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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.
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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.
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Biomarcadores Tumorais , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Sarcoma Sinovial , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Sarcoma Sinovial/metabolismo , Humanos , Prognóstico , Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Feminino , Masculino , Bases de Dados Genéticas , Biologia Computacional/métodos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: This study sought to identify associations between the Yost Index, a geocoded area neighborhood socioeconomic status (nSES) score, and race/ethnicity with patient refusal of recommended surgery for metastatic bone disease. METHODS: Patients with metastatic bone disease were extracted from the Surveillance, Epidemiology, and End Results database. The Yost Index was geocoded using factor analysis and categorized into quintiles using census tract-level American Community Service (ACS) 5-year estimates and seven nSES measures. Multivariable logistic regression models calculated odds ratios (ORs) of refusal of recommended surgery and 95% confidence intervals (CIs), adjusting for clinical covariates. RESULTS: A total of 138,257 patients were included, of which 14,943 (10.8%) were recommended for surgical resection. Patients in the lowest nSES quintile had 57% higher odds of refusing surgical treatment than those in the highest quintile (aOR = 1.57, 95% CI 1.30-1.91, p < 0.001). Patients in the lowest nSES quintile also had a 31.2% higher age-adjusted incidence rate of not being recommended for surgery compared with those in the highest quintile (186.4 vs. 142.1 per 1 million, p < 0.001). Black patients had 34% higher odds of refusing treatment compared with White patients (aOR = 1.34, 95% CI 1.14-1.58, p = 0.003). Advanced age, unmarried status, and patients with aggressive cancer subtypes were associated with higher odds of refusing surgery (p < 0.001). CONCLUSIONS: nSES and race/ethnicity are independent predictors of a patient refusing surgery for metastatic cancer to bone, even after adjusting for various clinical covariates. Effective strategies for addressing these inequalities and improving the access and quality of care of patients with a lower nSES and minority backgrounds are needed.
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Neoplasias Ósseas , Programa de SEER , Classe Social , Recusa do Paciente ao Tratamento , Humanos , Feminino , Masculino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Idoso , Pessoa de Meia-Idade , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Seguimentos , Prognóstico , Adulto , Características da Vizinhança , Estados Unidos/epidemiologiaRESUMO
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.
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Single-cell transcriptomics profiling has increasingly been used to evaluate cross-group differences in cell population and cell-type gene expression. This often leads to large datasets with complex experimental designs that need advanced comparative analysis. Concurrently, bioinformatics software and analytic approaches also become more diverse and constantly undergo improvement. Thus, there is an increased need for automated and standardized data processing and analysis pipelines, which should be efficient and flexible too. To address these, we develop the single-cell Differential Analysis and Processing Pipeline (scDAPP), a R-based workflow for comparative analysis of single cell (or nucleus) transcriptomic data between two or more groups and at the levels of single cells or "pseudobulking" samples. The pipeline automates many steps of pre-processing using data-learnt parameters, uses previously benchmarked software, and generates comprehensive intermediate data and final results that are valuable for both beginners and experts of scRNA-seq analysis. Moreover, the analytic reports, augmented by extensive data visualization, increase the transparency of computational analysis and parameter choices, while facilitate users to go seamlessly from raw data to biological interpretation. Availability and Implementation: scDAPP is freely available for non-commercial usage as an R package under the MIT license. Source code, documentation and sample data are available at the GitHub (https://github.com/bioinfoDZ/scDAPP).
