Multilevel Pedicle Subtraction Osteotomy for Correction of Thoracolumbar Kyphosis in Ankylosing Spondylitis: Clinical Effect and Biomechanical Evaluation.

OBJECTIVE: To compare the clinical outcomes and biomechanical characteristics of 1-, 2-, and 3-level pedicle subtraction osteotomy (PSO), and establish selection criteria based on preoperative radiographic parameters. METHODS: Patients undergone PSO to treat ankylosing spondylitis from February 2009 to May 2019 in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were enrolled. According to the quantity of osteotomy performed, the participants were divided into group A (1-level PSO, n = 24), group B (2-level PSO, n = 19), and group C (3-level PSO, n = 11). Clinical outcomes were assessed before surgery and at the final follow-up. Comparisons of the radiographic parameters and quality-of-life indicators were performed among and within these groups, and the selection criteria were established by regression. Finite element analysis was conducted to compare the biomechanical characteristics of the spine treated with different quantity of osteotomies under different working conditions. RESULTS: Three-level PSO improved the sagittal parameters more significantly, but resulted in longer operative time and greater blood loss (p < 0.05). Greater stress was found in the proximal screws and proximal junction area of the vertebra in the model simulating 1-level PSO. Larger stress of screws and vertebra was observed at the distal end in the model simulating 3-level PSO. CONCLUSION: Multilevel PSO works better for larger deformity correction than single-level PSO by allowing greater sagittal parameter correction and obtaining a better distribution of stress in the hardware construct, although with longer operation time and greater blood loss. Three-level osteotomy is recommended for the patients with preoperative of global kyphosis > 85.95°, T1 pelvic angle > 62.3°, sagittal vertical alignment > 299.55 mm, and pelvic tilt+ chin-brow vertical angle > 109.6°.

Postoperative quality of life in patients with ankylosing spondylitis and thoracolumbar kyphosis: risk factors and personalized sagittal reconstruction strategy.

OBJECTIVE: The aim of this study was to investigate the factors affecting postoperative quality of life in patients with ankylosing spondylitis (AS) and thoracolumbar kyphosis (TLK), and establish a personalized sagittal reconstruction strategy. METHODS: Patients with AS and TLK who underwent pedicle subtraction osteotomy (PSO) from February 2009 to May 2019 were retrospectively included. Quality of life and spinal sagittal radiographic parameters were collected before surgery and at the last follow-up. Patients were divided into two groups based on the attainment of minimal clinically important difference (MCID) on the Bath Ankylosing Spondylitis Functional Index and Oswestry Disability Index. Comparisons of radiographic parameters and clinical outcomes were conducted between and within groups. Regression analysis was used to identify the risk factors within the missing MCID cohort. Sagittal reconstruction equations were established using the pelvic incidence (PI) and thoracic inlet angle (TIA) in the reached MCID cohort. RESULTS: The study comprised 82 participants. Significant improvements were observed in most radiographic parameters and all quality-of-life indicators during the final follow-up compared with the preoperative measures (p < 0.05). Factors including cervical lordosis (CL) ≥ 18° (OR 9.75, 95% CI 2.26-58.01, p = 0.005), chin-brow vertical angle (CBVA) ≥ 25° (OR 14.7, 95% CI 3.29-91.21, p = 0.001), and pelvic tilt (PT) ≥ 33° (OR 21.77, 95% CI 5.92-103.44, p < 0.001) independently correlated with a failure to attain MCID (p < 0.05). Sagittal realignment targets were constructed as follows: sacral slope (SS) = 0.84 PI - 17.4° (R2 = 0.81, p < 0.001), thoracic kyphosis (TK) = 0.51 PI + 10.8° (R2 = 0.46, p = 0.002), neck tilt (NT) = 0.52 TIA - 5.8° (R2 = 0.49, p < 0.001), and T1 slope (T1S) = 0.48 TIA + 5.8° (R2 = 0.45, p = 0.002). CONCLUSIONS: PSO proved efficacious in treating AS complicated by TLK, yielding favorable outcomes. CBVA ≥ 25°, CL ≥ 18°, and PT ≥ 33° were the primary factors affecting postoperative quality of life in patients with AS. The personalized sagittal reconstruction strategy in this study focused on the subjective sensations and daily needs of patients with AS, which were delineated by the equations SS = 0.84 PI - 17.4°, TK = 0.51 PI + 10.8°, NT = 0.52 TIA - 5.8°, and T1S = 0.48 TIA + 5.8°.

