Primary Malignant Bone Tumor Research Articles

Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, the underlying molecular mechanism of these discrepancies remains unclear. The potential role of mechanotransduction in tumorigenicity is of particular interest. To this end, we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo. We utilized a sphere culture model, a soft agar assay, and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells. Additionally, we quantified the expression of sensor proteins, including four kinases and seven cytoskeletal proteins, in OS cell lines. The upstream core transcription factors of rigidity-sensing proteins were further investigated. We detected anoikis resistance in transformed OS cells. The mechanosensing function of transformed OS cells was also impaired, with general downregulation of rigidity-sensing components. We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells. We further uncovered a novel TP53 mutation (R156P) in transformed OS cells, which acquired gain of function to inhibit rigidity sensing, thus sustaining transformed growth. Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment. In addition, the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.

Exploration of s new biomarker in osteosarcoma and association with clinical outcomes: TOP2A+ cancer associated fibroblasts.

Osteosarcoma (OS) is the leading malignant primary bone tumor in young adults and children and has a high mortality rate. Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment, influencing cancer progression and metastasis. However, there is no systematic study on the role of CAF in OS. We collected six OS patients' single-cell RNA sequencing data from the TISCH database, which was processed using the Seurat package. We selected gene sets from the well-known MSigDB database and resorted to the clusterprofiler package for gene set enrichment analysis (GSEA). The least absolute shrinkage and selection operator (LASSO) regression model was used for identification of the variables. Receiver operating characteristic and decision curve analyses were utilized for determining the efficacy of the monogram model. TOP2A+ CAFs was recognized as the carcinogenic CAFs subset, given its intense interaction with OS malignant cells and association with the critical cancer driver pathway. We intersected the differentially expressed genes of TOP2A+ CAFs with the prognostic genes selected from 88 OS samples. The acquired gene set was selected using the LASSO regression model and integrated with clinical factors to obtain a monogram model of high prognosis predicting power (area under the curve of 5year survival at 0.883). Functional enrichment analysis revealed the detailed difference between two risk groups. We identified TOP2A+ CAFs as a subset of oncogenic CAFs in OS. Based on differentially expressed genes derived from TOP2A+ CAFs, combined with bulk transcriptome prognostic genes, we constructed a risk model that can efficiently predict OS prognosis. Collectively, our study may provide new insights for future studies to elucidate the role of CAF in OS.

Predicting metastasis at initial diagnosis and radiotherapy effectiveness in patients with metastatic osteosarcoma.

Osteosarcoma is a primary malignant bone tumor affecting mostly children and adolescents. The overall 10year survivals of patients with metastatic osteosarcoma are typically less than 20% in the literature and remain concerning. We aimed to develop a nomogram for predicting the risk of metastasis at initial diagnosis in patients with osteosarcoma and evaluate the effectiveness of radiotherapy in patients with metastatic osteosarcoma. Clinical and demographic data of patients with osteosarcoma were collected from the surveillance, epidemiology, and end results database. We randomly split our analytical sample into the training and validation cohorts, then established and validated a nomogram for predicting the risk of osteosarcoma metastasis at initial diagnosis. The effectiveness of radiotherapy was evaluated by performing propensity score matching in patients underwent surgery + chemotherapy and those underwent surgery + chemotherapy + radiotherapy, among patients with metastatic osteosarcoma. 1439 patients met the inclusion criteria and were included in this study. 343 of 1439 had osteosarcoma metastasis by the time of initial presentation. A nomogram for predicting the likelihood of osteosarcoma metastasis by the time of initial presentation was developed. In both unmatched and matched samples, the radiotherapy group demonstrated a superior survival profile comparing with the non-radiotherapy group. Our study established a novel nomogram to evaluate the risk of osteosarcoma with metastasis, and demonstrated that radiotherapy combined with chemotherapy and surgical resection could improve 10-year survival in patients with metastasis. These findings may guide the clinical decision-making for orthopedic surgeons.

18F-FDG PET/CT in the Management of Osteosarcoma.