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BACKGROUND: The effect of socioeconomic status (SES) on the outcomes of patients with metastatic cancer to bone has not been adequately studied. We analyzed the association between the Yost Index, a composite geocoded SES score, and overall survival among patients who underwent nonprimary surgical resection for bone metastases. METHODS: This population-based study used data from the National Cancer Institute's Surveillance, Epidemiology, and End Results database (2010 to 2018). We categorized bone and joint sites using International Classification of Disease-O-3 recodes. The Yost Index was geocoded using a factor analysis and categorized into quintiles using census tract-level American Community Service 5-year estimates and seven measures: median household income, median house value, median rent, percent below 150% of the poverty line, education index, percent working class, and percent unemployed. Multivariate Cox regression models were used to calculate adjusted hazard ratios of overall survival and 95% confidence intervals. RESULTS: A total of 138,158 patients were included. Patients with the lowest SES had 34% higher risk of mortality compared with those with the highest SES (adjusted hazard ratio of 1.34, 95% confidence interval: 1.32 to 1.37, P < 0.001). Among patients who underwent nonprimary surgery of the distant bone tumor (n = 11,984), the age-adjusted mortality rate was 31.3% higher in the lowest SES patients compared with the highest SES patients (9.9 versus 6.8 per 100,000, P < 0.001). Patients in the lowest SES group showed more racial heterogeneity (63.0% White, 33.5% Black, 3.1% AAPI) compared with the highest SES group (83.9% White, 4.0% Black, 11.8% AAPI, P < 0.001). Higher SES patients are more likely to be married (77.5% versus 59.0%, P < 0.0001) and to live in metropolitan areas (99.6% versus 73.6%, P < 0.0001) compared with lower SES patients. DISCUSSION: Our results may have implications for developing interventions to improve access and quality of care for patients from lower SES backgrounds, ultimately reducing disparities in orthopaedic surgery.
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Neoplasias , Classe Social , Humanos , Estados Unidos/epidemiologia , Pobreza , Modelos de Riscos Proporcionais , EscolaridadeRESUMO
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.
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Neoplasias Ósseas , Osteossarcoma , Animais , Humanos , Camundongos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Carcinogênese , Inibidor de Quinase Dependente de Ciclina p27/genética , Camundongos Knockout , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Microambiente TumoralRESUMO
Osteosarcoma is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in osteosarcoma is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that Skp2 knockout in murine osteosarcoma improved survival and delayed tumorigenesis. Here, we performed RNA sequencing (RNA-seq) on tumors from a transgenic osteosarcoma mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage ("DKO": Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout ("TKO": Osx1-Cre;Rb1lox/lox;p53lox/lox;Skp2-/-), followed by qPCR and immunohistochemistry validation. To investigate the clinical implications of our results, we analyzed a human osteosarcoma patient cohort ("NCI-TARGET OS") with RNA-seq and clinical data. We found large differences in gene expression after SKP2 knockout. Surprisingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors, especially the signature genes for macrophages and to a lesser extent, T cells, B cells, and vascular cells. We also uncovered a set of relevant transcription factors that may mediate these changes. In osteosarcoma patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET osteosarcoma and the TCGA Sarcoma cohorts. Overall, our findings indicate that SKP2 may mediate immune exclusion from the osteosarcoma tumor microenvironment, suggesting that SKP2 modulation in osteosarcoma may induce antitumor immune activation.
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Neoplasias Ósseas , Osteossarcoma , Animais , Humanos , Camundongos , Neoplasias Ósseas/genética , Modelos Animais de Doenças , Camundongos Knockout , Camundongos Transgênicos , Osteossarcoma/genética , Osteossarcoma/patologia , Prognóstico , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Purpose: Osteosarcoma (OS) is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in OS is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that SKP2 knockout in murine OS improved survival and delayed tumorigenesis. Here we aim to define the SKP2 drives transcriptional program and its clinical implication in OS. Experimental Design: We performed RNA-sequencing (RNA-seq) on tumors from a transgenic OS mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage ("DKO": Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout ("TKO": Osx1-Cre;Rb1lox/lox;p53lox/lox;SKP2-/-). We validated our RNA-seq findings using qPCR and immunohistochemistry. To investigate the clinical implications of our results, we analyzed a human OS patient cohort ("NCI-TARGET OS") with RNA-seq and clinical data. Results: We found large differences in gene expression after SKP2 knockout. Strikingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors. We observed significant increases in signature genes for macrophages and to a lesser extent, T cells, B cells and vascular cells. We also uncovered a set of relevant transcription factors that may mediate the changes. In OS patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET OS and the TCGA Sarcoma cohort. Conclusion: Our findings indicate that SKP2 may mediate immune exclusion from the OS tumor microenvironment, suggesting that SKP2 modulation in OS may induce anti-tumor immune activation.
