Neonatal osteofibrous dysplasia: Synchronous tibial and fibular involvement is common

Osteofibrous dysplasia is a rare non-malignant fibro-osseous bone tumour, first described and characterised under this name by Campanacci (1976). It is most commonly encountered in the tibia of children and young adults, but less frequently seen in the neonate with only few prior reports in the literature. We report a case of neonatal congenital osteofibrous dysplasia, presenting with unilateral limb deformity at birth. Radiographs demonstrated well-defined mixed lytic-sclerotic lesions, in a previously unreported distribution in this age-group, confined to the distal metadiaphysis of the affected tibia and fibula. Open surgery was performed for deformity correction, with tissue biopsy confirming the radiographically-suspected diagnosis. We present the up-to-date clinical, radiological, and pathological findings in this case of a rare pathology with some novel features, within this age group, in disease distribution and consequent radiographic appearances. OFD should be considered in the differential of similar congenital deforming bone lesions of the lower limb. We also review the small number of previously published cases of congenital OFD in the neonate, noting in particular that the frequency of ipsilateral fibular involvement appears to be higher than that observed in older patients.

A Case Report: Post-Operative Physiotherapy Rehabilitation Program for a Patient with Tibial Osteosarcoma

Tumour or bone tumour can occur in any bone and called it as a Osteosarcoma. It is more prone in the long bones of the body especially at metaphyseal growth plate of the bone. Femur, Tibia and Humours are the most common bone for the osteosarcoma and in some research pelvis bone and skull or jaw bone also involved. There are many factors which cause the sarcoma might be due lack of physical activity. The Chondroblastoma as Giant Cell Tumour of the Humours of Epiphysial Chondromatous in nature. Proximal humerus and Knee are the most common and most affected bone by the Chondroblastomas at the level of epiphyses of the longer bone. 62% cases show the thinning of the Subchondral structure and 33% cases shows the collapse and chondral breach Mostly (90%) it is found in the age group of 5 to 25 years of age with the male and female ratio is of 2:1. Psychological and physical improvement is seen in the patient of sarcoma and enhances participation in the exercise with great enthusiasm and help in the reduction the impact of symptoms of diseases. Physical therapy exercise protocol starts from low to moderate intensity which involved resistance exercise, aerobic exercise and combination of both exercises. Conclusion: Physiotherapy has been demonstrated to be useful in post-operative osteosarcoma patients in our case study. Physiotherapy assists the patient in de-stressing from both mental and physical stress. The goal of improving function through health-care management and goal-setting was met on schedule. Taking excellent care of yourself after surgery can help you avoid issues.

Osteosarcoma: novel prognostic biomarkers using circulating and cell-free tumour DNA

Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Despite treatment with curative-intent, many patients die of this disease. Biomarkers for assessment of disease burden and prognoses for osteosarcoma are not available. Circulating-free (cfDNA) and -tumour DNA (ctDNA) are promising biomarkers for disease surveillance in several major cancer types, however only two such studies are reported for OS. In this combined discovery and validation study, we identified four novel methylation-based biomarkers in 171 OS tumours (test set) and comprehensively validated our findings in silico in two independent osteosarcoma sample datasets (n= 162, n=107) and experimentally using digital droplet PCR (ddPCR, n=20 OS tumours). Custom ddPCR assays for these biomarkers were able to detect ctDNA in 40% of pre-operative plasma samples (n=72). ctDNA was detected in 5/17 (29%) post-operative plasma samples from patients who experienced a subsequent relapse post-operatively. Both cfDNA levels and ctDNA detection independently correlated with overall survival, p=0.0015, p=0.0096, respectively. Combining both assays increased the prognostic value of the data. Our findings illustrate the utility of mutation-independent methylation-based markers, broadly applicable ctDNA assays for tumour surveillance and prognostication. This study lays the foundation for multi-institutional collaborative studies to explore the utility of plasma-derived biomarkers for predicting clinical outcome of OS.