Osteosarcoma is the most common type of primary malignant bone tumor. 18F-FDG PET/CT is useful for staging, detecting recurrence, monitoring response to neoadjuvant chemotherapy, and predicting prognosis. Here, we review the clinical aspects of osteosarcoma management and assess the role of 18F-FDG PET/CT, in particular with regard to pediatric and young adult patients.

A Novel Approach to Reducing Lung Metastasis in Osteosarcoma: Increasing Cell Stiffness with Carbenoxolone

Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo. We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX. Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young's modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01). In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo.

Different Subtypes of Osteosarcoma: Histopathological Patterns and Clinical Behaviour

Osteosarcoma (OS) is a primary malignant bone tumour that usually occurs in children and adolescents. OS is a highly aggressive tumour type with a propensity for local invasion and systemic early metastasis to the lungs or other bones. According to the World Health Organization, there are different subtypes of OS, including conventional OS (osteoblastic, chondroblastic, fibroblastic), telangiectatic OS, low-grade OS, small-cell OS, parosteal OS, periosteal OS, and high-grade surface OS. In this mini review, we will discuss the background of OS and histopathological patterns and clinical behaviour of the disease. Understanding the subtypes of OS and their pathogenesis is crucial for developing more precise and effective therapies for OS patients.

Shedding Light on Osteosarcoma Cell Differentiation: Impact on Biomineralization and Mitochondria Morphology.

Osteosarcoma (OS) is the most common primary malignant bone tumor and its etiology has recently been associated with osteogenic differentiation dysfunctions. OS cells keep a capacity for uncontrolled proliferation showing a phenotype similar to undifferentiated osteoprogenitors with abnormal biomineralization. Within this context, both conventional and X-ray synchrotron-based techniques have been exploited to deeply characterize the genesis and evolution of mineral depositions in a human OS cell line (SaOS-2) exposed to an osteogenic cocktail for 4 and 10 days. A partial restoration of the physiological biomineralization, culminating with the formation of hydroxyapatite, was observed at 10 days after treatment together with a mitochondria-driven mechanism for calcium transportation within the cell. Interestingly, during differentiation, mitochondria showed a change in morphology from elongated to rounded, indicating a metabolic reprogramming of OS cells possibly linked to an increase in glycolysis contribution to energy metabolism. These findings add a dowel to the genesis of OS giving new insights on the development of therapeutic strategies able to restore the physiological mineralization in OS cells.

Imaging Assessment of the Efficacy of Chemotherapy in Primary Malignant Bone Tumors: Recent Advances in Qualitative and Quantitative Magnetic Resonance Imaging and Radiomics.

Recent studies have shown that MRI demonstrates promising results for evaluating the chemotherapy efficacy in bone sarcomas. This article reviews current methods for evaluating the efficacy of malignant bone tumors and the application of MRI in this area, and emphasizes the advantages and limitations of each modality. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

Decision tree-based data mining approach for the evaluation of survival in primary malignant bone tumors: A surveillance, epidemiology and end results database study.

This study aimed to conduct a large-scale population-based study to understand the epidemiological characteristics of Primary Malignant Bone Tumors (PMBTs) and determine the prognostic factors by concurrently using the classical statistical method and data mining methods. Patients included in this study were extracted from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database: "Incidence-SEER Research Data, 18 Registries, Nov 2020 Sub". Patients with unclassified and incomplete information were excluded. This search algorithm resulted in a dataset comprising 6234 cases. Survival analyses were performed with Kaplan-Meier curves and the Log-rank test. Multivariate Cox regression analysis determined the independent prognostic factors of PMBT. A decision tree-based data mining technique was used in this study to confirm the prognostic factors. 5-years survival rate was 63.6% and 10-years survival rate was 55.3% in the patients with PMBT. Sex, age, median household income, histology, primary site, grade, stage, metastasis, and the total number of malignant tumors were determined as independent risk factors associated with overall survival (OS) in the multivariate COX regression analysis. The prognostic factors resulting in five terminal nodes in the decision tree (DT) included stage, age, and grade. The stage was the most important determining factor for vital status. The terminal node with the shortest number of surviving patients included 801 (72.3%) deaths in 1102 patients with distant stage, and hazard ratio was calculated as 5.4 (95% CI: 4.9-5.9; p < .001). These patients had a median survival of only 17 months. Rules extracted from DTs provide information about risk factors in specific patient groups and can be used by clinicians making decisions on individual patients. We recommend using DTs in combination with COX regression analysis to determine risk factors and the effect of these factors on survival.

Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression via BMP signaling.

Osteosarcoma, the most common primary malignant bone tumor, is defined by the formation of neoplastic osteoid and/or bone. This sarcoma is a highly heterogeneous disease with a wide range of patient outcomes. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in various types of malignant tumors. We previously reported that CD109 is expressed in osteoblasts and osteoclasts in normal human tissues and plays a role in bone metabolism in vivo. While CD109 has been shown to promote various carcinomas through the downregulation of TGF-β signaling, the role and mechanism of CD109 in sarcomas remain largely unknown. In this study, we investigated the molecular function of CD109 in sarcomas using osteosarcoma cell lines and tissue. Semi-quantitative immunohistochemical analysis using human osteosarcoma tissue revealed a significantly worse prognosis in the CD109-high group compared with the CD109-low group. We found no association between CD109 expression and TGF-β signaling in osteosarcoma cells. However, enhancement of SMAD1/5/9 phosphorylation was observed in CD109 knockdown cells under bone morphogenetic protein-2 (BMP-2) stimulation. We also performed immunohistochemical analysis for phospho-SMAD1/5/9 using human osteosarcoma tissue and found a negative correlation between CD109 expression and SMAD1/5/9 phosphorylation. In vitro wound healing assay showed that osteosarcoma cell migration was significantly attenuated in CD109-knockdown cells compared with control cells in the presence of BMP. These results suggest that CD109 is a poor prognostic factor in osteosarcoma and affects tumor cell migration via BMP signaling.

Molecular In-Depth Characterization of Chondrosarcoma for Current and Future Targeted Therapies.

Chondrosarcoma (CHS) are heterogenous, but as a whole, represent the second most common primary malignant bone tumor entity. Although knowledge on tumor biology has grown exponentially during the past few decades, surgical resection remains the gold standard for the treatment of these tumors, while radiation and differentiated chemotherapy do not result in sufficient cancer control. An in-depth molecular characterization of CHS reveals significant differences compared to tumors of epithelial origin. Genetically, CHS are heterogenous, but there is no characteristic mutation defining CHS, and yet, IDH1 and IDH2 mutations are frequent. Hypovascularization, extracellular matrix composition of collagen, proteoglycans, and hyaluronan create a mechanical barrier for tumor suppressive immune cells. Comparatively low proliferation rates, MDR-1 expression and an acidic tumor microenvironment further limit therapeutic options in CHS. Future advances in CHS therapy depend on the further characterization of CHS, especially the tumor immune microenvironment, for improved and better targeted therapies.

Survey of Palliative Care Use in Primary Malignant Bone Tumors: A National Cancer Database Review.

Background/Objectives: Palliative care (PC) has been associated with reduced patient symptom burden, improved physician satisfaction, and reduced cost of care. However, its use in primary bone tumors has not been well classified. Design/Setting and Subjects: Patients diagnosed with primary malignant bone tumors (osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma) between 2004 and 2018 were identified in the National Cancer Database. Cross tabulations with chi-square analysis were performed to evaluate frequencies of PC use by patient, facility, and tumor characteristics. Multivariate logistic binary regression was performed to evaluate relationships between patient, treatment facility, and tumor characteristics and the use of PC. Results: Around 24,401 patients were identified. Overall, 2.52% had any form of PC utilization. Of those receiving PC, 55.5-65.1% were treated with only noncurative surgery, radiation, chemotherapy, or any combination of these modalities. Odds of PC utilization were decreased for patients with chordomas, patients living >24 miles from the treatment facility, or patients with private insurance, Medicare, or unknown insurance status. Odds of PC utilization were increased in patients with greater tumor diameter or unknown tumor size, tumors in midline, increased tumor grade, stage IV tumors, or living in urban areas. Conclusion: PC use in patients with primary bone tumors increases with tumor stage, tumor grade, tumor size, and if the tumor is midline, and in patients living in urban areas. However, overall utilization remains markedly low. Future studies should be done to investigate these patterns of care and help expand the utilization of PC.

