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Background: Head and neck osteosarcoma (HNOS) is the most common bone malignancy in the head and neck region, accounting for 10% of all osteosarcoma cases. Perineural invasion (PNI) is a notable indication of aggressive tumor behavior, which includes the phenomenon of tumor cells invading any of the 3 layers of the nerve sheath or tumor cells gathering, encircling one-third of the nerve circumference, and infiltrating and metastasizing along the nerve. PNI has been reported in various malignant tumors and is considered to be linked to poor prognosis., Purpose: The study's purpose is to measure the association between PNI and survival outcomes in patients with HNOS., Study Design, Setting, Sample: This retrospective cohort study focused on HNOS patients who underwent surgery at the Department of Oral and Maxillofacial Head and Neck Oncology, Shanghai Ninth People's Hospital School of Medicine, Shanghai Jiao Tong University, from January 1, 2019 to December 31, 2021. Patients who did not undergo complete surgical resection of the tumor, did not receive a conventional osteosarcoma diagnosis, and had positive surgical margins were eliminated., Predictor Variable: The predictor variable is PNI status. The pathological section of the tumor was consistent with any of the PNI features, which was considered PNI-positive., Main Outcome Variable(s): The primary outcome variables were 3-year disease-free survival (DFS) and 3-year overall survival. Secondary outcomes were 3-year tumor local recurrence and 3-year metastasis (MT)., Covariates: Covariates were categorized into the following categories: demographic variables (age, sex), clinical variables (tumor region, primary tumor), and treatment variables (chemotherapy, radiotherapy)., Analyses: Analytic statistical methods were used for the data analysis. Pearson χ 2 or Fisher's exact test was used to describe the baseline data. Kaplan-Meier is used to calculate survival rates. The Cox regression model was adapted for univariate and multivariate analysis. A P value less than .05 indicated statistical significance., Results: The study sample comprised 70 patients; 33 (47.1%) were male, and the mean age was 42.2 (standard deviation: 16.7) years. There were 15 (21.4%) cases of PNI. The 3-year DSF rate and OS rate were 67.3% and 82.0%, respectively. PNI-positive resulted in higher risk for MT (P ＜ .01, hazard ratio: 5.95, 95% confidence interval: 1.62-21.86) and negative impact on DFS (P < .01, hazard ratio: 6.35, 95% confidence interval: 2.11-19.17) for HNOS patients., Conclusion and Relevance: Positive PNI status was associated with decreased DFS and increased risk of MT., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Platelets have received growing attention for their roles in hematogenous tumor metastasis. However, the tumor-platelet interaction in osteosarcoma (OS) remains poorly understood. Here, using platelet-specific focal adhesion kinase (FAK)-deficient mice, we uncover a FAK-dependent F3/TGF-β positive feedback loop in OS. Disruption of the feedback loop by inhibition of F3, TGF-β, or FAK significantly suppresses OS progression. We demonstrate that OS F3 initiated the feedback loop by increasing platelet TGF-β secretion, and platelet-derived TGF-β promoted OS F3 expression in turn and modulated OS EMT process. Immunofluorescence results indicate platelet infiltration in OS niche and we verified it was mediated by platelet FAK. In addition, platelet FAK was proved to mediate platelet adhesion to OS cells, which was vital for the initiation of F3/TGF-β feedback loop. Collectively, these findings provide a rationale for novel therapeutic strategies targeting tumor-platelet interplay in metastatic OS., Competing Interests: Declaration of Competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction:  A semiknee mega endoprosthesis (SKMEP) was used to replace the resected distal femur or proximal tibia in skeletally immature bone sarcoma patients. This study investigated the surgical technique, endoprosthesis survival rate, functional outcome, complications, and approaches to resolve limb-length discrepancy (LLD) following this procedure., Patients and Methods:  In total, 15 girls and 16 boys with a mean age of 9.1 years (range, 4-12) and 8.9 years (range, 5-13), respectively, were included in this study. The mean length of the resected distal femur (15 cases) and proximal tibia (16) was 145.0 and 122.8 mm, respectively. Altogether, 19 custom-made SKMEPs and 12 modular units were used to reconstruct the bone and joint defects., Results:  The average follow-up was 82.8 months (range, 4-225 months). Five patients died of disease. Seven SKMEPs were revised to total knee endoprosthesis after a mean of 40.3 months. Nineteen patients retained the original SKMEP, and the mean LLD was 4.3 cm (range, 0-10 cm). One case each of Henderson type 1B, type 2A, type 2B, and type 5B failures was observed. Knee subluxation occurred in two cases. Although a slight laxity of the knee was identified on physical examination, the average Musculoskeletal Tumor Society 93(MSTS93) functional score was 84.5% (range, 57-97%). The estimated implant survival was 70.5% at 5 years., Conclusion:  This was the largest retrospective study reporting the application of SKMEP in bone sarcoma patients. For selected skeletally immature bone sarcoma patients, SKMEP is an option with satisfactory functional outcomes and survival rates. However, heightening pads or shoes to compensate the LLD were indispensable before subsequent LLD was adjusted by further operation(s)., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis., Patients and Methods: This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3., Results: Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population., Conclusions: Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma., (©2022 American Association for Cancer Research.)