Investigating the association between serum ADAM/ADAMTS levels and bone mineral density by mendelian randomization study.

PURPOSE: A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders. METHODS: The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship. RESULTS: The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (ß = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship. CONCLUSION: Our study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

Application of vertebral body compression osteotomy in pedicle subtraction osteotomy on ankylosing spondylitis kyphosis: Finite element analysis and retrospective study.

Background: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease, with pathological characteristics of bone erosion, inflammation of attachment point, and bone ankylosis. Due to the ossified intervertebral disc and ligament, pedicle subtraction osteotomy (PSO) is one of the mainstream surgeries of AS-related thoracolumbar kyphosis, but the large amount of blood loss and high risk of instrumental instability limit its clinical application. The purpose of our study is to propose a new transpedicular vertebral body compression osteotomy (VBCO) in PSO to reduce blood loss and improve stability. Methods: A retrospective analysis was performed on patients with AS-related thoracolumbar kyphosis who underwent one-level PSO in our hospital from February 2009 to May 2019. A total of 31 patients were included in this study; 6 received VBCO and 25 received eggshell vertebral body osteotomy. We collected demographic data containing gender and age at diagnosis. Surgical data contained operation time, estimated blood loss (EBL), and complications. Radiographic data contained pre-operative and follow-up sagittal parameters including chin brow-vertical angle (CBVA), global kyphosis (GK), thoracic kyphosis (TK), and lumbar lordosis (LL). A typical case with L2-PSO was used to establish a finite element model. The mechanical characteristics of the internal fixation device, vertebral body, and osteotomy plane of the two osteotomy models were analyzed under different working conditions. Results: The VBCO could provide comparable restoring of CBVA, GK, TK, and LL in the eggshell osteotomy procedure (all p > 0.05). The VBCO significantly reduced EBL compared to those with eggshell osteotomy [800.0 ml (500.0-1,439.5 ml) vs. 1,455.5 ml (1,410.5-1,497.8 ml), p = 0.033]. Compared with the eggshell osteotomy, VBCO showed better mechanical property. For the intra-pedicular screw fixation, the VBCO group had a more average distributed and lower stress condition on both nails and connecting rod. VBCO had a flattened osteotomy plane than the pitted osteotomy plane of the eggshell group, showing a lower and more average distributed maximum stress and displacement of osteotomy plane. Conclusion: In our study, we introduced VBCO as an improved method in PSO, with advantages in reducing blood loss and providing greater stability. Further investigation should focus on clinical research and biomechanical analysis for the application of VBCO.

Circulating Monocytes Act as a Common Trigger for the Calcification Paradox of Osteoporosis and Carotid Atherosclerosis via TGFB1-SP1 and TNFSF10-NFKB1 Axis.

Background: Osteoporosis often occurs with carotid atherosclerosis and causes contradictory calcification across tissue in the same patient, which is called the "calcification paradox". Circulating monocytes may be responsible for this unbalanced ectopic calcification. Here, we aimed to show how CD14+ monocytes contribute to the pathophysiology of coexisting postmenopausal osteoporosis and carotid atherosclerosis. Methods: We comprehensively analyzed osteoporosis data from the mRNA array dataset GSE56814 and the scRNA-seq dataset GSM4423510. Carotid atherosclerosis data were obtained from the GSE23746 mRNA dataset and GSM4705591 scRNA-seq dataset. First, osteoblast and vascular SMC lineages were annotated based on their functional expression using gene set enrichment analysis and AUCell scoring. Next, pseudotime analysis was applied to draw their differentiated trajectory and identify the key gene expression changes in crossroads. Then, ligand-receptor interactions between CD14+ monocytes and osteoblast and vascular smooth muscle cell (SMC) lineages were annotated with iTALK. Finally, we selected calcification paradox-related expression in circulating monocytes with LASSO analysis. Results: First, we found a large proportion of delayed premature osteoblasts in osteoporosis and osteogenic SMCs in atherosclerosis. Second, CD14+ monocytes interacted with the intermediate cells of the premature osteoblast and osteogenic SMC lineage by delivering TGFB1 and TNFSF10. This interaction served as a trigger activating the transcription factors (TF) SP1 and NFKB1 to upregulate the inflammatory response and cell senescence and led to a retarded premature state in the osteoblast lineage and osteogenic transition in the SMC lineage. Then, 76.49% of common monocyte markers were upregulated in the circulating monocytes between the two diseases, which were related to chemotaxis and inflammatory responses. Finally, we identified 7 calcification paradox-related genes on circulating monocytes, which were upregulated in aging cells and downregulated in DNA repair cells, indicating that the aging monocytes contributed to the development of the two diseases. Conclusions: Our work provides a perspective for understanding the triggering roles of CD14+ monocytes in the development of the calcification paradox in osteoporosis- and atherosclerosis-related cells based on combined scRNA and mRNA data. This study provided us with an elucidation of the mechanisms underlying the calcification paradox and could help in developing preventive and therapeutic strategies.

