Novel candidate metastasis-associated genes for synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with poor prognosis due to late recurrence and metastasis. Metastasis is an important prognostic factor of SS. This study aimed to identify the core genes and mechanisms associated with SS metastasis. Microarray data for GSE40021 and GSE40018 were obtained from the Gene Expression Omnibus database. 186 differentially expressed genes (DEGs) were identified. The biological functions and signalling pathways closely associated with SS metastasis included extracellular matrix (ECM) organization and ECM-receptor interaction. Gene set enrichment analysis showed that the terms cell cycle, DNA replication, homologous recombination and mismatch repair were significantly enriched in the metastasis group. Weighted gene co-expression network analysis identified the most relevant module and 133 hub genes, and 31 crossover genes were identified by combining DEGs. Subsequently, four characteristic genes, EXO1, NCAPG, POLQ and UHRF1, were identified as potential biomarkers associated with SS metastasis using the least absolute shrinkage and selection operator algorithm and validation dataset verification analysis. Immunohistochemistry results from our cohort of 49 patients revealed visible differences in the expression of characteristic genes between the non-metastatic and metastatic groups. Survival analysis indicated that high expression of characteristic genes predicted poor prognosis. Our data revealed that primary SS samples from patients who developed metastasis showed activated homologous recombination and mismatch repair compared to samples from patients without metastasis. Furthermore, EXO1, NCAPG, POLQ and UHRF1 were identified as potential candidate metastasis-associated genes. This study provides further research insights and helps explore the mechanisms of SS metastasis.

The clinical effectiveness and safety of Zone III REBOA for resection of sacropelvic tumors in patients older than 70 years.

BACKGROUND: REBOA is a method used to manage bleeding during surgery involving sacropelvic tumors. Nevertheless, studies on the use of REBOA among elderly people are lacking. The aim of this research was to investigate the efficacy and safety of Zone III REBOA in patients aged more than 70 years. METHODS: A comparative study was conducted using case-control methods. A group of patients, referred to as Group A, who were younger than 70 years was identified and paired with a comparable group of patients, known as Group B, who were older than 70 years. Continuous monitoring of physiological parameters was conducted, and blood samples were collected at consistent intervals. RESULTS: Totally, 188 participants were enrolled and received REBOA. Among the 188 patients, seventeen were aged more than 70 years. By implementing REBOA, the average amount of blood loss was only 1427 ml. Experiments were also conducted to compare Group A and Group B. No notable differences were observed in terms of demographic variables, systolic blood pressure (SBP), arterial pH, lactate levels, blood creatinine levels, potassium levels, or calcium levels at baseline. Additionally, after the deflation of the REBOA, laboratory test results, which included arterial pH, lactate, potassium concentration, calcium concentration, and blood creatinine concentration, were not significantly different (P > 0.05). CONCLUSION: This study indicated that in selected patients aged more than 70 years can achieve satisfactory hemodynamic and metabolic stability with Zone III REBOA. LEVEL OF EVIDENCE: Therapeutic study, Level III.

Post-operative Patellar Tilt More than 10° Can Affect Certain Components of Knee Society Score After Total Knee Arthroplasty at 2-Year Follow-Up.

Introduction: The effect of post-operative patella tilt on functional outcomes after total knee arthroplasty remains unclear. Our study aimed to analyze the relationship of post-operative patellar tilt with functional outcome scores after total knee arthroplasty. Materials and Methods: Patient data were retrieved from our institution's prospectively maintained total knee arthroplasty. Three hundred three patients who underwent unilateral TKA from Jan 2012 to March 2017 were included in the study. After excluding patients with incomplete and lost follow-up data, 213 patients were analyzed. Radiographs of pre-operative and post-operative skyline views were used for patella tilt and patella displacement measurement at pre-op, post-op 1 year, and post-op 2 years. Three functional outcome scoring systems, SF-36, KSS, and WOMAC, were applied for function evaluation at different post-operative time points. Patients were divided into three subgroups according to the patella tilt, which includes less than 5°, 5.1-10°, and more than 10°. Statistical analysis was done to identify the relationship between patella tilt and functional outcomes. Results: Mean post-operative patella tilt was significantly lower than the mean pre-operative patella tilt (3.35 ± 3.91 vs. 5.65 ± 4.41, p < 0.001). There was no significant difference in patella displacement among pre- and post-operative status. KSS functional score was significantly poor at post-op 1 year and KSS objective score at post-op 2 years in patients with more than 10° patella tilt. SF-36 and WOMAC were not significantly different among the groups. There was no significant difference in post-operative function between non-resurfaced and resurfaced patella patients evaluated with three scoring systems. Conclusion: We have found significantly less post-operative patella tilt after TKA than pre-operative patella tilt with or without patella resurfacing. Increased post-operative patella tilt of more than 10° can affect specific functional outcomes. Patella resurfacing does not affect the post-operative functional outcome compared to non-resurfacing of the patella post-op 2 years. Level of Evidence: III. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-023-01077-0.