Osteosarcoma (OS) is the most common malignant bone tumor. However, treatment strategies have not changed over the past 30 years. The relationship between OS and the immune microenvironment may provide a basis for the establishment of novel therapeutic targets. In this study, a large-scale gene expression dataset (GSE42352) was used to identify key genes in OS. A Target-OS dataset from the Cancer Genome Atlas was used as a validation set. Ecotropic viral integration site 2B ( EVI2B ) was significantly upregulated in OS tumor samples. Differentially expressed genes (DEGs) were identified between samples with high and low EVI2B expression in both the test and validation cohorts. The top three functions of DEGs determined by a gene set enrichment analysis (GSEA) were chemokine signaling, cytokine-cytokine receptor interaction, and Human T-cell leukemia virus 1 infection. A prognostic prediction model including EVI2B , DOCK2 , and CD33 was constructed by a Cox regression analysis. This model indicated that EVI2B is an independent protective prognostic marker in OS. An analysis of immune infiltration further showed that high EVI2B expression levels were correlated with high levels of macrophage infiltration. Protein expression data derived from the Human Protein Atlas suggested EVI2B to be highly expressed in monocytes. Finally, we validated the elevated expression of EVI2B in OS cell lines and OS tissue samples; these results were consistent with those of the analyses of the GSE42352 and Target-OS datasets. Our integrative bioinformatics analysis and experimental results provide clear evidence for the prognostic value of EVI2B in OS and its close relationship with monocyte and macrophage infiltration.