Special type of distal junctional failure exhibits pelvic incidence changes: sacroiliac joint-related pain following lumbar spine surgery.

Background: Currently, change in pelvic incidence (PI) in patients after spinal surgery have not been associated with clear clinical symptoms. This study sought to compare changes in the sagittal parameters of different patients before and after thoracolumbar spine surgery, the relationship between PI change and sacroiliac joint pain (SIJP) after surgery was clarified, and the correlation between PI change and sacroiliac joint (SIJ) activity was verified. Methods: This study retrospectively analyzed the data of patients who underwent thoracolumbar fusion at Sun Yat-sen Memorial Hospital from January 2019 to June 2021. The spinal and pelvic parameters [including pelvic tilt (PT), sacral slope (SS), PI, lumbar lordosis (LL) angle, etc.] of 409 patients with standard standing lateral radiographs before and after surgery were compared and analyzed. Postoperative follow-up of all patients with standardized SIJP assessment. The incidence of postoperative SIJP, and its correlation with sagittal parameters of the spine and pelvis, surgical methods, and the basic characteristics of patients were analyzed. The Chi-square test was used for categorical variables, the independent-sample t-test was used for generally conformed normally distributed continuous variables. Risk factors associated with the development of SIJP were analyzed using logistics regression. Correlations among SS, PI, and the 4 other sagittal parameters were analyzed using the Pearson correlation coefficient (r). Results: Postoperative PI changes tended to be larger in the lowest instrumented vertebra (LIV) (L4 and above: 1.63°; L5: 2.43°; S1: 3.83°; P<0.05) and longer fixed segment. The risk factors for SIJP included a PI >4° [odds ratio (OR) =13.051; P<0.001], LIV S1 (OR =3.378; P=0.023), and fixed total segment ≥3 (OR =2.632; P=0.038). ∆PI was significantly correlated with ∆SS in patients with non-S1 distal fixation vertebrae (R2=0.388; P<0.01), but no such correlation was found in patients with S1 distal fixation vertebrate. Conclusions: Changes in PI values after thoracolumbar spine surgery can correctly reflect the motion state of the SIJ. Excessive changes in PI (>4°) are similar to the mechanism of distal junctional kyphosis (DJK), while such changes make patients prone to SIJP following lumbar spine surgery.

A Comprehensive Understanding of the Genomic Bone Tumor Landscape: A Multicenter Prospective Study.

Complexity and heterogeneity increases the difficulty of diagnosis and treatment of bone tumors. We aimed to identify the mutational characterization and potential biomarkers of bone tumors. In this study, a total of 357 bone tumor patients were recruited and the next generation sequencing (NGS)-based YuanSu450 panel, that includes both DNA and RNA sequencing, was performed for genomic alteration identification. The most common mutated genes in bone tumors included TP53, NCOR1, VEGFA, RB1, CCND3, CDKN2A, GID4, CCNE1, TERT, and MAP2K4. The amplification of genes such as NCOR1, VEGFA, and CCND3 mainly occurred in osteosarcoma. Germline mutation analysis reveal a high frequency of HRD related mutations (46.4%, 13/28) in this cohort. With the assistance of RNA sequencing, 16.8% (19/113) gene fusions were independently detected in 20% (16/79) of patients. Nearly 34.2% of patients harbored actionable targeted mutations, of which the most common mutation is CDKN2A deletion. The different mutational characterizations between juvenile patients and adult patients indicated the potential effect of age in bone tumor treatment. According to the genomic alterations, the diagnosis of 26 (7.28%) bone tumors were corrected. The most easily misdiagnosed bone tumor included malignant giant cell tumors of bone (2.8%, 10/357) and fibrous dysplasia of bone (1.7%, 6/357). Meanwhile, we found that the mutations of MUC16 may be a potential biomarker for the diagnosis of mesenchymal chondrosarcomas. Our results indicated that RNA sequencing effectively complements DNA sequencing and increased the detection rate of gene fusions, supporting that NGS technology can effectively assist the diagnosis of bone tumors.