Chondrosarcoma of the Proximal Humerus: Does the Margin Affect Survival?

Chondrosarcoma (CS) is the second most common primary malignant bone tumour and, in the absence of reliable chemotherapy and radiotherapy, is effectively a surgical disease. Overall disease specific survival (DSS) is affected by tumour grade, whilst resection margin contributes to local recurrence free survival (LRFS). The aim of this study was to investigate factors that affect the local and systemic prognoses for conventional central CSs arising from the proximal humerus. A multi-centre, retrospective study from three international collaborative sarcoma centres identified 110 patients between 1995 and 2020 undergoing treatment for a conventional central CS of the proximal humerus; 58 patients (53%) had a grade 1 tumour, 36 (33%) had a grade 2 tumour, and 16 patients (13%) had a grade 3 CS. The mean age of patients was 50 years (range 10-85). The incidence of local recurrence (LR) was 9/110 (8.2%), and the disease specific mortality was 6/110 (5.5%). The grade was a statistically significant factor for LRFS (p < 0.001). None of the grade 1 tumours developed LR. The DSS was affected by the grade (p < 0.001) but not by the LR (p = 0.4). Only one patient with a grade 2 tumour died from the disease. The proximal humeral grade 1 CS behaved as a benign tumour, having no cases of LR nor death due to disease. Grade 2 CSs of the proximal humerus behaved in a more indolent way when compared with comparable grade tumours elsewhere in the appendicular skeleton, being locally aggressive with a higher LR rate than grade 1 CSs but still having very low mortality and a high rate of DSS. The LR in grade 2 CSs did not affect the DSS; therefore, surgical management in proximal humeral grade 2 CSs should have a greater emphasis on preserving function whilst maintaining an adequate margin for resection. The proximal humeral grade 3 CS was, as elsewhere in the skeleton, an aggressive, high-grade tumour. Therefore, surgical management should include en bloc resection with clear margins to avoid LR.

Abstract LB329: A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma

Abstract Introduction: Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgery combined with multimodal chemotherapy remains as the standard treatment for osteosarcoma patients. However, patients with osteosarcoma metastasis have a five-year survival rate of less than 30%, and their long-term outcomes have not improved over the last 30 years. CSF-1/CSF-1R signaling is crucial for the survival, function, proliferation and differentiation of myeloid lineage cells, including osteoclasts and monocytes/macrophages. Targeting CSF-1R either on tumor cells or tumor-associated macrophages has been reported to limit osteosarcoma progression in preclinical models. ABSK021, an oral, highly potent and selective small molecule inhibitor of CSF-1R discovered by Abbisko, has entered into Phase I trial (NCT04192344) and showed significant anti-tumor activity and favorable safety profile in patients with advanced tenosynovial giant cell tumor. Here, we conducted a series of preclinical in vitro and in vivo experiments, as well as human osteosarcoma profiling, to investigate the treatment potential of ABSK021 for osteosarcoma patients. Methods: Cellular potency of ABSK021 was evaluated by Celltiter-Glo assay in osteosarcoma cell lines and CSF-1R expression was evaluated by western blot. In vivo efficacy studies were conducted in murine osteosarcoma models and pharmacodynamics changes were measured. CSF-1R IHC staining was conducted in tissue microarray samples from osteosarcoma patients. Results: ABSK021 potently inhibited the proliferation of K7M2, a murine osteosarcoma cell line with high expression of CSF-1R. In animal, ABSK021 showed strong anti-tumor activity on K7M2 syngeneic model and SA4094 osteosarcoma PDX model without causing significant body weight loss. Pharmacodynamics analysis displayed robust inhibition of macrophage infiltration and CSF-1R signaling by ABSK021, confirming its effective target engagement in vivo. Parallel IHC analysis of human tissue microarray samples revealed high prevalence of positive CSF-1R staining in osteosarcoma patients. Conclusion: Taken together, these results demonstrate that ABSK021 has strong inhibition of CSF-1R activity and corresponding anti-tumor activity in preclinical osteosarcoma models. High prevalence of CSF-1R expression was also found in osteosarcoma patients, suggesting great potential of utilizing ABSK021 as a novel therapy to treat osteosarcoma patients in clinic. Citation Format: Nannan Zhang, Cheng Dai, Jiacheng Zhang, Shuqun Yang, Jie Wang, Jie Zhang, Manqi Liu, Zhui Chen. A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB329.

