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      Current Status and Prospects of Clinical Treatment of Osteosarcoma

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          Abstract

          Osteosarcoma, one of the common malignant tumors in the skeletal system, originates in mesenchymal tissue, and the most susceptible area of occurrence is the metaphysis with its abundant blood supply. Tumors are characterized by highly malignant spindle stromal cells that can produce bone-like tissue. Most of the osteosarcoma are primary, and a few are secondary. Osteosarcoma occurs primarily in children and adolescents undergoing vigorous bone growth and development. Most cases involve rapid tumor development and early blood metastasis. In recent years, research has grown in the areas of molecular biology, imaging medicine, biological materials, applied anatomy, surgical techniques, biomechanics, and comprehensive treatment of tumors. With developments in molecular biology and tissue bioengineering, treatment methods have also made great progress, especially in comprehensive limb salvage treatment, which significantly enhances the quality of life after surgery and improves the 5-year survival rate of patients with malignant tumors. This article provides a review of limb salvage, immunotherapy, gene therapy, and targeted therapy from traditional amputation to neoadjuvant chemotherapy, providing a reference for current clinical treatments for osteosarcoma.

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          PI3Kγ is a molecular switch that controls immune suppression.

          Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8(+) T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.
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            Mechanisms of receptor tyrosine kinase activation in cancer

            Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
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              Current and future therapeutic approaches for osteosarcoma.

              Current treatment of osteosarcoma includes surgical resection of all gross disease in conjunction with systemic chemotherapy to control micro-metastatic disease. This yields a 5-year event free survival (EFS) of approximately 70% for patients with localized osteosarcoma while patients with metastatic or recurrent disease fare poorly with overall survival rates of less than 20%. Areas covered: This review outlines the current and future approach towards the treatment of osteosarcoma. A literature search was performed utilizing PubMed. Several recent clinical trials are reviewed in detail, as is innovative research evaluating novel agents and surgical techniques which hold promise. Expert commentary: The outcome for patients with osteosarcoma has not changed in several decades. This plateau in survival rates highlights the need for a novel approach towards research. There remains a great deal of interest in utilizing the very high risk population of recurrent osteosarcoma patients to rapidly and sequentially evaluate novel agents to determine if any of these agents hold promise. Several phase II studies are ongoing or in development that offer hope based on intriguing preclinical data. Furthermore, initiatives in obtaining specimens to further explore the genetic and immunological profile behind osteosarcoma will be essential towards identifying novel pathways and targets to exploit.
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                Author and article information

                Journal
                Technol Cancer Res Treat
                Technol Cancer Res Treat
                TCT
                sptct
                Technology in Cancer Research & Treatment
                SAGE Publications (Sage CA: Los Angeles, CA )
                1533-0346
                1533-0338
                21 September 2022
                2022
                : 21
                : 15330338221124696
                Affiliations
                [1 ]Department of Hand Surgery, Ringgold 380381, universityShenzhen Longhua District People’s Hospital; , Shenzhen, China
                [2 ]Institute of Oncology, Ringgold Nantong University, universityAffiliated Tumor Hospital of Nantong University; , Nantong, China
                [3 ]Department of Orthopedics, Zhongshan Hospital, Ringgold 12478, universityFudan University; , Shanghai, China
                [4 ]Cancer Institute, Ringgold 74754, universityLonghua Hospital; , Shanghai University of Traditional Chinese Medicine, Shanghai, China
                [5 ]Department of General Surgery, Ruijin Hospital, Ringgold 12474, universityShanghai Jiaotong University School of Medicine; , Shanghai, China
                Author notes
                [*]

                These authors contributed equally to this work.

                [*]Da Fu, Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Email: fu800da900@ 123456126.com
                [*]Yu-Shui Ma, Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Email: mayushui@ 123456tongji.edu.cn
                [*]Xiao-Feng Wang, Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Email: wang.xiaofeng@ 123456zs-hospital.sh.cn
                Author information
                https://orcid.org/0000-0002-0878-2575
                Article
                10.1177_15330338221124696
                10.1177/15330338221124696
                9500272
                36128851
                e81b0a2c-e694-42d9-bfd6-ed11e3e2f342
                © The Author(s) 2022

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 09 June 2022
                : 15 August 2022
                : 19 August 2022
                Funding
                Funded by: Wu Jieping Medical Foundation, FundRef https://doi.org/10.13039/100007452;
                Award ID: 320.6750.14326
                Categories
                Review
                Custom metadata
                ts19
                January-December 2022

                osteosarcoma,treatment,chemotherapy,immunotherapy,prognosis
                osteosarcoma, treatment, chemotherapy, immunotherapy, prognosis

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