease of myeloma patients predicts inferior survival.

The aim of the study was to investigate the expression of epithelial to mesenchymal transition (EMT)-inducing transcription factors, including Twist1 and ZEB1, in skeletal extramedullary disease (EMD) of multiple myeloma (MM) patients and to clarify the effects on clinical outcomes. The expression of Twist1 and ZEB1 in the bone marrow (BM) and the masses of skeletal EMD from 70 MM cases with skeletal EMD and 30 MM patients without skeletal EMD were determined by immunohistochemistry. The results demonstrated that the percentage of high nuclear staining for Twist1 was 24.3% (17/70) in skeletal EMD, which was significantly higher than in the BM of these patients as well as those without skeletal EMD (P=0.030 and P=0.011). The microvessel density (MVD, P=0.004) was significantly higher in patients with high nuclear expression of Twist1 (Twist1-high) than in those with low expression. Patients with Twist1-high experienced a lower rate of progression-free survival (PFS, 11.8% vs. 35.0%, P=0.000) and overall survival (OS, 52.5% vs. 83.7%, P=0.001) compared to those with low expression. Multivariate analysis showed that Twist1-high was independently associated with inferior PFS (HR=2.161; 95%CI: 1.116-4.183; P=0.022) and OS (HR=3.111; 95%CI: 1.114-8.685; P=0.030). We concluded that Twist1-high is associated with a poor prognosis and may be correlated with angiogenesis in the skeletal EMD of MM patients.

[Analysis of risk factors for deep vein thrombosis of the lower extremity for patients with bone metastases].

OBJECTIVE: To analyze the risk factors for deep vein thrombosis (DVT) of the lower extremity in patients with bone metastases. METHODS: Ninety patients with bone metastases were admitted to our hospital From January 2010 to December 2011, and their clinical data were retrospectively analyzed. There were 57 males and 33 females with a mean age of 61 years (range, 27 to 78 years). On admission, all cases were detected by color Doppler ultrasonography for DVT of bilateral lower extremities. Univariate and multivariate analyses were performed to determine the probable risk factors including gender, age, body weight, tumor location, bed confinement and etc. RESULTS: Among the 90 patients, DVT was found in 24 patients on admission and the DVT incidence was 26.7% (24/90). The univariate analysis showed that bed confinement, multiple metastasis, pathological fracture, primary lesion detected, blood group, fibrinogen and hematocrit were significantly related to the incidence of DVT (P < 0.05). The logistic multivariate regression analysis showed that bed confinement, pathological fracture and fibrinogen were independent risk factors for the incidence of DVT. CONCLUSIONS: Bed confinement, pathological fracture and fibrinogen are independent risk factors for the incidence of DVT for patients with bone metastases. Patients with bed confinement >3 days, pathological fracture or fibrinogen >4 g/L should be routinely screened for lower extremity DVT on admission. Once identified, the DVT patients should be treated as early as possible.

[An analysis of prognostic factors for malignant fibrous histiocytoma of bone].

OBJECTIVE: To study the risk factors related to the survival rate, recurrence and metastasis of malignant fibrous histiocytoma of bone. METHODS: From July 1997 and July 2010, 56 patients with malignant fibrous histiocytoma of bone were treated. Univariate and multivariate analysis were performed to determine the probable risk factors including gender, age, tumor location, tumor size and so on. RESULTS: Forty-four cases were followed up ranged from 2 weeks to 78 months (medium 33.3). The 5-year overall survival rate was 50.1%, local recurrence rate 40.9% with a median time of 12 months (3 to 60 months) and metastatic rate 27.5% (11/40) with a median time of 6.5 months (2 to 23 months). Univariate analysis indicated that gender, condition of presentation (primary case or recurrence case), tumor location, surgical margin and surgical stage were significantly related to survival rate (P < 0.05), and tumor location and surgical margin were related to local recurrence rate (P < 0.05), and important vessel or nerve invasion was related to metastatic rate (P < 0.05). Multivariate analysis showed that surgical margin and surgical stage were independent risk factors for survival rate, of which surgical margin was the independent risk factor for recurrence rate. CONCLUSIONS: Surgical margin and surgical stage are independent risk factors for survival rate, of which surgical margin is the independent risk factor for recurrence rate.

[Diagnosis and treatment of osteoid osteoma].

OBJECTIVE: To study the clinical features and surgical treatment of osteoid osteoma and improve the diagnostic therapeutic level. METHODS: Clinical data of 35 patients (25 males and 10 females) with osteoid osteoma diagnosed and treated between January 1997 to October 2009 were retrospectively reviewed. The average age was 21 years (ranged, 6 to 49 years). The average interval time between onset of symptoms and diagnosis was 12 months (ranged, 1 to 24 months). The most common sites were the tibia (13 patients) and the femurs (7 patients). The most common presenting complaints for patients with osteoid osteoma was pain which usually responded to NSAIDs and was generally more severe at night. The imaging manifestations revealed a circular or oval nidus. All the patients underwent surgical treatment. The tumors were treated with curettage or excision with autograft or allograft in 19 patients, simple surgical resection in 9 patients, curettage or excision with autograft or allograft and fixation in 7 patients. RESULT: The mean follow-up period was 49 months (ranged,2 months to 12 years). The symptom of pain disappeared after operation. There were no evidence of recurrence. Tibial pathological fracture happened in one patient 4 months postoperatively, and the patient got healing after plate-screw internal fixation. One patient with sinus formation 5 years postoperatively got wound healing after sinus resection, intramedullary nail removal and debridement. CONCLUSION: According to the typical clinical presentation, radiographic findings, the diagnosis of osteoid osteoma is not difficult. Once the diagnosis is confirmed, the operation should be carried out as early as possible to relieve the symptoms, improve the quality of life and prevent long-term complications.