Comparison of outcomes of 2 surgical treatments for proximal humerus giant cell tumors: a multicenter retrospective study.

BACKGROUND: The incidence of giant cell tumors in the proximal humerus is low. We evaluated 2 surgical treatments for giant cell tumors of the proximal humerus and postoperative upper-extremity function. METHODS: This study retrospectively analyzed the clinical data of 27 cases of giant cell tumors of the proximal humerus at 4 Chinese medical centers specializing in bone oncology collected between January 2002 and June 2015. All patients were followed up for more than 2 years. The surgical procedures performed for treatment included curettage in 14 patients and segmental resection in 13. The Campanacci grade, occurrence of pathologic fracture, surgical method, complications, and Musculoskeletal Tumor Society score were recorded for each cohort. RESULTS: The recurrence rate was 7.1% in the curettage group and 15.4% in the segmental resection group. Other postoperative complications occurred in 4 patients with segmental resection, including resorption of the osteoarticular allograft in 2, subluxation of the glenohumeral joint in 1, and prosthetic loosening and exposure in 1. A significant difference in postoperative upper-extremity function was noted between the 2 groups (P < .001). CONCLUSIONS: Postoperative upper-extremity function in the curettage group was significantly better than that in the segmental resection group. Segmental resection and reconstruction with a large segmental osteoarticular allograft were considered unadvisable. We suggest that extensive curettage should be selected to treat proximal humerus giant cell tumors as much as possible.

Clinical significance of serum soluble B7-H3 in patients with osteosarcoma.

BACKGROUND: Increasing data has indicated an association between increased soluble B7-H3 (sB7-H3) levels and unfavorable prognosis in patients with malignancies. However, the level of sB7-H3 and its clinical significance in osteosarcoma (OS) are not well known. In this present study, we investigated whether sB7-H3 levels in serum could be as a tool for differential diagnosis of OS patients. METHODS: Peripheral blood samples from healthy controls, benign bone tumors, and OS patients were collected. Levels of sB7-H3 in serum samples were measured by enzyme-linked immunosorbent assays. The correlation between OS-derived sB7-H3 and clinical features was analyzed, and prognostic significance of the sB7-H3 concentrations and tumor expressions of the biomarkers was then evaluated. RESULTS: sB7-H3 concentrations were significantly increased in patients with OS than in osteochondroma patients, bone fibrous dysplasia patients and healthy people (p < 0.05, respectively). Using 60.94 ng/mL as a cutoff value, the sensitivity and specificity of sB7-H3 was to differentiate between OS patients and other bone benign tumor patients were 75.7% and 83.8%, respectively. In addition, upregulated serum sB7-H3 in patients with OS associated with tumor differentiation, tumor stage, and metastasis status (p < 0.05, respectively). The area under the curve value for sB7-H3 (0.868) was markedly higher than those for ALP (0.713) and CA125 (0.789) for differentiating between OS patients and other begin bone tumor patients. CONCLUSIONS: We demonstrated that enhanced sB7-H3 levels correlated with the clinical characteristics of OS patients, and B7-H3 might be a potential biomarker and associated with the pathogenesis of OS.

Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway.

Recurrence and metastasis are important features of osteosarcoma (OS) that cause its poor prognosis. Aberrant expression of Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) has been reported in various kinds of cancers. However, the expression and function of Siglec-15 in OS remain unclear. In cultured OS cells (143B cells and MNNG/HOS cells) and their xenograft mouse models, we found that downregulation of Siglec-15 could inhibit the proliferation, migration and invasion of by inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, Siglec-15 overexpression promoted the growth, migration and invasion of OS cells in a significant manner. Then, we screened a number of differentially expressed genes (DEGs) between Siglec-15-knockdown group and control group by RNA-Seq assay. Among these DEGs, we found that dual-specificity phosphatase 1 (DUSP1/MKP1) was significantly downregulated after Siglec-15 silencing. We investigated the DUSP1 functions in influencing OS cells' biology, and found that the proliferation, migration and invasion of OS cells were promoted by overexpressing DUSP1 and crucially, the proliferation, migration and invasion of Siglec-15-knockdown OS cells were rescued by overexpressing DUSP1. Mechanically, we further showed that DUSP1-mediated inhibition of p38/MAPK and JNK/MAPK expression was attenuated when Siglec-15 expression was inhibited, suggesting that Siglec-15 promotes the malignant progression of OS cells by suppressing DUSP1-mediated suppression of the MAPK pathway. Moreover, we showed that both Siglec-15 and DUSP1 were highly expressed in human OS tissues by immunohistochemistry. High Siglec-15 expression was associated with OS lung metastasis, and high DUSP1 expression was associated with the high Enneking stage. Kaplan-Meier analysis indicated that high expression of Siglec-15 could predict poor prognosis of OS patients. Altogether, these results showed that Siglec-15 expression promoted OS development and progression by activating DUSP1 and might be a novel target in OS treatment.