Development of a Chemoresistant Risk Scoring Model for Prechemotherapy Osteosarcoma Using Single-Cell Sequencing.

Background: Chemoresistance is one of the leading causes that severely limits the success of osteosarcoma treatment. Evaluating chemoresistance before chemotherapy poses a new challenge for researchers. We established an effective chemoresistance risk scoring model for prechemotherapy osteosarcoma using single-cell sequencing. Methods: We comprehensively analyzed osteosarcoma data from the bulk mRNA sequencing dataset TARGET-OS and the single-cell RNA sequencing (scRNA-seq) dataset GSE162454. Chemoresistant tumor clusters were identified using enrichment analysis and AUCell scoring. Its differentiated trajectory was achieved with inferCNV and pseudotime analysis. Ligand-receptor interactions were annotated with iTALK. Furthermore, we established a chemoresistance risk scoring model using LASSO regression based on scRNA-seq-based markers of chemoresistant tumor clusters. The TARGET-OS dataset was used as the training group, and the bulk mRNA array dataset GSE33382 was used as the validation group. Finally, the performance was verified for its discriminatory ability and calibration. Results: Using bulk RNA data, we found that osteogenic expression was upregulated in chemoresistant osteosarcoma as compared to chemosensitive osteosarcoma. Then, we transferred the bulk RNA findings to scRNA-seq and noticed osteosarcoma tumor clusters C14 and C25 showing osteogenic cancer stem cell expression patterns, which fit chemoresistant characteristics. C14 and C25 possessed bridge roles in interactions with other clusters. On the one hand, they received various growth factor stimulators and could potentially transform into a proliferative state. On the other hand, they promote local tumor angiogenesis, bone remodeling and immunosuppression. Next, we identified a ten-gene signature from the C14 and C25 markers and constructed a chemoresistant risk scoring model using LASSO regression model. Finally, we found that chemoresistant osteosarcoma had higher chemoresistance risk score and that the model showed good discriminatory ability and calibration in both the training and validation groups (AUCtrain = 0.82; AUCvalid = 0.84). Compared with that of the classic bulk RNA-based model, it showed more robust performance in validation environment (AUCvalid-scRNA = 0.84; AUCvalid-bulk DEGs = 0.54). Conclusions: Our work provides insights into understanding chemoresistant osteosarcoma tumor cells and using single-cell sequencing to establish a chemoresistance risk scoring model. The model showed good discriminatory ability and calibration and provided us with a feasible way to evaluate chemoresistance in prechemotherapy osteosarcoma.

Construction of survival-related co-expression modules and identification of potential prognostic biomarkers of osteosarcoma using WGCNA.

Background: Osteosarcoma (OS) is a primary malignant bone tumor. Patients with different immune characteristics respond differently to chemotherapy and have a lower chance of survival. The potential pathogenesis and therapeutic targets of OS must be investigated further. Methods: OS expression profile data and clinical information were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and the Gene Expression Omnibus (GEO) databases. The immune-related gene set was obtained from the ImmPort database, and the immune-related gene expression profiles were used for non-negative matrix factorization (NMF) cluster analysis of patients in the 2 databases to find the best clustering number. In the TARGET database, OS patients were classified into low-risk and high-risk groups based on the differences in their survival rates. Weighted correlation network analysis (WGCNA) was applied to the low-risk and high-risk groups to determine the module with the lowest conservatism in order to differentiate the prognosis of the 2 groups. Results: A total of 500 key genes associated with poor prognosis were identified. Gene Ontology (GO) enrichment analysis revealed that the biological processes of these genes were primarily focused on the regulation of small guanosine triphosphatase (GTPase) mediated signal transduction, collagen-containing extracellular matrix, and Rho GTPase binding. A random survival forest identified EPHB3, TEAD1, and KRR1P1 as key genes. Their expression level was linked to overall survival. We discovered that the core genes were associated to immune cell infiltration. Simultaneously, paired survival analysis of two genes revealed differences in survival. We also reverse-predicted the main genes and developed their competitive endogenous RNA (ceRNA) network. Finally, utilizing the CellMiner database, we observed that the genes TEAD1 and EPHB3 were connected to drug sensitivity. Conclusions: In this study, we identified the modules and key genes related to the poor prognosis of OS patients by using WGCNA, and verified their impact on the prognosis of OS patients and their role in the immune microenvironment of OS. In addition, targeted gene related antitumor drugs were screened out. The discoveries may lead to novel molecular targets and treatment methods for OS patients. Keywords: Osteosarcoma (OS); weighted gene co-expression network analysis (WGCNA); gene.