Diagnostic accuracy of fine needle aspiration cytology of bone lesions: A study of Tertiary Care Institute.

The aim is to study the spectrum and cytomorphological features of bone lesions and find out the diagnostic accuracy of Fine needle aspiration cytology (FNAC) on the same. The study was a cross-sectional study conducted in the Department of Pathology and Orthopedics in a tertiary institute in north India over a period of 1 year in 55 patients. All the patients were subjected to FNAC of bone lesions followed by tru-cut or open bone biopsy. Cytosmears were stained with May Grunwald Giemsa and Hematoxylin and Eosin were done on biopsy specimens. Sensitivity and specificity were calculated in percentage with a 95% confidence interval with reference to biopsy specimens. Two peaks were observed; one between 11 and 40 years with 32 cases and another at 51 and 60 years with 12 cases. The male to female ratio was 1.4:1. In the present study, inflammatory lesions were present in 17 (31%) cases, 2 were tumor-like conditions; 10 (18%) cases of primary benign tumors, 26 (47.2%) cases were malignant. Out of these, 15 (27.2%) were primary malignant bone tumors and 11 (20%) were secondary in nature. The sensitivity, specificity, and diagnostic accuracy of the FNA of bone lesions were 55.17%, 79.04%, and 73.46%, respectively. Although there are a few limitations of FNAC such as low cellularity, small representative sample, and hemorrhagic aspirate, it can still be used as an initial diagnostic modality with proper clinical context for the management of bone lesions.

Integrative analyses of ferroptosis and immune related biomarkers and the osteosarcoma associated mechanisms

Osteosarcoma (OS) is the most common primary malignant bone tumor with high metastatic potential and relapse risk. To study the regulatory mechanism of the OS microenvironment, a complex regulatory network involving the ferroptosis- and immune response-related genes remains to be established. In the present study, we determined the effect of a comprehensive evaluation system established on the basis of ferroptosis- and immune-related genes on the immune status, related biomarkers, prognosis, and the potential regulatory networks underlying OS based on the TARGET and Gene Expression Omnibus databases that contain information on OS patients by bioinformatics analyses. We first characterized individual ferroptosis scores and immune scores through gene set variation analysis (GSVA) against TARGET-OS datasets. We then identified differentially expressed genes by score groups. Weighted gene co-expression network analysis was performed to identify the most relevant ferroptosis-related and immune-related gene modules, which facilitated the identification of 327 ferroptosis gene and 306 immune gene candidates. A 4-gene (WAS, CORT, WNT16, and GLB1L2) signature was constructed and valuation using the least absolute shrinkage and selection operator-Cox regression models to effectively predict OS prognosis. The prediction efficiency was further validated by GSE39055. We stratified patients based on the prognostic scoring systems. Eight hub genes (namely CD3D, CD8A, CD3E, IL2, CD2, MYH6, MYH7, and MYL2) were identified, and TF–miRNA target regulatory networks were constructed. Furthermore, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and GSVA were used to determine the signature’s potential pathways and biological functions, which showed that the hub genes were enriched in ferroptosis-associated biological functions and immune-associated molecular mechanisms. Thereafter, we investigated the proportion and infiltration extent of 22 infiltrating immune cells by using CIBERSORT, which revealed significant subgroup differences in CD8 + T cells, M0 macrophages, and M2 macrophages. In conclusion, we determined a new ferroptosis-related and immune-related gene signature for predicting OS patients’ prognosis and further explored the ferroptosis and immunity interactions during OS development, which provides insights into the exploration of molecular mechanisms and targeted therapies in patients with OS.