Purpose: Malignant pleural effusion (MPE) is an adverse prognostic factor in patients with osteoblastic osteosarcoma; however, the cellular contexts of MPE are largely unknown., Experimental Design: We performed single-cell RNA-sequencing (scRNA-seq) on 27 260 cells from seven MPE samples and 91 186 cells from eight osteosarcoma tissues, including one recurrent, one lung metastasis and six primary tumour (PT) samples, to characterize their tumour microenvironment., Results: Thirteen main cell groups were identified in osteosarcoma tumour and MPE samples. Immune cells dominate the cellular contexts in MPE with more T/NK cells and less osteoclasts compared to PT samples. Of T/NK cells, CD8 + GNLY + , CD8 + KLRC2 + T cells and FCGR3A + NK cells were enriched in MPE but CD4 + FOXP3 + Tregs were enriched in PT samples. Naïve IGHD + B and immune regulatory IGHA1 + B cells were largely identified in MPE, whereas bone metabolism-related CLEC11A + B cells were significantly enriched in osteosarcoma PT. M2-type TAMs, including CLEC11A&#95;TAM, C1QC&#95;TAM and Prolif&#95;TAMs, among myeloid cells were enriched in PT, which may suppress cytotoxicity activities of T cells through multiple ligand-receptor interactions. Mature LAMP3 + DCs were transformed from CD1C + DC and CLEC9A + DC sub-clusters when exposure to tumour alloantigens, which may improve T cell cytotoxicity activities on tumour cells under anti-PD-L1 treatments. In further, immune cells from MPE usually present up-regulated glycolysis and down-regulated oxidative phosphorylation and riboflavin metabolism activities compared to those in PT samples., Conclusions: Our study provided a novel cellular atlas of MPE and PT in patients with advanced osteosarcoma, which may provide potential therapeutic targets in the future., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Few investigations of venous tumor thrombus (VTT) in primary pelvic bone sarcomas are available. We aimed to identify the prevalence, associated factors, and prognosis of VTT across different types of pelvic sarcomas and to propose an algorithm for management., Methods: We included 451 consecutive cases of primary, bone-derived, treatment-naive, pelvic sarcomas in this study. Demographic data and the results of initial laboratory tests, imaging examinations, and oncological evaluations were extracted and analyzed. Forty-four cases of VTT were diagnosed with radiographic examinations, and 18 of them were verified histologically., Results: The cohort consisted of chondrosarcomas (41.2%), osteosarcomas (30.4%), Ewing sarcomas (15.5%), bone-derived undifferentiated pleomorphic sarcomas (5.8%), and other bone sarcomas (7.1%). The prevalence of VTT was 9.8% in the whole group, and associated factors included a lactate dehydrogenase (LDH) level of ≥230.5 U/L and invasion of the L5-S1 intervertebral foramen. Patients with pelvic osteosarcoma had a high prevalence of VTT (22.6%), and the associated factors in this group included a chondroblastic subtype, an LDH level of ≥187 U/L, and invasion of the obturator foramen and the L5-S1 intervertebral foramen. Patients with VTT had a poor prognosis with a median overall survival time of 14 months. Subgroup analyses of localized pelvic osteosarcoma indicated that the presence of VTT decreased the median overall survival time (21.5 versus 54.0 months for those without VTT, p = 0.003), median recurrence-free survival time (18.6 versus 32.4 months, p = 0.020), and median metastasis-free survival time (11.2 versus 41.0 months, p < 0.001)., Conclusions: VTT is most common in patients with pelvic osteosarcoma as compared with patients with other primary bone sarcomas, and it is associated with several factors. It is a negative prognostic factor. An algorithm for management of pelvic sarcomas with VTT stratified by the classification of the VTT might be beneficial, but further validation is necessary., Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This work was supported by grants from the Beijing Municipal Science & Technology Commission (No. Z181100001918025) and the National Natural Science Foundation of China, NSFC (No. 81872180). The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G469)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Objective: Limb salvage in pediatric patients remains a challenge. We describe a staged strategy. The procedure includes: (i) tumor removal and non-hinged static endoprosthesis reconstruction; (ii) leg length discrepancy (LLD) correction by shoe lift or distraction osteogenesis; and (iii) maturity reconstruction by regular endoprosthesis. The aim of the study was to investigate the results of non-hinged static megaprosthesis reconstruction and staged LLD correction in the treatment of malignant tumors in the distal femur in children., Methods: Non-hinged megaprostheses were implanted in 12 pediatric patients with osteosarcoma in the distal femur. The prosthesis consists of a femoral component with constrained condylar knee (CCK) design, and a tibial component with a small-diameter press-fit stem and derotation fins. A posterior stabilizing polyethylene component is fixed on the tibial component. The cases were prospectively followed up with focus on the growth rate of adjacent uninvolved bone in the salvaged limb, joint stability, knee stability, function outcome, length discrepancy, and surgery-related complications., Results: There were five girls and seven boys included in the study, with an average age at the time of primary surgery of 10.0 years (range, 8-12 years). All the tumors were located in the distal femur. The average follow up was 76.3 months (range, 24-139 months). The Ligament Augmentation and Reconstruction System (LARS) ligament was used in two patients to enhance the soft tissue reattachment and reconstruct medial collateral ligament (MCL). Ten patients were alive at the final follow-up and two had died of lung metastases. Expected LLD was 6.7 cm (range, 3.0-13.2 cm) at initial surgery. At the final follow-up, nine patients reached skeletal maturity and the actual LLD at the femur was 5.3 cm (range, 3.0-10.1 cm), excluding 1 cm correction at initial surgery by endoprosthesis. The proximal tibia physis showed an average of 86.7% (range, 56.5%-100%) growth of the contralateral side. The mean reduction in tibial length was 1.2 cm (range, 0.5-4.7 cm). Six patients received distraction osteogenesis at a mean length of 5.4 cm (range, 3.0-9.1 cm). Range of knee movement was between 85° and 125°, with an average of 102.5°. The Musculoskeletal Tumor Society 93 score of patients alive was 80.6 (range, 60-90)., Conclusion: Non-hinged static megaprosthesis followed by LLD correction with shoe lift or staged distraction osteogenesis appears to be an alternative option to treat children with malignant bone tumors around the knee., (© 2019 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Objective: To analyze the effectiveness of free vascularized fibula grafts (FVFG) for extensive bone defects after resection of lower limb malignant bone tumors., Methods: Between November 2015 and July 2018, 15 cases of lower limb malignant bone tumors were treated. There were 12 males and 3 females with an average age of 12.3 years (range, 9-21 years). There were 11 cases of osteosarcoma and 4 cases of Ewing's sarcoma. The tumor located at middle femur in 8 cases, lower femur in 4 cases, and middle tibia in 3 cases. The disease duration was 2-6 months (mean, 3.2 months). The tumor was completely removed, and the length of the bone defect was 8-23 cm (mean, 17.7 cm). The bone defect was repaired by FVFG, and combined inactivated tumor bone was used in 8 cases of femoral bone defect., Results: The average operation time was 280 minutes (range, 180-390 minutes). The average blood loss was 310 mL (range, 200-480 mL). All incisions healed by first intention. All patients were followed up 2-24 months with an average of 14.5 months. Bone healing achieved in all patients at 9-18 months (mean, 12.3 months) after operation except 1 patient which was followed up only 2 months. The fibula grafts had active metabolism and the average bone metabolism score was 184 (range, 111-257) in effected side and 193 (range, 127-259) in contralateral side. There was no difference between bilateral sides. The average Enneking score was 24.6 (range, 20-30) at last follow-up. No ankle instability or paralysis of common peroneal nerve occurred., Conclusion: FVFG appeared very efficient in repair of extensive bone defect after resection of lower limb malignant bone tumor.