Thoracolumbar kyphosis in postmenopausal osteoporosis patients without vertebral compression fractures.

Background: To investigate whether thoracolumbar kyphosis (TLK) of the spine is related to the reduction of bone mineral density (BMD) in postmenopausal osteoporosis women, and whether BMD of postmenopausal osteoporosis women can predict the occurrence of TLK. Methods: This retrospective cohort study included 224 postmenopausal female patients hospitalized for osteoporosis from December 2017 to December 2020, and the control group included 270 postmenopausal female patients hospitalized for thoracolumbar degenerative diseases. The age, body mass index (BMI), visual analogue scale (VAS), and BMD of the lumbar spine [BMD(L)] and femoral neck [BMD(F)] of all patients during admission were recorded. We measured and recorded the Cobb angle of thoracolumbar and the height of the thoracolumbar intervertebral space in the spinal X-ray lateral radiograph. The Pearson and Spearman correlation coefficients were used to calculate the correlation between each parameter in the group. The Chi-square test was used for categorical variables, the independent-sample t-test was used for normally distributed continuous variables, and two-sample non-parametric tests were used for non-normally distributed variables. Binary logistic regression analysis and receiver operating characteristic (ROC) curves were applied to determine independent risk factors and cut-off values, respectively. Results: There were significant differences in the BMD(L), BMD(F), thoracolumbar junction Cobb angle, lumbar spine Cobb angle, T11/12-L1/2 height difference of the posterior and anterior edge of intervertebral space (HDPAIS), single vertebra Cobb angle (SVC), procollagen type 1 N-terminal propeptide (PINP) and 25-hydroxyvitamin D [25-(OH)D] between the study and control groups. Through binary logistic regression analysis, we found that BMD(L), PINP, bone alkaline phosphatase, and 25-(OH)D were independent risk factors for future TLK in postmenopausal women. According to the ROC curve, the prediction accuracy of BMD(L) was the highest. By calculating the critical value, we found that when the BMD(L) T-score <-1.65, postmenopausal women were more likely to develop TLK. Conclusions: In postmenopausal osteoporosis patients, TLK will occur even if there is no compression fracture, and when the BMD(L) T-score <-1.65, postmenopausal women are more likely to develop TLK in the future.

M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression.

Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening showed that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson's disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has preclinical value to be repurposed for OS.

Comprehensive metabolomic profiling of osteosarcoma based on UHPLC-HRMS.

INTRODUCTION: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. An increasing number of studies have demonstrated that tumor proliferation and metastasis are closely related to complex metabolic reprogramming. However, there are limited data to provide a comprehensive metabolic picture of osteosarcoma. OBJECTIVES: Our study aims to identify aberrant metabolic pathways and seek potential adjuvant biomarkers for osteosarcoma. METHODS: Serum samples were collected from 65 osteosarcoma patients and 30 healthy controls. Nontargeted metabolomic profiling was performed by liquid chromatography-mass spectrometry (LC-MS) based on univariate and multivariate statistical analyses. RESULTS: The OPLS-DA model analysis identified clear separations among groups. We identified a set of differential metabolites such as higher serum levels of adenosine-5-monophosphate, inosine-5-monophosphate and guanosine monophosphate in primary OS patients compared to healthy controls, and higher serum levels of 5-aminopentanamide, 13(S)-HpOTrE (FA 18:3 + 2O) and methionine sulfoxide in lung metastatic OS patients compared to primary OS patients, revealing aberrant metabolic features during the proliferation and metastasis of osteosarcoma. We found a group of metabolites especially lactic acid and glutamic acid, with AUC values of 0.97 and 0.98, which could serve as potential adjuvant diagnostic biomarkers for primary osteosarcoma, and a panel of 2 metabolites, 5-aminopentanamide and 13(S)-HpOTrE (FA 18:3 + 2O), with an AUC value of 0.92, that had good monitoring ability for lung metastases. CONCLUSIONS: Our study provides new insight into the aberrant metabolic features of osteosarcoma. The potential biomarkers identified here may have translational significance.