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Proteins that regulate the cell cycle are accumulated and degraded in a coordinated manner during the transition from one cell cycle phase to the next. The rapid loss of a critical protein, for example, to allow the cell to move from G1/G0 to S phase, is often regulated by its ubiquitination and subsequent proteasomal degradation. Protein ubiquitination is mediated by a series of three ligases, of which the E3 ligases provide the specificity for a particular protein substrate. One such E3 ligase is SCFSkp1/Cks1, which has a substrate recruiting subunit called S-phase kinase-associated protein 2 (Skp2). Skp2 regulates cell proliferation, apoptosis, and differentiation, can act as an oncogene, and is overexpressed in human cancer. A primary target of Skp2 is the cyclin-dependent kinase inhibitor p27 (CDKN1b) that regulates the cell cycle at several points. The RB1 tumour suppressor gene regulates Skp2 activity by two mechanisms: by controlling its mRNA expression, and by an effect on Skp2's enzymatic activity. For the latter, the RB1 protein (pRb) directly binds to the substrate-binding site on Skp2, preventing protein substrates from being ubiquitinated and degraded. Inactivating mutations in RB1 are common in human cancer, becoming more frequent in aggressive, metastatic, and drug-resistant tumours. Hence, RB1 mutation leads to the loss of pRb, an unrestrained increase in Skp2 activity, the unregulated decrease in p27, and the loss of cell cycle control. Because RB1 mutations lead to the loss of a functional protein, its direct targeting is not possible. This perspective will discuss evidence validating Skp2 as a therapeutic target in RB1-deficient cancer.
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Quinases relacionadas a CDC2 e CDC28 , Neoplasias , Quinases relacionadas a CDC2 e CDC28/genética , Quinases relacionadas a CDC2 e CDC28/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Humanos , Neoplasias/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Proteína do Retinoblastoma , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
There are an increasing number of patients who present with metastatic bone disease as the survival of patients with cancer improves in recent decades. The pelvis is the second most common site for skeletal metastases. Metastatic lesions in the pelvis can be largely divided into periacetabular lesions (Enneking zone II) and non-periacetabular lesions (zones I, III, and IV). Traditionally, patients with a symptomatic zone II lesion are treated with a cemented total hip arthroplasty (THA) using variations on the traditional Harrington method. These open surgeries are accompanied by many inherent risks. Both a prolonged recovery and wide range of potential complications may delay or interrupt the adjuvant radiation and systemic therapy. It was observed that the articular surface of the hip joint was often intact and that the femoral side was frequently not involved in these patients. A novel minimally invasive technique for hip joint preservation has recently been developed. Three large-bore cannulated screws are placed percutaneously under fluoroscopy in a tripod configuration to reinforce the mechanical axis of the acetabulum. Increased stability improves pain control and permits immediate weight bearing. When the disease progresses, this construct can be easily converted to a cemented THA using the tripod screws as rebar to support an acetabular cup, as part of a staged Harrington procedure. This approach is technically demanding. A detailed guide for the tripod technique should encompass indications, preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, modifications, postoperative care, and subsequent conversion to a cemented THA, if needed.
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Artroplastia de Quadril , Neoplasias , Acetábulo/cirurgia , Artroplastia de Quadril/métodos , Fluoroscopia , Humanos , Neoplasias/patologia , Neoplasias/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The pelvis is one of the most common locations for metastatic bone disease. While many of the publications that describe surgical treatments focus on periacetabular lesions (Enneking zone II), there is a lack of investigation into lesions in the non-periacetabular areas (zones I, III, and IV). We recently described a minimally invasive percutaneous screw application for metastatic zone-II lesions with excellent results. In the present study, we aimed to extend this approach to the other pelvic areas. METHODS: Twenty-two consecutive patients with painful non-periacetabular pelvic metastatic cancer were included based on retrospective chart review. There were 16 women and 6 men with an average age of 60 years (range, 36 to 81 years). The most common primary cancers were multiple myeloma (7 cases) and breast (5 cases). The most common locations were the sacrum and the ilium. A pathologic fracture was identified in 15 patients. Most of the lesions were treated with multiple large-diameter screws, except for the isolated zone-III lesions. All of the procedures were completed in a standard operating room without the need for special instruments. Radiation therapy was given to 19 patients; the average dose was 15 Gy. The studied outcomes were pain and functionality as assessed by a visual analog scale (VAS) score and the Eastern Cooperative Oncology Group score (ECOG), respectively. RESULTS: There were no surgical complications and no need for blood transfusion. The average follow-up time was 7 months (range, 0.3 to 34.0 months). Two patients died within 4 weeks of surgery due to COVID-19 infection. There was significant improvement in the postoperative VAS pain score (p < 0.0001) and the ECOG score (p < 0.05) when compared with the preoperative scores. There was no implant failure or revision surgery. Local bone-healing was observed in 12 of 14 patients (86%) who survived for >3 months after surgery. CONCLUSIONS: Percutaneous screw application is safe and effective in the treatment of metastatic non-periacetabular pelvic lesions. Given the simplicity of the technique and the instrumentation and the tolerance for concomitant treatments, this approach is worthy of broader consideration. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.