Clinical outcomes in patients with neurological disorders following periacetabular tumor removal and endoprosthetic reconstruction of the hemipelvis.

Background: Surgical treatment of musculoskeletal tumors in the periacetabular region present extremely difficult due to the complex anatomy and need for reconstruction. Orthopedic surgeons face more difficulties in patients with neurological conditions, which can cause increased muscle tone, an elevated risk of fractures, and compromised bone quality. There is limited evidence regarding endoprosthetic reconstruction for periacetabular tumors in individuals with neurological disorders. Methods: We conducted a single-center retrospective study to examine the outcomes of patients with preexisting neurological conditions who underwent surgery to remove periacetabular tumors and who underwent endoprosthesis reconstruction. Clinical presentation, detailed neurological conditions, complications, and functional outcomes were studied. Results: Sixteen out of the 838 patients were identified (1.91%), with a mean follow-up time of 33 months. The primary neurological conditions encompassed Parkinson's disease, Alzheimer's disease, dementia, and cerebral ischemic stroke. Every patient was diagnosed with periacetabular lesions that were either primary or oligometastatic. They underwent tumor resection and subsequently received endoprosthetic reconstruction of the hemipelvis. Three patients developed metastasis lesions later, and two patients experienced tumor recurrence. Five cases experienced hip dislocation-one with periprosthetic fracture and one with surgical site infection. The position of the prosthetic rotating center was not correlated with dislocation. The reoperation rate was 31.25%. The cohort of patients all presented with more extended hospital stays and rehabilitation. In 3 patients, the general functional score was good, while in 6 patients, it was fair; in 7 patients, it was regarded as poor. The average MSTS93 score was 49.71%. Conclusion: Endoprosthetic reconstruction after periacetabular tumor resection is an effective way to eliminate tumors and salvage limbs. However, this group of patients has an increased likelihood of secondary surgery, complications, extended hospital stay, and no significant improvement in functional outcomes. Despite the diverse nature of the cohort, it is recommended to consider enhanced soft tissue reconstruction, supervised functional recovery and rehabilitation training.

Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncovers Skp2 function in metastasis, genomic instability and immune activation and reveals additional target pathways.

Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout of Skp2 in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout of Rb1 and Trp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption of Skp2: one with Skp2 knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in the Skp2 disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in the Skp2-disrupted OS, which we validated by observation of a strong reduction in lung metastasis in the Skp2 knockout mice. Finally, we report several potential mechanisms of escape from targeting Skp2 in OS, including upregulation of Myc targets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.

Artificial intelligence assisted preoperative planning and 3D-printing guiding frame for percutaneous screw reconstruction in periacetabular metastatic cancer patients.

Background: The percutaneous screw reconstruction technique, known as the "Tripod Technique," has demonstrated favorable clinical outcomes in the management of metastatic periacetabular lesions, as evidenced by our prior investigations and corroborated by independent studies. Nevertheless, there is a steep learning curve in handling this technique, with possible complications such as intraarticular screw placement. Methods: Preoperative pelvic CT scans were acquired before surgery and utilized for the guiding frame design. A convolutional neural network model was trained with annotated data to identify the starting point and trajectory of each potential screw. A model boundary intersection detection technology was used to determine the optimal diameter and length of each screw. A non-rigid registration technology was matched with a prefabricated model of the body surface to design personalized anchoring skin pads. Finally, a polylactic acid-based guiding frame for intraoperative was custom-made with a 3D printer. Results: 12 patients underwent a guiding frame-assisted Tripod procedure for treatment of periacetabular metastatic lesions. An intraoperative CT scan was performed in all cases to confirm screw trajectories. Among 36 screws that were implanted, 26 screws were implanted as designed. The remaining ten screws drifted, but all remained within the intra-osseous conduit without any complications. The mean surgical time was 1.22 h with the guiding frame compared with 2.3 h without the guiding frame. Following the surgical procedure, a noteworthy enhancement in pain management, as evidenced by a reduction in scores on the visual analog scale (p < 0.01), and an improvement in functional status, as assessed through the Eastern Cooperative Oncology Group score (p < 0.01), were observed when compared to the patient's pre-operative condition. Conclusion: This proof-of-concept investigation demonstrates that the amalgamation of AI-assisted surgical planning and additive manufacturing can improve surgical accuracy and shorten surgical duration. While access to this technology is currently constrained during its early stages of development, it is anticipated that these limitations will diminish as the potential of AI and additive manufacturing in facilitating complex orthopedic procedures becomes more evident, leading to a surge in interest and adoption of this approach.

Targeted inhibition of SCFSKP2 confers anti-tumor activities resulting in a survival benefit in osteosarcoma.

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2 complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2 triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2 also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.