Integral Analyses of Competing Endogenous RNA Mechanisms and DNA Methylation Reveal Regulatory Mechanisms in Osteosarcoma

Background: Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents, with rapid growth, frequent metastasis, and a poor prognosis, but its pathogenesis has not been fully elucidated. Exploring the pathogenesis of OS is of great significance for improving diagnoses and finding new therapeutic targets.Methods: Differentially expressed circRNAs (DECs), miRNAs (DEMs), methylated DNA sites (DMSs), and mRNAs (DEGs) were identified between OS and control cell lines. GSEA of DEGs and functional enrichment analysis of methylated DEGs were carried out to further identify potential biological processes. Online tools were used to predict the miRNA binding sites of DECs and the mRNA binding sites of DEMs, and then construct a circRNA-miRNA-mRNA network. Next, an analysis of the interaction between methylated DEGs was performed with a protein-protein interaction (PPI) network, and hub gene identification and survival analysis were carried out. The expression pattern of circRNA-miRNA-mRNA was validated by real-time PCR.Results: GSEA and functional enrichment analysis indicated that DEGs and methylated DEGs are involved in important biological processes in cancer. Hsa_circ_0001753/has_miR_760/CD74 network was constructed and validated in cell lines. Low expression levels of CD74 are associated with poor overall survival times and show good diagnostic ability.Conclusion: Methylated DEGs may be involved in the development of OS, and the hsa_circ_0001753/has_miR_760/CD74 network may serve as a target for the early diagnosis of and targeted therapy for OS.

The Release of Inflammatory Mediators from Acid-Stimulated Mesenchymal Stromal Cells Favours Tumour Invasiveness and Metastasis in Osteosarcoma

Osteosarcoma is the most frequent primary malignant bone tumour with an impressive tendency to metastasise. Highly proliferative tumour cells release a remarkable amount of protons into the extracellular space that activates the NF-kB inflammatory pathway in adjacent stromal cells. In this study, we further validated the correlation between tumour glycolysis/acidosis and its role in metastases. In patients, at diagnosis, we found high circulating levels of inflammatory mediators (IL6, IL8 and miR-136-5p-containing extracellular vesicles). IL6 serum levels significantly correlated with disease-free survival and 18F-FDG PET/CT uptake, an indirect measurement of tumour glycolysis and, hence, of acidosis. In vivo subcutaneous and orthotopic models, co-injected with mesenchymal stromal (MSC) and osteosarcoma cells, formed an acidic tumour microenvironment (mean pH 6.86, as assessed by in vivo MRI-CEST pH imaging). In these xenografts, we enlightened the expression of both IL6 and the NF-kB complex subunit in stromal cells infiltrating the tumour acidic area. The co-injection with MSC also significantly increased lung metastases. Finally, by using 3D microfluidic models, we directly showed the promotion of osteosarcoma invasiveness by acidosis via IL6 and MSC. In conclusion, osteosarcoma-associated MSC react to intratumoural acidosis by triggering an inflammatory response that, in turn, promotes tumour invasiveness at the primary site toward metastasis development.

Downregulation of CD44 Inhibits Proliferation, Invasion and Migration of Osteosarcoma Cells by Regulating the Expression of Cathepsin S

BackgroundOsteosarcoma (OS) is a malignant bone tumour of mesenchymal origin. These tumours are characterised by rich vascularisation, therefore promoting rapid proliferation and facilitating metastasis. CD44 has been reported to be involved in OS, but its role and molecular mechanisms in the pathogenesis of the disease are not fully determined. MethodsIn this study, we investigated the antitumor effect of CD44 on the development of OS and further explored the molecular mechanisms. The expression of CD44, cathepsin S and MMP-9 was detected by Western blot (WB) and reverse transcription-polymerase chain reaction (RT-qPCR) in different cell lines (MG63, U2OS OS and hFOB 1.19). To elucidate the role of CD44 in OS, MG63 and U2OS cells were treated with small interference RNA (siRNA) to knock down CD44, and the knockdown efficiency was validated with GFP and RT-qPCR. Furthermore, cell proliferation was assayed using Cell Counting Kit‑8 (CCK-8) and colony formation assays, and cell migration and invasion were assayed by transwell and wound-healing assays. ResultsWe found that CD44 expression in the MG63 and U2OS OS cell lines was markedly increased compared to that of the human osteoblast hFOB 1.19 cell line. Knockdown of CD44 inhibited proliferation, migration, and invasion of MG63 and U2OS cells, possibly by regulating the expression of cathepsin S in OS. ConclusionTaken together, our data reinforced the evidence that CD44 knockdown inhibited cell proliferation, migration, and invasion of OS cells accompanied by altered expression of cathepsin S. These findings offer new clues for OS development and progression, suggesting CD44 as a potential therapeutic target for OS.