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INTRODUCTION: There is currently no consensus regarding the best techniques or surgical strategies with which to maximize intercalary allograft reconstruction outcomes. The purpose of the current study was to assess which techniques and methods are being utilized by North American orthopaedic oncologists. METHODS: Members of the Musculoskeletal Tumor Society (MSTS) were invited to complete an anonymous online questionnaire. The survey presented participants with two clinical scenarios and interrogated them on their preferred type of allograft, method of compression and fixation, and additional techniques used. RESULTS: One hundred and twenty-six physicians completed the questionnaire. The majority studied in the United States (82%) and worked at an academic medical center (71%). Over half (54%) reported seeing over 10 primary bone tumors every year. Respondents were split between preferring a structural allograft alone or using a combined allograft-vascularized fibular graft. A majority indicated a preference for plate(s) and screw fixation but were divided between the use of two compression plates with a spanning plate, a single compression plate with a spanning plate, and two compression plates with an intramedullary nail. Screw fixation preferences were split between the use of unicortical locking only, bicortical locking only, and a combination of unicortical and bicortical locking. Almost equal percentages of respondents reported they would have used two, three, or four screws in both scenarios. Respondents were split between placing screws equidistantly and placing them peripherally within the allograft, adjacent to the allograft-host junction. DISCUSSION: There is no clear surgical preference for intercalary reconstruction following tumor extirpation within this sample of orthopaedic oncologists. The current survey demonstrates variability across nearly every aspect of allograft reconstruction, which may, in part, explain the wide spectrum of outcomes reported within the literature. Prospective studies are warranted to better evaluate technique-specific outcomes in an effort to maximize reconstructive longevity and minimize allograft related complications.
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Neoplasias Ósseas/cirurgia , Transplante Ósseo/métodos , Neoplasias Femorais/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Aloenxertos , Cimentos Ósseos , Neoplasias Ósseas/patologia , Placas Ósseas , Transplante Ósseo/normas , Neoplasias Femorais/patologia , Humanos , Procedimentos de Cirurgia Plástica/normas , Inquéritos e QuestionáriosRESUMO
Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene; p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCFSKP2 E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27T187A KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27T187A KI mice were crossed on to the DKO background, p27T187A protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27T187A promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCFSKP2 -p27T187A axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2-p27 axis may represent a desirable therapeutic strategy for this cancer.
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Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Proteínas Quinases Associadas a Fase S/metabolismo , Animais , Carcinogênese/genética , Células Cultivadas , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proto-Oncogene Mas , Proteínas de Ligação a Retinoblastoma/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Six cell surface receptors, human epidermal growth factor receptor-2 (Her-2), platelet-derived growth factor receptor-ß (PDGFR-ß), insulin-like growth factor-1 receptor (IGF-1R), insulin receptor (IR), c-Met, and vascular endothelial growth factor receptor-3 (VEGFR-3), previously demonstrated variable expression across varying patient-derived and standard osteosarcoma (OS) cell lines. The current study sought to validate previous expression patterns and evaluate whether these receptors offer prognostic and/or therapeutic value. METHODS: Patient-derived OS cell lines (n = 52) were labeled with antibodies to Her-2, PDGFR-ß, IGF-1R, IR, c-Met, and VEGFR-3. Expression was characterized using flow cytometry. The difference in geometric mean fluorescent intensity (geoMFIdiff = geoMFIpositive - geoMFInegative) was calculated for each receptor across all cell lines. Receptor expression was categorized as low (Q1), intermediate (Q2, Q3), or high (Q4). The event-free survival (EFS) and overall survival for the six cell surface receptors were estimated by the Kaplan-Meier method. Differences in hazard for EFS event and overall survival event for patients in each of the three expression levels in each of the six cell surface receptors were assessed using the log-rank test. RESULTS: All 6 receptors were variably expressed in the majority of cell lines. IR and PDGFR-ß expressions were found to be significant predictors for EFS amongst patients with nonmetastatic disease (p=0.02 and 0.01, respectively). The hazard ratio for EFS was significantly higher between high IR and intermediate IR expression (HR = 2.66, p=0.02), as well as between high PDGFR-ß and intermediate PDGFR-ß expression (HR = 5.68, p=0.002). Her-2, c-Met, IGF-1R, and VEGFR-3 were not found to be significant predictors for either EFS or overall survival. CONCLUSION: The six cell surface receptors demonstrated variable expression across the majority of patient-derived OS cell lines tested. Limited prognostic value was offered by IR and PDGFR-ß expression within nonmetastatic patients. The remaining receptors do not provide clear prognostic utility. Nevertheless, their consistent, albeit variable, surface expression across a large panel of patient-derived OS cell lines maintains their potential use as future therapeutic targets.
