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国立がん研究センター 中央病院

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Department of Musculoskeletal Oncology and Rehabilitation

Hirokazu Chuuman, Akira Kawai, Fumihiko Nakatani, Yoshikazu Tanzawa, Eisuke Kobayashi, Makoto Endo, Nokitaka Setsu, Kouki Shimizu, Tomoaki Mori, Yoshihiro Araki, Masazumi Sugawara

Introduction

Malignant tumors arising from connective tissue are extremely rare, estimated to account for only 0.01% of newly developed cancers. The rarity itself sometimes causes several problems in treating patients with bone and soft tissue tumors, including retardation of accurate diagnoses and a lack of understanding regarding standardized therapeutic approaches. Since 1962, the Musculoskeletal Oncology Division of the National Cancer Center Hospital (NCCH) has been accumulating a vast array of clinical knowledge regarding musculoskeletal tumors in collaboration with radiologists and pathologists specializing in sarcomas, which has enabled us to offer well-organized treatment strategies to patients with various types of bone and soft tissue tumors. We have also been conducting basic and clinical studies using accumulated clinical samples and information to establish novel diagnostic methods and therapeutic approaches for treating musculoskeletal tumors. In addition, we have given weight to clinical trials on three different but inseparable fields: surgery, chemotherapy and radiation therapy for bone and soft tissue tumors.

Routine activities

The Musculoskeletal Oncology Division of the NCCH consists of six staff doctors, four residents and four physiotherapists, one occupational therapist and one speech therapist. Occasionally, several fellows from Japan and overseas join our group. Outpatient consultations are held every weekday. A constant number of over 25 patients are hospitalized for operation, chemotherapy or radiation therapy. Six or 10 major operations are routinely performed every week. In 2015, 410 operations were performed, including palliative operations for pathological fractures or spinal cord compression from metastatic bone and soft tissue tumors. Sarcomas in the trunk, including the 13 in the thoracic wall, 46 in the retroperitoneal space and three head and neck lesions were excised in cooperation with thoracic, general, urological or head-neck surgeons, respectively. A total of 66 reconstructive operations were conducted in collaboration with plastic surgeons to achieve adequate soft tissue coverage after the resection of malignant tumors of the trunk or limb-salvage operations for sarcomas of the extremities. As a result, almost 90% of the operations were performed with a limb-sparing approach. With regard to the patients' postoperative course, we have been collaborating with a physical therapist to rehabilitate the musculoskeletal system in cancerbearing patients.

As for chemotherapy, we have been conducting neo-adjuvant and adjuvant chemotherapy for high-grade bone and soft tissue tumors, palliative chemotherapy for metastatic bone and soft tissue sarcomas, where necessary in collaboration with medical oncologists. We have been collaborating with pediatric oncologists for chemotherapeutic treatment of children and adolescents with sarcomas.

Research activities

Since 2004, we have been collaborating with the NCC Research Institute to develop novel molecular target therapies or tailormade treatments for sarcoma patients. With a genome-wide microarray system or a proteinwide two dimensional fluorescence difference gel electrophoresis system, we have been analyzing the complete expression levels of mRNA and protein in the tumor samples from patients with Ewing's family tumors, osteosarcomas and soft tissue sarcomas. Combined with each patient's clinical information, we have been establishing novel biomarkers for prediction of patients' prognoses or effects of the chemotherapeutic agents. Using the same method, we also have been searching for new genes or proteins for the molecular-targeted treatment approach. Since 2009, we have also been focusing on the aberrant microRNA expressions in Ewing's sarcoma and osteosarcoma with the aim of developing novel molecular targeted therapies or biomarkers.

Clinical trials

We also have been focus ingon the standardization of adjuvant and second-line chemotherapy regimens for bone and soft tissue sarcomas. Four multi-institutional clinical trials are active as follows:

  1. A multi-institutional phase III clinical trial of multi-drugs adjuvant chemotherapy for osteosarcomas (The Japan Clinical Oncology Group (JCOG) 0905) since 2010.
  2. A multi-institutional phase 2 study of trabectedin for advanced soft tissue sarcoma since 2012.
  3. A multi-institutional phase III clinical trial of multidrugs adjuvant chemotherapy for osteosarcomas (JCOG 1306) since 2014.
  4. Phase II clinical study of DXR vs. DXR + olaratumab (PDGFR α monoclonal antibody)

Education

Each resident performs 60-70 operations supervised by staff members every year, joins many domestic and international conferences and publishes several medical articles or reports during training courses. All staff members teach all clinical procedures and information related to oncological skills for bone and soft part sarcomas.

Future prospects

Our clinical divisions and translational study groups do many clinical trials of novel therapeutic innovations and promote clinical trials of novel drugs or targeted compounds for sarcomas and will continue to make focused efforts in the future.


Table 1. Number of patients (2015) Table 2. Type of procedure (2015)

