Demographic, clinico-pathological features and management pattern of primary bone tumors in a tertiary care hospital of South India

<p><strong>Background</strong>: Primary bone tumors are very rare tumors. The true incidence of bone tumors is not well established and is under reported due to rarity and lack of accurate registries. Hence it is essential to study about the demographic, clinico-pathological features and the pattern of surgical management of bone tumors. The aim of this study is to analyze the demographic and clinico-pathological features of primary bone tumors that were managed by surgery.</p><p><strong>Methods</strong>: A retrospective analysis of all patients with primary bone tumor who were treated by surgery from 2012 to 2019 was done. The age, sex distribution, histopathology, location of the tumor and surgical procedure done were analyzed.</p><p><strong>Results</strong>: Among 103 patients analyzed, 66 (64%) were men and 37 (36%) were women. Primary bone tumors most commonly presented in 11 to 20 years of age with 35 (33.9%) patients occurring in this age group. Osteosarcoma was the most common primary bone tumor and it occurred in 49 (47.6%) patients, out of which 34 (69.3%) patients were below 20 years of age. Giant cell tumor was the most common benign bone tumor and it occurred in 22 patients, out of which nine (40.9%) patients were of age 21 to 30 years. Distal femur was the most common site with 39 (37.9%) patients. The limb preservation rate for malignant appendicular bone tumors was 69.0%.</p><p><strong>Conclusions</strong>: The diagnosis of bone tumor depends not only on histopathological features but also needs correlation with age, clinical features, tumor location and radiological features for confirmation of diagnosis.</p>

Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.

Rho-GEF Trio regulates osteosarcoma progression and osteogenic differentiation through Rac1 and RhoA

Osteosarcoma (OS) is the most common primary bone tumor. Its high mortality rate and metastasis rate seriously threaten human health. Currently, the treatment has reached a plateau, hence we urgently need to explore new therapeutic directions. In this paper, we found that Trio was highly expressed in osteosarcoma than normal tissues and promoted the proliferation, migration, and invasion of osteosarcoma cells. Furthermore, Trio inhibited osteosarcoma cells’ osteogenic differentiation in vitro and accelerated the growth of osteosarcoma in vivo. Given Trio contains two GEF domains, which have been reported as the regulators of RhoGTPases, we further discovered that Trio could regulate osteosarcoma progression and osteogenic differentiation through activating RhoGTPases. In summary, all our preliminary results showed that Trio could be a potential target and prognostic marker of osteosarcoma.

Simultaneous bilateral thoracotomy in patients with osteosarcoma and bilateral pulmonary metastases: the experience of the D. Rogachev NMRCPHOI

Osteosarcoma (OS) is the most common primary bone tumor in children and adults. In 15–20% of patients, distant metastases are detected at the time of diagnosis of OS. In more than 80% of cases, metastases are located in the lungs and are the most common disease-related cause of death in OS patients. OS can only be cured if complete surgical remission (CSR) in the lungs is achieved through surgery involving palpation, identification and resection of all detected metastases. Among thoracic surgeons, it is common practice to perform wedge resection of the affected lung parenchyma as it spares more healthy lung tissue. Lobectomy or pneumonectomy can be carried out if either is indicated in the patient. There is, however, no consensus on the best surgical approach for metastasectomy. Our study includes 24 patients who underwent simultaneous bilateral thoracotomy at the Department of Oncology and Pediatric Surgery of the D. Rogachev NMRCPHOI in the period from February 2018 to May 2021. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. Eighteen patients underwent primary surgery as part of combination protocol treatment, and six patients were surgically treated for relapse. In 66.7% of the patients treated with upfront surgery, the number of lesions was underestimated, as evident from computed tomography images and intraoperative findings. Post-treatment necrosis grade IV was detected only in 3 patients, in 21.1% of the resected metastases. The median time from bilateral thoracotomy to systemic anti-cancer therapy reinitiation was 12 days. Two patients experienced progression of metastatic disease in the lungs during and immediately the protocol treatment. At the last follow-up, 3 patients were alive with evidence of disease, and 2 patients had died of OS progression. A total of 33.3% of the patients who had had primary surgery developed metastatic (n = 6) and local (n = 1) relapses.