Clinicopathological significance of SOX9 and β-catenin expression in pre-neoadjuvant chemotherapy cases of osteosarcoma: molecular and immunohistochemical study

ABSTRACT The molecular pathogenesis of osteosarcoma (OS), the most frequent primary malignant bone tumor of all age groups, is still obscure. Since multidrug chemotherapeutic regimens were introduced in the 1970s, survival rates have been stationary. The Wnt-β-catenin signaling cascade and SOX9 have a significant contribution to skeletal growth, development, and tumorigenesis. In the present work, an attempt was made to examine the role and clinicopathological significance of β-catenin and SOX9 in 46 cases of pre-neoadjuvant chemotherapy OS tissues compared to 10 cases of non-neoplastic bone. The mRNA levels of both markers were assessed by qRT-PCR, and protein levels of β-catenin were analyzed by immunohistochemistry. The results were correlated with different clinicopathological parameters. SOX9 mRNA levels were significantly elevated in OS compared to non-neoplastic bone, and higher levels were significantly associated with the occurrence of fluid-fluid levels (indicating blood-containing cystic spaces) and osteolytic radiological pattern. Although β-catenin mRNA and protein levels were higher in OS compared to non-neoplastic bone, only the protein levels reached statistical significance. Higher β-catenin mRNA levels were significantly associated with tumor size, while higher protein levels were significantly associated with the histologic subtype, mitotic count, and radiological pattern. No significant association was noted with any of the other evaluated parameters. OS showing higher SOX9 mRNA expression and lower β-catenin mRNA and protein expression exhibited longer estimated overall survival times approaching statistical significance. To conclude, while high expression of β-catenin and SOX9 suggests their possible involvement in OS development, their prognostic role may need further research.

Use of LARS for soft tissue function reconstruction during tumor-type hemi-shoulder replacement achieves a good prognosis: a retrospective cohort study

BackgroundShoulder soft tissue function reconstruction during tumor-type hemishoulder replacement is an important step to restore shoulder function. This study evaluates the functional prognosis and postoperative complications of ligament advanced reinforcement system (LARS)-assisted soft tissue functional reconstruction in tumor-type hemi-shoulder replacement.Materials and methodsTwenty-two patients with an average age of 37.5 ± 17.8 years diagnosed with benign invasive tumors, primary malignant bone tumors, or bone metastases were enrolled in this study. The patient’s medical records (history and surgical details), histological sections, imaging files, oncological prognosis, functional prognosis, and postoperative complications were collected. The upper limb function and shoulder joint function were evaluated using the Musculoskeletal Tumor Society (MSTS) system and American Shoulder and Elbow Surgeons (ASES) scoring criteria, respectively.ResultsTwenty-two patients comprising 12 males and 10 females were enrolled. Overall, 9 patients had preoperative pathological fractures. The mean lesion length was 8.6 ± 3.0 cm. The local recurrence was observed in 3 cases, including 2 cases of osteosarcoma and 1 case of MGCT. A further 4 cases had pulmonary metastasis, including 2 cases with local tumor recurrence. The average postoperative MSTS score was 25.8 ± 1.7, and the score of postoperative ASES was 85.7 ± 6.0, both of which showed satisfactory functional recovery. Two cases experienced postoperative complications requiring surgical intervention, including one periprosthetic fracture and one giant cell granuloma. Prosthesis dislocation occurred in 1 case. None of the cases of periprosthetic infection or postoperative complications resulted in implant failure.ConclusionsLARS-assisted soft tissue function reconstruction in benign and malignant proximal humerus tumors after a tumor-type hemi-shoulder replacement is an effective technical improvement, which can effectively repair the integrity of the joint capsule to restore joint stability, provide a medium for soft tissue attachment to rebuild the muscular dynamic system, and eliminate residual dead space around the prosthesis, effectively improving limb function and reduce postoperative infection complications.