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Symptomatic peri-acetabular metastatic lesions are often treated with open surgery such as modified Harrington procedures. In an effort to avoid surgical complications inherently associated with open surgical approaches, we developed and recently reported a novel Tripod percutaneous screw technique. The tripod technique is minimally invasive and was found to yield excellent outcomes regarding both pain control and functionality. The procedure is performed in a standard operative theater using fluoroscopic guided percutaneous screws. Despite the simplicity of intraoperative set-up and instrumentation, it is technically demanding. Obtaining the correct fluoroscopic views and troubleshooting intraoperative hurdles can be challenging for even an experienced orthopedic surgeon. The technique and bony conduits were previously described in the trauma literature, however, there are key points of difference in the setting of metastatic disease. Here we provide a compilation of a stepwise graphic guide for the tripod model in the setting of metastatic peri-acetabular lesions, as well as the tips and tricks based on our own experience. These encompass preoperative preparation, operating room settings, intraoperative fluoroscopic guidance, postoperative care, and subsequent conversion to a cemented total hip arthroplasty, if needed.
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Acetábulo/cirurgia , Artroplastia de Quadril/métodos , Neoplasias Ósseas/cirurgia , Parafusos Ósseos , Fixação Interna de Fraturas/métodos , Neoplasias/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Neoplasias Ósseas/secundário , Fluoroscopia , Humanos , Neoplasias/patologia , PrognósticoRESUMO
BACKGROUND: Outcome of patients with osteosarcoma (OS) and Ewing sarcoma (EWS) is dependent on presence of metastases. Imaging guidelines for OS and EWS include radiographs, computed tomography (CT), and magnetic resonance imaging for primary tumor evaluation and CT chest and bone scintigraphy (BS) for metastatic detection. 18Fluorodeoxyglucose (18FDG) positron emission tomography (PET)/CT has become more common for disease evaluation, yet there is no consensus for its use in this population. OBJECTIVE: We aimed to compare identification of osseous metastases using BS versus 18FDG PET/CT in our patient population. We hypothesized that 18FDG PET/CT is more likely to detect osseous metastases both at diagnosis and relapse. MATERIALS AND METHODS: We performed retrospective chart reviews of pediatric sarcoma patients treated at our institution from 2008 to 2019. Paired BS and 18FDG PET/CT scans were reviewed. Review of the literature was also performed. RESULTS: Thirty-three patients had paired BS and 18FDG PET/CT during diagnosis or treatment. Fifteen patients had distant osseous metastases. In the OS cohort, 8/16 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 75% on BS. Thirty-one bony lesions were seen on imaging in OS patients; 100% of these were identified on 18FDG PET/CT but only 29% on BS. In the EWS cohort, 6/15 patients had osseous metastases; 100% of these patients were detected on 18FDG PET/CT and 50% on BS. Eighteen bony lesions were seen on imaging in EWS patients; 94% of these were identified on 18FDG PET/CT, but only 28% on BS. CONCLUSION: For patients in our institution with OS or EWS, osseous metastases were more likely detected using 18FDG PET/CT.