Clinical Significance of the Radiological Relationship between the Tumor and the main blood vessels in Enneking IIB Osteosarcoma of the extremities.

Aim: Osteosarcoma is one of the most prevalent primary bone malignancies in children and adolescents. Magnetic resonance imaging (MRI) has been considered a very critical tool to provide anatomical information of tumor and surrounding main blood vessels. To evaluate the prognostic significance of the radiological vascular involvement according to the pre-treatment MRI in patients with Enneking IIB osteosarcoma. Methods: In this retrospective study, we included 482 patients younger than 50 years old with Enneking IIB primary osteosarcoma of the extremities with complete clinical records from 2005 to 2015.Univariate and multivariable analyses were conducted to identify the risk factors for OS (Overall survival) and EFS (Event-free survival). The correlations between the risk factors was performed using Spearman analysis. The Kaplan-Meier method was used to calculate survival curves. Based on the radiological relationship between the tumor lesion and the surrounding reactive area with the main blood vessels as shown on pretreatment MRI findings. Results: Radiological vascular involvement assessed via pretreatment MRI is an important risk factor for Enneking IIB primary patients with osteosarcoma (HROS=2.32/HREFS=1.81 P<0.01) according to the univariate and multivariable analyses. Enneking IIB patients with osteosarcoma were assigned to three subtypes based on the radiological relationship between the main blood vessels and the lesion or reactive area. The 5-year cumulative OS of patients classified by the three types were 81.6% (type I), 67.1% (type II) and 44.8% (type III)(P<0.01). The 5-year cumulative EFS of the three types were 60.2% (type I), 46.7% (type II) and 30.2% (type III)(P<0.05). The total 5-year cumulative OS and EFS for all patients were 68.3% and 48.3%, respectively. Conclusion: Vascular involvement according to radiological findings from pretreatment MRI is an independent risk factor for cumulative OS and EFS in patients with Enneking IIB primary osteosarcoma of the extremities. The new subtyping based on the relationship between the tumors and surrounding reactive area with the main blood vessels based on pretreatment MRI can predict the prognosis of patients with osteosarcoma and provide certain directive information for selecting the appropriate surgical procedure for individual patients.

Multimodal Risk-Adapted Treatment in Surgical Patients With Synovial Sarcoma: A Preoperative Nomogram-Guided Adjuvant Treatment Strategy.

Background: Synovial sarcoma is characterized by heterogeneous clinical manifestations, making it difficult to evaluate individual patients' prognoses and design personal treatment schemes. We established an effective preoperative nomogram to predict cancer-specific survival (CSS) and present a risk-adapted adjuvant treatment strategy in surgical patients with synovial sarcoma. Methods: This retrospective study included patients from the Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed with synovial sarcoma between 1996 and 2015. The patients were randomly divided into training and validation groups. The predictors were selected using univariate and multivariate Cox hazards models. The nomogram performance was verified for its discriminatory ability and calibration. We further stratified the patients into different risk groups according to the nomogram scores and compared the efficacy of chemotherapy, radiotherapy, and combination of radiotherapy and chemotherapy. Results: There were 915 patients enrolled in our study, with 874 patients either alive or dead due to synovial sarcoma. We established a nomogram to predict 5-year CSS based on independent factors, including sex, age, grade, tumor size, location, and extent (all p < 0.05). Our model showed a consistently good discriminatory ability and calibration for predicting 5-year CSS in both the training (c-index = 0.78, 95% CI 0.75-0.81) and validation (c-index = 0.73, 95% CI 0.68-0.78). Based on their nomogram scores, we divided patients into 5 groups. Compared to patients without adjuvant treatment, nomogram I patients with adjuvant treatment had no improvements in 5-year CSS (100.0% vs. 100.0%), nomogram II patients had higher 5-year CSS with radiotherapy or chemotherapy (92.9% vs. 72.2%, p = 0.015), nomogram III patients had higher 5-year CSS with combination of chemotherapy and radiotherapy (70.1% vs. 47.2%, p = 0.004), nomogram IV patients had higher 5-year CSS with radiotherapy (41.3% vs. 15.6%, p = 0.015), and nomogram V patients had no improvements in 5-year CSS rates with adjuvant treatment (28.9% vs. 16.9%, p = 0.18). Conclusion: The nomogram showed a satisfactory discriminatory ability and calibration for predicting 5-year CSS in synovial sarcoma patients. Based on this nomogram, we stratified synovial sarcoma patients according to risk levels, which enabled us to provide a useful grouping scheme that can inform multimodal risk-adapted treatment in synovial sarcoma.