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.

hsa_circ0021347 as a Potential Target Regulated by B7-H3 in Modulating the Malignant Characteristics of Osteosarcoma.

In our previous study, we showed that B7-H3 played crucial roles in osteosarcoma (OS) development and might serve as a negative regulator of in osteoimmunology and help tumor cells escape immune surveillance. However, little is known about B7-H3 deficiency and its corresponding circRNA alteration or their relationship with osteosarcoma progression. Therefore, we established stable silencing of B7-H3 in OS cells and validated our results with western blotting and real-time PCR detection. Then, we performed a circRNA array to analyze the differential expression of circRNAs between the control and B7-H3 knockdown cells. The association between target circRNA expression and the clinicopathological features of patients with OS was further analyzed. As a result, hsa_circ0021347 was selected and validated to be significantly downregulated in OS tissues and cell lines and showed a strong negative relationship with B7-H3 expression in OS. In addition, clinicopathological features showed that hsa_circ0021347 in OS tissues was negatively associated with Enneking stage and positively associated with patients' survival. Finally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and PANTHER pathway analyses were performed to predict a network of hsa_circ0021347/miRNAs interactions to help us develop potential biomarkers for clinical diagnosis and design therapeutic strategies for OS.

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.

Prognostic Differences in Patients with Solitary and Multiple Spinal Metastases.

OBJECTIVES: To investigate the association between the number of metastases to the spine and survival in patients with metastatic spinal cord compression (MSCC), as well as the prognosis difference between patients with solitary spinal metastasis (SSM) and multiple spinal metastases (MSM). METHODS: Three institutional databases were searched to identify all patients who had undergone spinal surgery for metastatic spinal tumors between March 2002 and June 2010. As well as age and gender, preoperative medical conditions were collected from medical records, including primary tumor, preoperative Frankel score, other bone metastases, preoperative Karnofsky performance status (KPS), number of involved vertebrae, pathological fracture metastasis site, serum albumin, sphincter dysfunction and the time of developing motor deficits before surgery. Survival data were obtained from medical records or via telephone follow-ups. Univariate and multivariate predictors of overall survival for each group were assessed using the Cox proportional hazards model. RESULTS: The median postoperative survival time was 6.0 ± 0.6 months (95% confidence interval [CI] 4.8-7.2) in patients with SSM and 7.0 ± 1.0 months (95% CI 5.1-8.9) in patients with MSM (P = 0.238). The difference in survival was not significant between groups. Furthermore, univariate analysis showed that the number of spinal metastases had no significant association with survival (P = 0.075). Primary tumor (P = 0.004) and preoperative KPS (P < 0.001) were independent prognostic factors in the whole cohort; primary tumor (P = 0.020), time of developing motor deficit (P = 0.041) and preoperative KPS (P = 0.038) were independent prognostic factors in patients with SSM; while preoperative KPS (P = 0.001) and serum album level (P < 0.001) were independent prognostic factors in patients with MSM. CONCLUSION: The number of spinal metastases has not proven to be useful in predicting the prognosis for patients with MSCC. Consequently, more aggressive operations should be considered for patients with multiple spinal metastases.

Patient Characteristics Following Surgery for Spinal Metastases: A Multicenter Retrospective Study.