List of papers published in 2015

Journal

  1. Asano N, Yoshida A, Ogura K, Kobayashi E, Susa M, Morioka H, Iwata S, Ishii T, Hiruma T, Chuman H, Kawai A. Prognostic Value of Relevant Clinicopathologic Variables in Epithelioid Sarcoma: A Multi-Institutional Retrospective Study of 44 Patients. Ann Surg Oncol, 22:2624-2632, 2015
  2. Miyamoto S, Fukunaga Y, Fujiki M, Nakatni F, Tanzawa Y, Sakuraba M. Accompanying artery of sciatic nerve as recipient vessel for free-flap transfer: a computed tomographic angiography study and case reports. Microsurgery, 35:284-289, 2015
  3. Kikuta K, Kubota D, Yoshida A, Morioka H, Toyama Y, Chuuman H, Kawai A. An analysis of factors related to the tail-like pattern of myxofibrosarcoma seen on MRI. Skeletal Radiol, 44:55-62, 2015
  4. Yoshida A, Asano N, Kawai A, Kawamoto H, Nakazawa A, Kishimoto H, Kushima R. Differential SALL4 immunoexpression in malignant rhabdoid tumours and epithelioid sarcomas. Histopathology, 66:252-261, 2015
  5. Ogura K, Uehara K, Akiyama T, Iwata S, Shinoda Y, Kobayashi E, Saita K, Yonemoto T, Kawano H, Chuman H, Davis AM, Kawai A. Cross-cultural adaptation and validation of the Japanese version of the Toronto Extremity Salvage Score (TESS) for patients with malignant musculoskeletal tumors in the lower extremities. J Orthop Sci, 20:1098-1105, 2015
  6. Ogura K, Fujiwara T, Yasunaga H, Matsui H, Jeon DG, Cho WH, Hiraga H, Ishii T, Yonemoto T, Kamoda H, Ozaki T, Kozawa E, Nishida Y, Morioka H, Hiruma T, Kakunaga S, Ueda T, Tsuda Y, Kawano H, Kawai A. Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi-institutional study. Cancer, 121:3844-3852, 2015
  7. Kimura H, Yamamoto N, Shirai T, Nishida H, Hayashi K, Tanzawa Y, Takeuchi A, Igarashi K, Inatani H, Shimozaki S, Kato T, Aoki Y, Higuchi T, Tsuchiya H. Efficacy of triplet regimen antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in bone and soft tissue sarcoma patients receiving highly emetogenic chemotherapy, and an efficacy comparison of single-shot palonosetron and consecutive-day granisetron for CINV in a randomized, single-blinded crossover study. Cancer Med, 4:333-341, 2015
  8. Ogura K, Miyamoto S, Sakuraba M, Fujiwara T, Chuman H, Kawai A. Intercalary reconstruction after wide resection of malignant bone tumors of the lower extremity using a composite graft with a devitalized autograft and a vascularized fibula. Sarcoma, 2015:861575, 2015
  9. Joo MW, Shin SH, Kang YK, Kawai A, Kim HS, Asavamongkolkul A, Jeon DG, Kim JD, Niu X, Tsuchiya H, Puri A, Wang EH, Chung SH, Chung YG. Osteosarcoma in Asian Populations Over the Age of 40 Years: A Multicenter Study. Ann Surg Oncol, 22:3557-3564, 2015
  10. Ogura K, Sakuraba M, Miyamoto S, Fujiwara T, Chuman H, Kawai A. Pelvic ring reconstruction with a double-barreled free vascularized fibula graft after resection of malignant pelvic bone tumor. Arch Orthop Trauma Surg, 135:619-625, 2015
  11. Zhang L, Lyer AK, Yang X, Kobayashi E, Guo Y, Mankin H, Hornicek FJ, Amiji MM, Duan Z. Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells. Int J Nanomedicine, 10:2913-2924, 2015
  12. Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Tanase T, Hasegawa T, Takahashi S. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol, 16:406- 416, 2015
  13. Yoshida A, Yoshida H, Yoshida M, Mori T, Kobayashi E, Tanzawa Y, Yasugi T, Kawana K, Ishikawa M, Sugiura H, Maeda D, Fukayama M, Kawai A, Hiraoka N, Motoi T. Myoepithelioma- like Tumors of the Vulvar Region: A Distinctive Group of SMARCB1-deficient Neoplasms. Am J Surg Pathol, 39:1102- 1113, 2015
  14. Fujiwara T, Fujiwara M, Numoto K, Ogura K, Yoshida A, Yonemoto T, Suzuki S, Kawai A. Second primary osteosarcomas in patients with retinoblastoma. Jpn J Clin Oncol, 45:1139-1145, 2015
  15. Kikuta K, Morioka H, Kawai A, Kondo T. Global protein-expression profiling for reclassification of malignant fibrous histiocytoma. Biochim Biophys Acta, 1854:696-701, 2015
  16. Yonemoto T, Hosono A, Iwata S, Kamoda H, Hagiwara Y, Fujiwara T, Kawai A, Ishii T. The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be favorable: experience of two cancer centers in Japan. Int J Clin Oncol, 20:613-616, 2015
  17. Ichikawa H, Yoshida A, Kanda T, Kosugi S, Ishikawa T, Hanyu T, Taguchi T, Sakumoto M, Katai H, Kawai A, Wakai T, Kondo T. Prognostic significance of promyelocytic leukemia expression in gastrointestinal stromal tumor; integrated proteomic and transcriptomic analysis. Cancer Sci, 106:115-124, 2015
  18. Kobayashi E, Setsu N. Osteosclerosis induced by denosumab. Lancet, 385:539, 2015
  19. Yamaga K, Kobayashi E, Kubota D, Setsu N, Tanaka Y, Minami Y, Tanzawa Y, Nakatani F, Kawai A, Chuman H. Pediatric myositis ossificans mimicking osteosarcoma. Pediatr Int, 57:996- 999, 2015
  20. Fujiwara T, Ogura K, Kobayashi E, Tanzawa Y, Nakatani F, Chuman H, Kawai A. Clinical Outcomes of Surgical Treatments for Primary Malignant Bone Tumors Arising in the Acetabulum. Sarcoma, 2015:430576, 2015
  21. Fujiki M, Miyamoto S, Nakatani F, Kawai A, Sakuraba M. Rotationplasty with vascular reconstruction for prosthetic knee joint infection. Case Rep Orthop, 2015:241405, 2015
  22. Miyamoto S, Fujiki M, Nakatani F, Sakisaka M, Sakuraba M. Free flow-through anterolateral thigh flap for complex knee defect including the popliteal artery. Microsurgery, 35:485-488, 2015