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Neoplasias Ósseas/secundário , Fluordesoxiglucose F18/metabolismo , Imageamento por Ressonância Magnética/métodos , Osteossarcoma/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Sarcoma de Ewing/patologia , Adolescente , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/metabolismo , Osteossarcoma/cirurgia , Prognóstico , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/cirurgia , Adulto JovemRESUMO
Introduction: Paget's disease is a metabolic bone disorder characterized by abnormal patterns in bone remodeling, resulting in variable degrees of chronic bone pain, deformation of the long bones and rarely, and pathologic fracture. These issues can pose difficult surgical challenges, particularly in the elderly frail population, where the benefits of orthopedic intervention must be balanced with minimizing inherent surgical risks. Such considerations often include reducing operative time and blood loss, allowing for early mobilization, stabilizing an impending fracture, and providing symptom relief. Case Report: A 77-year-old female with a 10-year history of Paget's disease presented to an outside orthopedic clinic with progressive right leg pain and worsening anterior bowing following minor trauma to the extremity. Ultimately, the patient was offered in situ prophylactic intramedullary (IM) nail fixation, intended to augment her bone's native strength and prevent further microfractures and subsequent deformation. A three-dimensional (3D) printed patient specific model was developed to permit for pre-contouring of an off-the-shelf implant and subsequent sterilization and use at a future point in time. She underwent uneventful IM nailing of her tibia with the pre-contoured implant and proceeded to progress clinically postoperatively. Conclusion: In this report, we present an innovative use of a 3D printed patient-specific tibia model to pre-contour an IM nail. This surgical approach was undertaken to treat an elderly patient with a symptomatic and progressive deformity of the tibia secondary to Paget's disease of bone.
RESUMO
Wnt molecules are a class of cysteine-rich secreted glycoproteins that participate in various developmental events during embryogenesis and adult tissue homeostasis. Since its discovery in 1982, the roles of Wnt signaling have been established in various key regulatory systems in biology. Wnt signals exert pleiotropic effects, including mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway in humans has been shown to be involved in a wide variety of disorders including colon cancer, sarcoma, coronary artery disease, tetra-amelia, Mullerian duct regression, eye vascular defects, and abnormal bone mass. The canonical Wnt pathway functions by regulating the function of the transcriptional coactivator ß-catenin, whereas noncanonical pathways function independent of ß-catenin. Although the role of Wnt signaling is well established in epithelial malignancies, its role in mesenchymal tumors is more controversial. Some studies have suggested that Wnt signaling plays a pro-oncogenic role in various sarcomas by driving cell proliferation and motility; however, others have reported that Wnt signaling acts as a tumor suppressor by committing tumor cells to differentiate into a mature lineage. Wnt signaling pathway also plays an important role in regulating cancer stem cell function. In this review, we will discuss Wnt signaling pathway and its role in osteosarcoma.
Assuntos
Neoplasias Ósseas , Proteínas Wnt , Via de Sinalização Wnt , Neoplasias Ósseas/metabolismo , Diferenciação Celular , Humanos , Osteossarcoma/metabolismo , Proteínas Wnt/metabolismo , beta CateninaRESUMO
SIGNIFICANCE: Diffuse optical spectroscopic imaging (DOSI) measures quantitative functional and molecular information in thick tissue in a noninvasive manner using near-infrared light. DOSI may be useful for diagnosis and prognosis of bone pathologies including osteosarcoma and Ewing's sarcoma, but little is currently known about DOSI-derived parameters in bony anatomic locations where this disease occurs. AIM: Our goal is to quantify the optical characteristics and chromophore content of bony anatomic locations of healthy volunteers and assess differences due to anatomic region, age, sex, ethnicity, race, and body fat. APPROACH: Fifty-five healthy volunteers aged 4 to 72 were enrolled in the study. The optical properties and quantitative tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water, and lipids were assessed at the distal humerus, distal femur, and proximal tibia. Body fat was assessed using skinfold calipers. One volunteer underwent a more comprehensive body scan from neck to foot to explore chromophore distributions within an individual. Regression analysis was used to identify the most important sources of variation in the measured data set. RESULTS: Statistical differences between bony locations were found for scattering, water, and lipids, but not for hemoglobin. All chromophores had statistical differences with sex, but there were no significant age-related correlations. Regression analysis revealed that body fat measured with skinfold calipers was the most important predictor of oxy-, deoxy-, total hemoglobin, and lipids. Hemoglobin and lipid levels were highly correlated (ρ ≥ 0.7) over the subject population and within the single-subject body scan. CONCLUSIONS: DOSI can successfully measure bony anatomic sites where osteosarcomas and Ewing's sarcomas commonly occur. Future studies of bone pathology using DOSI should account for the variation caused by anatomic region, sex, race and ethnicity, and body fat as these cause substantial variations in DOSI-derived metrics.