OBJECTIVES: To summarize the epidemiological characteristics of patients following surgery for spinal metastases retrospectively and make a univariate analysis to identify independent variables that could affect the operation decision making. METHODS: This was a multicenter retrospective review of patients with spinal metastasis who were treated with surgery from 1 January 2007 to 31 July 2019. Basic clinical data were analyzed retrospectively by univariate analysis to identify independent variables that could affect the decision of operation modalities, including gender, age, spinal metastatic site, Frankel score, Karnofsky performance score (KPS), spinal instability neoplastic score (SINS), visual analogue scale (VAS), Tokuhashi score, urinary and fecal incontinence, spinal pathological fracture, primary tumor, extraspinal metastasis, visceral metastasis, and bone lesion (osteolytic, osteoblastic or mixed). RESULTS: A total of 580 patients including 332 males and 248 females were enrolled in the study with an average age of 58.26 years old (range, 13-86 years old). The most common spinal metastatic level was the thoracic vertebra (190 [32.76%]), followed by the lumbar vertebra (146 [25.17%]), cervical vertebra (47 [8.10%]), and sacral vertebra (35 [6.03%]). Metastases involving more than two sites of the cervical, thoracic, lumbar, and sacral vertebrae arose in 162 (27.93%) patients. For primary tumor, there were 198 (34.14%) cases of lung cancer, 41 (7.07%) cases of kidney cancer, 39 (6.72%) cases of breast cancer, 38 (6.55%) cases of gastrointestinal cancer, 35 (6.03%) cases of lymphoma and myeloma, 25 (4.31%) cases of prostate cancer, 24 (4.14%) cases of liver cancer, 23 (3.97%) cases of mesenchymal tissue sarcoma, 20 (3.45%) cases of thyroid cancer, and 84 (14.48%) cases were tumor with unknown origin. Sixty-three (10.86%) patients received minimally invasive surgery, 460 (79.31%) patients received palliative surgery, and the remaining 57 (9.83%) received tumor resection. According to the univariate analysis, the KPS score, SINS score, VAS score, Tokuhashi score, urinary and fecal incontinence, spinal pathological fracture, and bone lesion (osteolytic, osteoblastic or mixed) were independent and favorable factors affecting the surgery modalities. CONCLUSIONS: Surgical treatment for spinal metastases was mainly to relieve pain, rebuild spinal stability, improve nerve function, control local tumors, and improve the quality of life of patients. For middle-aged and elderly patients with good general conditions, severe pain, spinal pathological fracture, spine instability and without urinary and fecal incontinence, early surgical treatment should be actively carried out.

Relationship Between Visceral Metastases and Survival in Patients with Metastasis-related Spinal Cord Compression.

OBJECTIVE: To investigate whether visceral metastases have a significant impact on survival in patients with metastasis-related spinal cord compression (MSCC), and to determine the difference in prognosis between patients with and without visceral metastases. METHODS: Three institutional databases were searched to identify all patients who had undergone spinal surgery for spinal metastases between March 2002 and June 2010. Data on patient characteristics including pre- and post-operative medical conditions, were collected from medical records or by telephone follow-up. Survival data were obtained either from medical records or by searching a governmental cancer registry. RESULTS: The mean age of study patients was 59.6 ± 10.5 years (range, 18-84 years), of whom 102 were male and 67 female. The median and mean postoperative survival times were 7.0 ± 0.5 (95% CI 6.0-8.0) months and 12.6 ± 1.2 (95% CI 10.1-15.0) months, respectively, in all patients, being 5.0 ± 0.5 (95% CI 4.0-6.0) months and 10.8 ± 2.4 (95% CI 6.1-15.5) months, respectively, for patients with visceral metastases and 7.0 ± 0.8 (95% CI 5.4-8.6) months and 13.0 ± 1.4 (95%CI 10.3-15.6) months, respectively, for patients without visceral metastases (P = 0.87). These survival times did not differ significantly between groups. Multivariate Cox proportional hazard regressions showed that visceral metastases had no statistically significant association with survival (P = 0.277), whereas rate of growth of primary tumor (P = 0.003), preoperative Karnofsky performance status (KPS) (P < 0.001), change in KPS (P < 0.001), and Frankel grade (P = 0.091) were independent prognostic factors in the whole cohort (P = 0.005). Changes in KPS (P = 0.001) and major complications (P = 0.003) were significantly associated with survival in patients with visceral metastases, whereas rate of growth of primary tumor (P = 0.016), change in KPS (P = 0.001), and preoperative KPS (P < 0.001) were significantly associated with survival in patients without visceral metastases. CONCLUSIONS: Visceral metastases do not appear to predict the prognosis of patients with MSCC; thus, more aggressive surgery should be considered in patients with MSCC who have visceral metastases. Additionally, prognostic factors differ according to visceral metastases status in these patients.

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.