Background: Venous tumor thrombus (VTT) in pelvic osteosarcoma has been regarded as a rare oncological condition and few literatures investigated this issue., Methods: We retrospectively reviewed 115 cases of pelvic osteosarcoma treated in our center from 2006 to 2016. Diagnosis of VTTs was made based on histo-pathological findings. We summarized the radiological manifestations of VTTs on CT, MRI, and PET/CT. We also compared the demographical, oncological, and radiological data between cases with or without VTTs to identify its predisposing factors., Results: Seventeen cases (14.8%) were diagnosed with VTT. Manifestations of VTTs on CT included increased caliber (64.7%), calcification (47.1%), low density on plain scan (100%), filling defect (100%), and streak-like enhancement (35.7%) on contrast enhancement. On MRI, the VTTs could be hypo- or iso-intense on T1WI (100%), hyperintense on T2WI (100%), and filling defect on contrast enhancement (100%). PET/CT showed high metabolic activity of the VTTs. The ranges of the VTTs included unilateral external iliac vein (EIV) (two cases), unilateral internal iliac vein (IIV) (one case), unilateral common iliac vein (CIV) and IIV (five cases), unilateral CIV + EIV (two cases), inferior vena cava (IVC) and unilateral CIV + EIV (one case), IVC and unilateral CIV + IIV (four cases), IVC and bilateral CIVs + IIVs (two cases). Multivariate analysis indicated that chondroblastic subtype and involvement of L5/S1 intervertebral foramen might predispose to VTTs., Conclusion: The incidence of VTTs in pelvic osteosarcoma was 14.8%. Comprehensive radiological studies help preoperative diagnosis of VTTs. Predisposing factors included chondroblasic subtype and involvement of L5/S1 intervertebral foramen., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Osteosarcoma is an aggressive bone malignancy presenting uncommonly in head and neck sites. Surgery is mainstay in treatment. However; trials show an improved survival with addition of chemotherapy in the treatment of extremity osteosarcoma. The head and neck osteosarcomas(HNOs) were excluded in these trials because of atypical presentation and disease course. Further; sufficient numbers were not possible for a trial. We present the largest retrospective study from single institute investigating the role of chemotherapy in the management of HNOs., Patients and Methods: The retrospective cohort of HNOs treated from 2007 to 2015 of a tertiary hospital were charted. The therapeutic and prognostic factors were analyzed for overall survival(OS), disease free survival(DFS), local control(LC) and metastasis(MT) in univariate and multivariate analysis. The minimum and median period of follow up was 12months and 56.04months respectively., Results: There was a total of 157 patients definitively treated with surgery in the time period. 7 patients had positive margins and all were maxillary or skull base tumors. The multivariate cox regression showed significance of tumor site(p=0.034), margin status (p=0.006), chemotherapy(p=0.025), histological subtype(p=0.012) as predictors of overall survival. The margin status(p=0.002), Radiotherapy(p=0.005) were significant predictors for local recurrence. The age and histology subtype(p=0.058) were borderline significant predictors of metastasis(p=0.065). The KM method for OS of different chemotherapy groups(p=0.013), and survival with and without chemotherapy(p=0.007) was significant. The OS was significantly better with adjuvant chemotherapy among various treatment plans(p=0.034)., Conclusion: Adjuvant chemotherapy improved OS while adjuvant radiotherapy improved local control of HNOs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Study Design: Twenty-six patients were treated surgically for sacral osteosarcomas in our center. The oncological and functional results are analyzed., Objective: To describe the general characteristics and evaluate the outcome of surgical treatment of primary osteosarcoma of the sacrum., Summary of Background Data: A very few reports have addressed the technique and outcome of surgical treatment of primary sacral osteosarcoma. The survival rate of such cases is low., Methods: The clinical data of 26 patients treated surgically for sacral osteosarcomas from June 2000 to December 2013 at our hospital were retrospectively reviewed., Results: There were 15 males and 11 females with a median age of 28 years (range, 12-68 years). Distal metastasis occurred in 13 patients (50%), and local recurrence occurred in 10 patients (38.5%, including 6 patients with additional distal metastasis). The 1-year and 5-year survival rates were 92.3% and 38.7%, respectively. Adequate and inadequate surgical margins were obtained in 16 and 10 cases, respectively. Patients with adequate margins had a significantly lower recurrence rate (P = 0.015) and higher event-free survival rate (P = 0.04) than those with inadequate margins. However, the overall survival rate did not differ significantly between patients with adequate and inadequate margins (P = 0.22). Only seven cases showed a good response based on necrosis rate (>90%). Patients with a better response to chemotherapy had better event-free and overall survival rates., Conclusion: Adequate surgical margins are achievable in most cases of sacral osteosarcomas. Adequate margins can significantly improve the recurrence rate and event-free survival rate compared with inadequate margins. However, sacrectomy is still a challenging surgical technique. Adequate margins are also difficult to obtain in sacrectomy. In addition, only a few patients had a good response to chemotherapy. These reasons lead to a low 5-year survival rate in primary sacral osteosarcoma patients., Level of Evidence: 4.

Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present, it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma, which, in a sense, have become a milestone as a second-line therapy for osteosarcoma. Although the recognization of muramyltripepetide phosphatidyl-ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival.

Osteosarcoma of head and neck is a rare condition comprising of <1% of all head and neck cancers, retrospective studies show difference in survival of mandibular osteosarcoma to other head and neck sites, necessitating investigation into site-specific survival and recurrence rates.

Background: Osteosarcoma is a common bone malignancy occurring infrequently in head and neck region, the NCDB database of osteosarcoma suggests that the survival and prognosis of the head and neck osteosarcomas lie midway among other sites of occurrence, poorest survival is pelvic region and best is upper extremity. The influence of other prognostic factors independently effecting survival and recurrence are not studied widely because of scarce data even in databases. More over; these database are underrepresent eastern population. The authors institute treated around 160 head and neck osteosarcomas (HNOS) from 2007 to 2013 which were evaluated retrospectively for prognostic factors effecting survival and recurrence in specific population., Patients and Method: The historical records of patients treated for head and neck osteosarcomas from 2007 to 2013 were charted. The clinical and pathological factors affecting the local recurrence (LR), overall survival (OS), disease free survival (DFS), metastasis (MT) were analyzed in univariate and multivariate cox regression model for survival., Results: A total of 160 HNOS patients were treated in the given time period, and 137 patients with follow up were analyzed. The median period of follow up was 3.067±0.356years for the alive patients. In the multivariate cox regression model for OS; surgical margin (p=0.000) was most significant, histological grade was borderline (p=0.062). For LR: surgical margin (p=0.002), histological subtype (p=0.048) and histological grade (p=0.024). For MT; surgical margin (p=0.000) was the significant factor., Conclusion: Histological grade and unclear margins are the significant independent prognostic factors effecting disease outcome of HNOS., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Neuropilin 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., Results: NRP2 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., Conclusions: Regulation 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.

Background: Shoulder function often is limited after tumor resection and endoprosthetic replacement of the proximal humerus. This is partly attributable to the inability to reliably reattach rotator cuff tendons to the prosthesis and achieve adequate shoulder capsule repair with a metallic prosthesis. An option to attain these goals is to use synthetic mesh for the reconstruction, although the value of this method has not been well documented in the literature., Questions/purposes: We asked whether patients who had shoulder reconstruction using synthetic mesh had (1) better shoulder function; (2) improved ROM compared with shoulder reconstructions without mesh; and (3) more stable joints compared with those in patients with similar resections who had reconstructions without synthetic mesh., Methods: During a 5-year period, we performed 41 intraarticular resections with endoprosthetic reconstructions for malignancies in the proximal humerus meeting specified criteria to generate similarity in the study groups. Twelve patients (29%) were lost to followup before 24 months, leaving 29 patients available for review at a mean of 45 months (range, 24-70 months). This retrospective study compared 14 patients with soft tissue reconstruction that included synthetic mesh with 15 patients with soft tissue reconstruction without the use of synthetic mesh. The choice was made during consultation between the patient and surgeon, after reviewing the perceived advantages and disadvantages of each approach. A tumor band (ligament advanced reinforcement system) was used as synthetic mesh and wrapped around the prosthesis of the proximal humerus for soft tissue reconstruction in the reconstruction-with-mesh group. Study endpoints included the Musculoskeletal Tumor Society (MSTS) function scores, American Shoulder and Elbow Surgeons (ASES) score, shoulder ROM, and proximal migration of the humeral prosthesis., Results: The mean MSTS score for patients without synthetic mesh reconstruction was 20 ± 3 points (66%), whereas for patients with synthetic mesh reconstruction, the mean score was 24 ± 2 points (79%; p = 0.001). Patients with synthetic mesh reconstruction had a higher mean total ASES score (85 ± 1.1 points versus 72 ± 1.7 points; p = 0.025), and better function for activities of daily living. They also had better ROM on mean active forward flexion (p = 0.020), abduction (p < 0.001), and external rotation (p < 0.001) than patients without synthetic mesh reconstruction. Proximal migration of the prosthesis was observed in five of 15 of patients in the group without synthetic mesh reconstruction and in none of those treated with synthetic mesh (p = 0.042)., Conclusions: Patients with intraarticular resection and endoprosthetic replacement of the proximal humerus with reconstruction that included synthetic mesh had better shoulder function and ROM, and more stable joints than patients who had reconstruction without synthetic mesh. This result supports prior observations by others and it remains to be shown whether use of the ligament advanced reconstruction system is superior to other types of mesh or other types of reconstructions. Further investigation is needed but our results indicate that using mesh should be considered for patients with tumor resection and endoprosthetic replacement of the proximal humerus.