Drug combination screening as a translational approach toward an improved drug therapy for chordoma

Purpose Drug screening programmes have revealed epidermal growth factor receptor inhibitors (EGFRis) as promising therapeutics for chordoma, an orphan malignant bone tumour, in the absence of a known genetic driver. Concurrently, the irreversible EGFRi afatinib (Giotrif®) is being evaluated in a multicentric Phase II trial. As tyrosine kinase inhibitor (TKI) monotherapies are invariably followed by resistance, we aimed to evaluate potential therapeutic combinations with EGFRis. Methods We screened 133 clinically approved anticancer drugs as single agents and in combination with two EGFRis (afatinib and erlotinib) in the clival chordoma cell line UM-Chor1. Synergistic combinations were analysed in a 7 × 7 matrix format. The most promising combination was further explored in clival (UM-Chor1, MUG-CC1) and sacral (MUG-Chor1, U-CH1) chordoma cell lines. Secretomes were analysed for receptor tyrosine kinase ligands (EGF, TGF-α, FGF-2 and VEGF-A) upon drug treatment. Results Drugs that were active as single agents (n = 45) included TKIs, HDAC and proteasome inhibitors, and cytostatic drugs. Six combinations were analysed in a matrix format: n = 4 resulted in a significantly increased cell killing (crizotinib, dabrafenib, panobinostat and doxorubicin), and n = 2 exhibited no or negligible effects (regorafenib, venetoclax). Clival chordoma cell lines were more responsive to combined EGFR-MET inhibition. EGFR-MET cross-talk (e.g. via TGF-α secretion) likely accounts for the synergistic effects of EGFR-MET inhibition. Conclusion Our screen revealed promising combinations with EGFRis, such as the ALK/MET-inhibitor crizotinib, the HDAC-inhibitor panobinostat or the topoisomerase-II-inhibitor doxorubicin, which are part of standard chemotherapy regimens for various bone and soft-tissue sarcomas.

The Epidemiology of Benign Proliferative Processes of the Skeletal System in Children

A suspicion of a proliferative bone lesion in a child seems to be a major diagnostic problem for clinicians. There are no diagnostic and treatment algorithms described in the literature and no reliable cohort epidemiological data. Our study was conducted among 289 paediatric patients (0–18 years old) with an initial diagnosis of a bone tumour or tumour-like lesion. The study comprised a retrospective epidemiological analysis, an assessment of the concordance of the initial diagnoses with the histopathological diagnoses and an analysis of the specific locations of the various bone lesions. The results obtained have made it possible to formulate the following conclusions. (1) The most common proliferative bone lesion in children is osteochondroma; also common are fibrous dysplasia, non-ossifying fibromas and bone cysts. (2) Verifying the initial diagnosis by means of biopsy is essential. (3) Osteochondromas are typically located in the metaphyses of long bones, fibrous dysplasia in the femur and skull, cyst-like lesions in the proximal humerus and non-osteochondral fibromas exclusively in the lower limbs. What could improve the quality of treatment for children with primary proliferative bone diseases is the establishment of centres of paediatric orthopaedic oncology skilled in early diagnosis and prompt management.

Diagnosis and staging of malignant bone tumours in children: what is due and what is new?

Purpose Although malignant bone tumours in children are infrequent, it is important to know how to properly diagnose and stage them, in order to establish an adequate treatment. Methods We present a review of the diagnostic workflow of malignant bone tumours in children, including history and clinical examination, imaging, laboratory tests and biopsy techniques. Moreover, the two most commonly used staging systems are reviewed. Results History, clinical examination and laboratory tests are nonspecific for diagnosing malignant bone tumours in children. Radiographs remain the mainstay for initial diagnosis, with MRI the modality of choice for local assessment and staging. Fluorine-18 labelled fluoro-deoxy-glucose-positron emission tomography scans provide a noninvasive method to assess the aggressiveness of the tumour and to rule out metastasis and is replacing the use of the bone scintigraphy. Biopsy must be always performed under the direction of the surgeon who is to perform the surgical treatment and after all diagnostic evaluation has been done. Staging systems are useful to study the extent of the tumour and its prognosis. They are expected to evolve as we better understand new molecular and genetic findings. Conclusion When a malignant bone tumour is suspected in a child, it is essential to make a correct diagnosis and referral to an experienced centre. Following an appropriate workflow for diagnosis and staging facilitates, prompt access to treatment improves outcomes. Level of Evidence Level V Expert opinion