Comparison of local control and survival outcomes between surgical and non-surgical local therapy on pelvic Ewing's sarcoma patients: a meta-analysis.

BACKGROUND: The efficacy of surgical therapy to nonsurgical therapy is still a controversial topic in pelvic Ewing's sarcoma (ES) management. We perform a systemic review and meta-analysis to compare the effect of local control (LC) and survival outcomes between surgical and nonsurgical local therapy on pelvic ES patients with systemic chemotherapy. METHODS: Published retrospective studies searched from PubMed, Embase, Cochrane and Web of Science databases that investigated the effects of surgical and nonsurgical local therapy on the LC and survival outcomes of patients with pelvic ES treated with chemotherapy were included in our study. Our primary outcome was the LC rate and progression-free survival (PFS) rate. The effect of confounders of extend of disease, surgical margin and chemotherapy respond on PFS was analyzed in subgroups. RESULTS: Ten studies with 782 pelvic ES patients were included in our analysis. Surgical patients showed higher LC and PFS rate comparing to nonsurgical patients [LC: risk ratio (RR) 0.72, 95% CI: 0.52-1.00, P=0.05, I2=0%; PFS: RR 0.72, 95% CI: 0.61-0.86, P=0.000, I2=15%]. Localized patients showed higher PFS with surgical therapy than nonsurgical patients (RR 0.67, 95% CI: 0.51-0.88, P=0.003).Patients with adequate resection and good chemotherapy respond improved PFS comparing to nonsurgical patients (adequate resection vs. nonsurgical: RR 0.59, 95% CI: 0.46-0.76, P<0.001, I2=0%; good respond vs. nonsurgical: RR 0.56, 95% CI: 0.41-0.77, P<0.001, I2=21%). But patients with inadequate resection and poor chemotherapeutic respond shows no statistical different PFS comparing to nonsurgical patients (inadequate resection vs. nonsurgical: RR 1.11, 95% CI: 0.87-1.41, P=0.41, I2=0%; poor respond vs. nonsurgical: RR 1.17, 95% CI: 0.90-1.52, P=0.25, I2=0%). CONCLUSIONS: Surgical therapy is primarily recommended in localized, resectable, good chemotherapeutic respond pelvic ES. Inadequate resection and poor chemotherapeutic respond are negative prognostic factors in surgical patients and their surviving are not improved comparing with nonsurgical patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020149224.

Regional lymph node involvement is associated with poorer survivorship in patients with upper extremity osteosarcoma than with lower extremity osteosarcoma: a SEER analysis.

BACKGROUND: Although the upper limb is the second most common site of osteosarcoma, investigations into clinical manifestation differences between upper and lower limb patients are still sporadic. We retrospectively investigated the characteristics of these patients to gain a better understanding of the differences between upper and lower limb osteosarcoma patients. METHODS: This retrospective study involved patients diagnosed with extremity osteosarcoma between 1997 and 2016 collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patient characteristics were analyzed with t-tests, rank sum tests and chi-square tests. Log-rank tests were applied to evaluate univariate significance, and Cox hazards models were performed in multivariate analysis. A binary logistics regression model was used to screen the risk factors related to lymph node involvement. RESULTS: In total, 1,882 patients, 1,588 (84.4%) with lower limb lesions and 294 (15.6%) with upper limb lesions were enrolled in our study. The patients with upper limb osteosarcoma exhibited poorer 5-year overall survival (OS) than patients with lower limb osteosarcoma (54.8% vs. 63.2%, P=0.02). The upper limb patients had more lymph node involvement (5.6% vs. 2.7%, P=0.03), which was found to be an independent prognostic factor (P=0.000). Tumors located in the upper limbs and the presence of distal metastasis were risk factors related to lymph node involvement in the extremity (P<0.05). The upper limb patients were tended to suffer greater risk of being affected by both metastasis and lymph node involvement (15.7% vs. 9.4%, P=0.18). CONCLUSIONS: Upper limb osteosarcoma patients are characterized by more lymph node involvement than lower limb patients, leading to poorer OS. In addition, upper limb patients are at greater risk for both lymph node involvement and distal metastasis. Our results suggest that upper limb patients should be screened more thoroughly for regional lymph node involvement.