RETURN TO SPORTS FOLLOWING LOWER LIMB MUSCULOSKELETAL TUMOUR SURGERY: A SYSTEMATIC REVIEW

Primary malignant bone and soft tissue tumours often occur in the lower extremities of active individuals including children, teenagers and young adults. Survivors routinely face long-term physical disability. Participation in sports is particularly important for active young people but the impact of sarcoma treatment is not widely recognised and clinicians may be unable to provide objective advice about returning to sports. We aimed to identify and summarise the current evidence for involvement in sports following treatment of lower limb primary malignant bone and soft tissue tumours.A comprehensive search strategy was used to identify relevant studies combining the main concepts of interest: (1) Bone/Soft Tissue Tumour, (2) Lower Limb, (3) Surgical Interventions and (4) Sports. Studies were selected according to eligibility criteria with the consensus of three authors. Customised data extraction and quality assessment tools were used.22 studies were selected, published between 1985 – 2020, and comprising 1005 patients. Fifteen studies with data on return to sports including 705 participants of which 412 (58.4%) returned to some form of sport at a mean follow-up period of 7.6 years. Four studies directly compared limb sparing and amputation; none of these were able to identify a difference in sports participation or ability.Return to sports is important for patients treated for musculoskeletal tumours, however, there is insufficient published research to provide good information and support for patients. Future prospective studies are needed to collect better pre and post-treatment data at multiple time intervals and validated clinical and patient sports participation outcomes such as type of sports participation, level and frequency and a validated sports specific outcome score, such as UCLA assessment. In particular, more comparison between limb sparing and amputation would be welcome.

Abstract 2903: Epigenetic modulation of NK cells to improve tumor trafficking and enhance therapeutic efficacy against osteosarcoma

Abstract Osteosarcoma is the most common primary malignant bone tumor. It metastasizes almost exclusively to the lung, and this constitutes the main cause of death in these patients. Immune therapy has shown limited benefit. We investigated whether epigenetic modulation of allogeneic NK cells by the HDAC inhibitor MS-275 will improve tumor trafficking and enhance therapeutic efficacy against osteosarcoma (OS) lung metastases. Human NK cells were purified and expanded from donor buffy coats using recombinant human IL-2 and genetically engineered K562 feeder cells and treated with MS-275 before injection into mice. RNA seq was performed in untreated and MS-275 pre-treated NK cells to determine differentially expressed genes. We also used ChiPseq to determine the histone post-translational modifications associated with the differentially expressed genes induced by the treatment. Culture media from untreated and treated NK cells was collected for cytokine analysis using the Isolight/Isoplexis system. We used our OS-17 human OS experimental lung metastases mouse model and injected untreated or pre-treated NK cells (0.5uM MS-275) IV labeled with near-infrared DiR dye twice a week. Tumor burden was assessed, and NK cells were tracked by Bioluminescence imaging (BLI). Mice were either euthanized 24 hours after the final NK cell treatment for histologic analysis of the lungs or, in a second experiment, analyzed for survival across treatment groups. Some mice from each group were selected for 3D imaging using the Xerra cryofluorescence tomography (CFT) imaging system, allowing for greater resolution of NK cell distribution as compared to the IVIS imaging system. We identified 547 differentially expressed genes between the untreated and MS-275 treated NK cells. Four immune related genes (L1CAM, IFNG, C3 and CD28) were upregulated in the MS-275 treated NK cells and histone H3 and H4 acetylation was found at the identified immunomodulatory genes. Culture media from MS-275 treated NK cells showed significantly increased MIP-1b, IL-6 and IFN-g. Furthermore, there was a significant decrease in lung micro-metastases in the MS-275 pre-treated NK cell group as compared to the untreated control group (199 vs 97 p=0.05). Lastly, Xerra CFT imaging demonstrated greater DiR signal in the lungs of the mice that received MS-275 treated NK cells compared to those that received untreated NK cells, suggesting that MS-275 might lead to greater persistence of NK cells at tumor sites. We conclude that MS-275 has an immunomodulatory effect on NK cells (increase L1CAM, IFNG, C3 and CD28) and increases H3 and H4 acetylation which leads to transcriptional activation of the immune-related genes that contribute to NK cell increased cytolytic function. Pre-treatment of NK cells with MS-275 enhances NK cell therapeutic efficacy and localization and persistence in the lungs. Citation Format: Ariana Rupp Anjier, Nancy Gordon, Shinji Maegawa, Vidya Gopalakrishnan, Juan Bournat, Donghang Cheng, Yanwen Yang, Charles Kingsley, Adam Kulp. Epigenetic modulation of NK cells to improve tumor trafficking and enhance therapeutic efficacy against osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2903.