Osteoblast-specific inactivation of p53 results in locally increased bone formation

Inactivation of the tumor suppressor p53 (encoded by the Trp53 gene) is relevant for development and growth of different cancers, including osteosarcoma, a primary bone tumor mostly affecting children and young adolescents. We have previously shown that deficiency of the ribosomal S6 kinase 2 (Rsk2) limits osteosarcoma growth in a transgenic mouse model overexpressing the proto-oncogene c-Fos. Our initial aim for the present study was to address the question, if Rsk2 deficiency would also influence osteosarcoma growth in another mouse model. For that purpose, we took advantage of Trp53fl/fl mice, which were crossed with Runx2Cre transgenic mice in order to inactivate p53 specifically in osteoblast lineage cells. However, since we unexpectedly identified Runx2Cre-mediated recombination also in the thymus, the majority of 6-month-old Trp53fl/fl;Runx2-Cre (thereafter termed Trp53Cre) animals displayed thymic lymphomas, similar to what has been described for Trp53-deficient mice. Since we did not detect osteosarcoma formation at that age, we could not follow our initial aim, but we studied the skeletal phenotype of Trp53Cre mice, with or without additional Rsk2 deficiency. Here we unexpectedly observed that Trp53Cre mice display a unique accumulation of trabecular bone in the midshaft region of the femur and the humerus, consistent with its previously established role as a negative regulator of osteoblastogenesis. Since this local bone mass increase in Trp53Cre mice was significantly reduced by Rsk2 deficiency, we isolated bone marrow cells from the different groups of mice and analyzed their behavior ex vivo. Here we observed a remarkable increase of colony formation, osteogenic differentiation and proliferation in Trp53Cre cultures, which was unaffected by Rsk2 deficiency. Our data thereby confirm a critical and tumorigenesis-independent function of p53 as a key regulator of mesenchymal cell differentiation.

LncRNA FOXP4-AS1 Promotes Progression of Ewing Sarcoma and Is Associated With Immune Infiltrates

Ewing sarcoma (ES) is a highly malignant primary bone tumor with poor prognosis. Studies have shown that abnormal expression of lncRNA influences the prognosis of tumor patients. Herein, we established that FOXP4-AS1 was up-regulated in ES and this correlated with poor prognosis. Further analysis illustrated that FOXP4-AS1 down-regulation repression growth, migration, along with invasion of ES. On the contrary, up-regulation of FOXP4-AS1 promoted the growth, migration, as well as invasion of ES. To explore the mechanism of FOXP4-AS1, Spearman correlation analysis was carried out to determine genes that were remarkably linked to FOXP4-AS1 expression. The potential functions and pathways involving FOXP4-AS1 were identified by GO analysis, Hallmark gene set enrichment analysis, GSEA, and GSVA. The subcellular fractionation results illustrated that FOXP4-AS1 was primarily located in the cytoplasm of ES cells. Then a ceRNA network of FOXP4-AS1 was constructed. Analysis of the ceRNA network and GSEA yielded two candidate mRNAs for FOXP4-AS1. Results of the combined survival analysis led us to speculate that FOXP4-AS1 may affect the expression of TMPO by sponging miR-298, thereby regulating the malignant phenotype of ES. Finally, we found that FOXP4-AS1 may modulates the tumor immune microenvironment in an extracellular vesicle-mediated manner. In summary, FOXP4-AS1 correlates with poor prognosis of ES. It promotes the growth, migration, as well as invasion of ES cells and may modulate the tumor immune microenvironment.

New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling

Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRβ) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy.

Anti-cancer properties of quercetin in osteosarcoma

Osteosarcoma is a primary bone tumor. Although it is a rare disease in general, it is the most common primary bone tumor among children. Despite the significant advances made in the field of osteosarcoma treatment, the outcomes of this disease are still unfavorable. Besides, there is still no targeted therapy for osteosarcoma that can be used in clinical settings. Quercetin is a member of the phytochemical family which is used for different diseases including cardiovascular diseases, diabetes, and cancer. Its anti-cancer effects are examined in many types of cancer including breast, colon, lung, prostate, and pancreatic cancers and have shown promising results. Herein, the studies dealing with the antitumor roles of quercetin in osteosarcoma are reviewed in this article. We take a look into quercetin’s ability to affect proliferation, apoptosis, invasion, and chemo-resistance of the osteosarcoma cells through regulating protein expression and signaling pathways.

Phosphoinositide Signal Transduction Pathway and Osteosarcoma Metastases

: Metastasis spreading confers a worse prognosis to the clinical outcome among patients suffering from osteosarcoma, the most common primary bone tumor in childhood and adolescence. The detection of molecules involved in metastasis spreading might contribute to understanding tumor dissemination mechanisms, thereby opening the way to novel therapeutic strategies. The Ezrin-radixin-moesin (ERM) family proteins are activated after interacting with molecules belonging to the phosphoinositide signal transduction pathway. The phosphatydil inositol (4,5) bisphosphate (PIP2), a crucial molecule in the PI pathway, stabilizes the ERM proteins or a more efficient receptor binding. The PIP2 levels in the pathway are a critical element for regulating several cell events. The PIP2 levels are regulated using enzymes, including the PI-specific Phospholipase C family. A decrease in the PIP2 levels induces the dissociation of the ERM protein from the membrane. In this regard, the PI-PLC enzymes regulate this event. In this paper, the role of the PI signal transduction molecules in osteosarcoma metastases is discussed.