title: Manipulation therapy prior to diagnosis induced primary osteosarcoma metastasis--from clinical to basic research.
abstract: Osteosarcoma (OS) patients who suffer manipulation therapy (MT) prior to diagnosis resulted in poor prognosis with increasing metastasis or recurrence rate. The aim of the study is to establish an in vivo model to identify the effects of MT on OS. The enrolled 235 OS patients were followed up in this study. In vivo nude mice model with tibia injection of GFP-labeled human OS cells were randomly allocated into MT(+) that with repeated massage on tumor site twice a week and no treatment as MT(-) group. The five-year survival, metastasis and recurrence rates were recorded in clinical subjects. X-ray plainfilm, micro-PET/CT scan, histopathology, serum metalloproteinase 2 (MMP2), metalloproteinase 9 (MMP9) level and human kinase domain insert receptor (KDR) pattern were assayed in mice model. The results showed that patient with MT decreased 5-year survival and higher recurrence or metastasis rate. Compatible with clinical findings, the decreased body weight (30.5 ± 0.65 g) and an increased tumor volume (8.3 ± 1.18 mm3) in MT(+) mice were observed. The increasing signal intensity over lymph node region of hind limb by micro-PET/CT and the tumor cells were detected in lung and bilateral lymph nodes only in MT(+) group. MMP2 (214 ± 9.8 ng/ml) and MMP9 (25.5 ± 1.81 ng/ml) were higher in MT(+) group than in MT(-) group (165 ± 7.8 ng/ml and 16.9 ± 1.40 ng/ml, individually) as well as KDR expression. Taking clinical observations and in vivo evidence together, MT treatment leads to poor prognosis of primary osteosarcoma; physicians should pay more attention on patients who seek MT before diagnosis.
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jir-You
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery and Institute of Clinical Medicine School, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Po-Kuei
authors.initials: PK
authors.lastname: Wu
authors.affiliation: Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Paul Chih-Hsueh
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chuen-Chuan
authors.initials: CC
authors.lastname: Yen
authors.affiliation: Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Giun-Yi
authors.initials: GY
authors.lastname: Hung
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery and Institute of Clinical Medicine School, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Cheng-Fong
authors.initials: CF
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Surgery and Institute of Clinical Medicine School, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
authors.forename: Shih-Fen
authors.initials: SF
authors.lastname: Tsai
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery and Institute of Clinical Medicine School, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery and Institute of Clinical Medicine School, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tain-Hsiung
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Orthopaedics, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery and Institute of Clinical Medicine School, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000818:Animals; D001859:Bone Neoplasms / Q000097:blood / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D051379:Mice; D008819:Mice, Nude; D026201:Musculoskeletal Manipulations / Q000009:adverse effects*; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000097:blood / Q000556:secondary*; D011379:Prognosis; D055815:Young Adult
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9