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.

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.

Background: Osteosarcoma (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., Results: In 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., Conclusions: Taken 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.

Objective: To evaluate the effectiveness of bipolar prosthetic replacement for proximal femoral tumors from the perspectives of patient survival, prosthesis survival, functional outcomes, and complication rates., Methods: Between July 2001 and July 2010, 96 patients with proximal femoral tumors underwent wide resection and bipolar prosthetic replacement, including 83 cases of primary femoral tumors and 13 cases of soft tissue sarcomas involving the proximal femur. There were 50 male and 46 female patients with a mean age of 43.2 years (range, 15-69 years). Prosthetic replacement for proximal femoral tumors was used in 85 patients and deactivated bone-prosthetic complex was used in 11 patients. According to Enneking staging, the patients were divided into 3 groups: group A, 24 patients at stages IA, IB, and benign lesion; group B, 56 patients at stages IIA and IIB; and group C, 16 patients at stage III, myeloma, and lymphoma. The American Musculoskeletal Tumor Society 1993 version (MSTS93) functional score was used to evaluate the lower limb function., Results: Primary healing of incision was obtained in 93 patients; 3 patients had poor healing, which was cured after debridement. Of the patients, 89 were followed up 6.5 years on average (range, 1-10 years). During follow-up, 28 patients died of tumor. The 5- and 10-year survival rates of patients were 100% in group A, and were 56.5% and 41.5% in group B respectively, and the 5-year survival rate was 18.4% in group C; there was significant difference among 3 groups (P < 0.01). The 5- and 10-year survival rates of prosthesis were 74.4% and 62.5%, which were significantly higher than those of patients in groups B and C (P < 0.01). Sixty-one patients were followed up 1-10 years (mean, 4.7 years) for functional evaluation. The mean MSTS93 score of the survival patients was 79% (range, 63%-95%) at last follow-up. Complications were observed in 15 patients (16.9%): hip dislocation in 2, delayed infection in 2, aseptic loosening in 8, severe acetabulum wear in 1, and hip pain in 2., Conclusion: Bipolar proximal femoral prosthetic replacement for proximal femoral tumors can provide a satisfactory functional outcome, especially for tumors at stage II or III and myeloma and lymphorma patients. Revision is needed because of main late complications of aseptic loosening, hip pain, and acetabulum wear.

Background and Objectives: The purpose of this study was to estimate the risk factors having relationships with pathologic fracture of osteosarcoma of extremities and to evaluate the role of limb salvage surgery in this group of patients., Methods: We retrospectively analyzed 28 consecutive cases of pathologic fracture of primary high-grade localized osteosarcoma of extremities between June 1, 2001 and June 30, 2009. All patients underwent limb salvage surgery and neo-adjuvant chemotherapy. They had a median age of 14 years (range, 6-30 years). The average follow-up time was 40.7 months (range, 9-108 months). Clinicopathological factors were analyzed in relation to pathologic fracture. Their recurrence and survival rates were compared to those in cohort of 171 osteosarcoma patients without pathologic fracture who underwent limb salvage surgery during the same period at the same institution., Results: Less than 15 years, telangiectatic histological subtype, tumor located at the proximal humerus, and radiographical manifested as osteolytic features were risk factors in relation to pathologic fracture. The overall 3- and 5-year survival rates were 50.5% and 45.4%, respectively, in the fracture group, and were not significantly different from those in the control group (71.0% and 61.9%, respectively). Of all 28 fracture patients, 4 experienced local recurrences (14.2%) and 14 developed distant metastasis (50%), which were not significantly different from the rates in the control group (8.8% and 37.4%, respectively)., Conclusion: Limb salvage surgery with adequate margins combined with neo-adjuvant chemotherapy for pathologic fracture of osteosarcoma did not seem to significantly increase the risk of local recurrence or distal metastasis., (Copyright © 2012 Wiley Periodicals, Inc.)

Background and Objectives: Surgical treatment of pelvic osteosarcoma is often challenging. The objective of this study was to assess the oncologic and functional outcome and the operation-related complications of patients with pelvic osteosarcoma who were treated in a single center in the past decade., Methods: Nineteen patients underwent surgical procedures between June 2000 and June 2009. There were 11 males and 8 females with a mean age of 30 years. According to Enneking and Dunham pelvic classification system, there were: Type I-3, Type I + IV-3, Type I + II-2, Type II + III-4, Type I + II+ III-1, Type III-1, and type I + II+ IV-5. All patients received chemotherapy., Results: Local recurrence rate was 26.3% (5/19). The 5-year overall survival rate was 44.9%. Seventeen patients received reconstruction after tumor resection. The average MSTS 93 score was 18 (10-23) for the 11 patients with hemipelvic endoprosthetic reconstruction and 23 (20-25) for 6 patients with rod-screw reconstruction. Complication was found in 7 of 19 patients (36.8%)., Conclusion: The oncological results of pelvic osteosarcoma are poor at best. Even with a higher complication rate, we believe restoration of pelvic ring continuity and hip joint mobility is reasonable option to achieve favorable functional outcomes in selected patients., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: To investigate the clinical outcome of consecutive pelvic osteosarcoma treated with surgery and chemotherapy in a single institution, and to discuss the surgical strategy, resection and reconstruction., Methods: Twenty-one consecutive cases with pelvic osteosarcoma underwent surgical procedures between June 2000 and June 2009. There were 12 male and 9 female with a mean age of 32 years. According to Enneking and Dunham pelvic classification system, type Iwas 3 cases, type I+IV 3 cases, type I+II 4 cases, type II+III 4 cases, type I+II+III 1 case, type III 1 case, and type I+II+IV 5 cases. Among the 21 cases, 19 were diagnosed as classical osteosarcoma and 2 were diagnosed as low-grade pathologically. All the tumors were stage IIB. All the patients received en-bloc resection with 13 wide resection and 8 marginal resection. Thirteen patients underwent modular hemi-pelvic endoprosthesis reconstruction, and 5 patients underwent rod-screw system reconstruction combined with autograft. Two patients received hemipelvectomy and one type III patients had resection without reconstruction. The mean follow-up period was 30.3 months (range, 6.0-87.0)., Results: Thirteen patients out of 21 survived after treatment. The overall survival rate was 61.9%, and 23.8% patients were alive without disease. The estimated 5-year survival rate was 44.2% based on Kaplan-Meier curve. The local recurrence rate was 28.6%, among which 4 cases were type II resection, 1 was type I resection, 1 was type I+IV resection.No local relapse was found on the hemipelvectomy and type III resection cases. The local recurrence rate after wide resection was 23.1%, and 37.5% for marginal resection.Nine patients had lung metastases and one patient was found bone and lymph node metastases. The MSTS 93 function score was 20.6 ± 5.4 for 13 patients, and 22.5 ± 2.1 for rod-screw reconstruction cases. The function score was 17.7 ± 5.5 for hemi-pelvic prosthetic reconstruction., Conclusion: Limb salvage procedures could be performed on most pelvic osteosarcoma cases, and satisfying function outcome could be achieved with proper reconstruction, however, the overall survival is still lower compared with those in extremities.

Given that arsenic trioxide (As(2)O(3)) has been successfully used as a chemotherapeutic agent for refractory malignant tumors, this study is aimed at investigating the effect of As(2)O(3) on human Adriamycin resistant osteosarcoma cell line Saos-2. The mechanism underlying multi drug resistance (MDR) in osteosarcoma cells and the anti-tumor effect of As(2)O(3) on Adriamycin resistant osteosarcoma cells were analyzed. In our experiment, we first selected Adriamycin resistant osteosarcoma cell line by growing the classic osteosarcoma cell line Saos-2 in the medium with increasing drug concentrations. Then, we compared the IC50s of the osteosarcoma cells treated with different anticancer drugs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Subsequently, we assessed the expression of classic MDR related molecules, Pgp, multidrug resistance-associated protein (MRP) and glutathione (GSH) activity in the wild type and Adriamycin resistant Saos-2 cells. Furthermore, the apoptosis was assessed by concerning DNA fragment and flow cytometry with Annexin-V staining. To elucidate the underlying mechanism of the apoptosis, related proteins Bcl-2, Bcl-xL, Bax, Bak, cleaved Caspase-3 and cleaved Caspase-9 were analyzed by western blotting. The data showed that the resistance to Adriamycin affected the sensitivity of osteosarcoma cell to other chemotherapeutic agents. The IC50s of Saos-2/ADM cells for methotrexate (1.74-fold), Cisplatin (1.43-fold) and As(2)O(3) (1.21-fold) were increased compared with Saos-2 control cells. The expression of Pgp was upregulated comparing with the control cells. No significant difference was detected about the MRP and the glutathione-S-transferase activity and intracellular GSH concentration among different treated osteosarcoma cells. Apoptosis was observed and proved. The western blotting showed that the expression of Bcl-2 and Bcl-xL was downregulated. Meanwhile, the level of Bax, Bak, cleaved Caspase-3 and cleaved Caspase-9 was upregulated after treated with As(2)O(3). The study suggests that Adriamycin resistant osteosarcoma cells have good response to As(2)O(3)-based chemotherapy in vitro, probably via the pathway of inducing apoptosis. And As(2)O(3) might serve as an excellent alternative candidate for adjuvant chemotherapeutic agent on this incurable pediatric sarcoma.

Objective: To discuss the reconstruction methods and treatment effects of osteosarcoma around the knee in skeletal immature children and adolescent patients., Methods: Between October 1996 and December 2005, 89 children and adolescent patients with osteosarcoma around the knee received limb salvage surgery. The average age was 13 years old. Tumor involved distal femur in 52 cases, proximal tibia in 36 cases, and both parts in one patient. Different limb salvage methods, including tumor recycle bone reimplantation (n = 20), partial endoprosthesis (n = 19) and total knee megaprosthesis replacement (n = 50) were chosen according to both the age of the patient and the skeletal. Expandable and special designed pediatric prosthesis some times might also be considered., Results: After average follow up of 42 months, 4 cases of local recurrence and 11 of metastasis occurred in tumor recycle bone group; 1 case of local recurrence and 4 of metastasis in partial endoprosthesis group; another 4 cases of local recurrence and 9 patients died of disease in total knee megaprosthesis group. The five-year survival rate was 47.1%, 71.7% and 68.2% in 3 groups respectively. There were 3 deep infections in all the cases, 2 subluxations and 1 amputation after operation for limb ischemia in partial endoprosthesis group. The average functional score of MSTS 93 was 21.43 point, 23.40 point and 25.32 point; and the average leg length discrepancy was 5.48, 4.50 and 3.12 cm in 3 groups respectively., Conclusions: Partial-joint prosthesis or other methods which can avoid injury of the opposite epiphysis should be used to decrease the possibility of limb length discrepancy and ease the following revised arthroplasty. For patient with almost mature skeletal, total knee megaprosthesis may be a proper choice for better function result.

Objective: To assess the clinical outcome of the limb salvage surgery and complications occurring in the lower extremities after a wide resection of sarcoma., Methods: A total of 167 patients underwent a limb-sparing procedure by means of the implantation of a custom-made or modular tumor endoprosthesis from July 1997 to July 2004. Of the 167 patients, 100 were followed up, including 56 males and 44 females, with their ages ranging from 13 to 57 years at surgery. In 5 patients, a proximal femur prosthesis was implanted; in 57 patients, a distal femur prosthesis was implanted; and in 38 patients, a proximal tibia prosthesis was implanted. According to the Enneking staging, 3 patients were grouped in the stage of II A, 85 in I B, and 12 in III. Seventy-one patients used a domestic prosthesis, and 29 patients used a prosthesis made in Link Company, Germany. For the reconstruction, 17 patients used an autograft prosthesis composite, 21 patients used the allograft prosthesis composite, and the remaining 62 patients used an artificial prosthesis. All the patients received chemotherapy for 1-2 courses and 3-5 courses before operation and after operation, respectively. After operation, The Musculoskeletal Tumor Society(MSTS) score was used to evaluate the recovery of their corresponding functions., Results: According to the follow-up for 1-8 years, with a median of 3.5 years, and the assessment by the Kaplan-Meier estimate, the 3-year survival rate of the prostheses was 81.8%, and the 5-year survival rate was 65%. As for the complications, prosthesis breakage occurred in 6 patients, periprosthesis infection in 13 patients, aseptic loosening in 2 patients, non-union between the host bone and graft bone in 5 patients, allograft absorption in 2 patients, prosthesis sinking in 2 patient, and periprosthesis fracture in 1 patient. Local recurrence developed in 7 patients within 6 months to 2 years after operation. Of the 7 patients, 4 had a recurrence of the soft tissue tumor for which resection was performed; the other 3 patients underwent amputation of the diseased limb. The mean MSTS score was 23. 30 +/- 5.17, with an excellent limb function in 62 patients, good in 27 patients, fair in 7 patients, and poor in 4 patients. The overall excellent and good function was obtained in 89% of the patients., Conclusion: We conclude that tumor prostheses can give a satisfactory functional outcome after the tumor around the knee is removed; however, the tumor prostheses still need to be further improved because of a high complication rate.