Department of Musculoskeletal Oncology and Rehabilitation

Hirokazu Chuuman, Akira Kawai, Fumihiko Nakatani, Yoshikazu Tanzawa, Eisuke Kobayashi, Makoto Endo, Nokitaka Setsu, Takenori Uehara, Kouki Shimizu, Tomoaki Mori, Takeshi Hirose, Masato Sugawara, Yoshihiro Araki, Shunichi Toki

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 Department of Musculoskeletal Oncology and Rehabilitation 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.

Our team and what we do

Table 1. Type of surgical procedures (2016)

The Department of Musculoskeletal Oncology and Rehabilitation of the NCCH consists of six staff doctors, eight residents, 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 to 10 major operations are routinely performed every week. In 2016, 430 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 14 in the thoracic wall, 14 in the retroperitoneal space, and four abdominal wall lesions were excised in cooperation with thoracic, general, or urological surgeons. A total of 62 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 cancer-bearing 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 targeted therapies or tailor-made treatments for sarcoma patients. With a genome-wide miRNA array system or a new generation sequence system, we have been analyzing the complete expression levels of miRNA and genomic alteration in the tumor samples or serum samples from patients with various types of bone and soft tissue sarcoma. Combined with each patient's clinical information, we have been establishing novel biomarkers for prediction of patients'prognoses or effects of the chemotherapeutic agents. We also have been developing a mouse xenograft model of sarcoma using the clinical samples of biopsied or resected tumors with the aim of creating novel molecular targeted therapies or biomarkers.

Table 2. Collaborative surgery (2016)

Clinical trials

We also have been focusing on the standardization of adjuvant and second-line chemotherapy regimens for bone and soft tissue sarcomas. Several multi-institutional clinical trials were conducted 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 III clinical trial of multi-drugs adjuvant chemotherapy for osteosarcomas (JCOG 1306) since 2014

3)A phase III clinical study of DXR vs. DXR + olaratumab (PDGFRα monoclonal antibody)

4)A phase II clinical trial of Nivolumab for unresectable or advanced clear cell sarcoma or alveolar soft part sarcoma

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.

Future prospects

Our department continues to focus on the development of novel therapeutic tools for patients with bone and soft tissue tumor by collaborating with other clinical departments and research institutes.

List of papers published in 2016

Journal

1.Yasui N, Yoshida A, Kobayashi E, Nakatani F, Kawamoto H. Successful Treatment of Extra-Renal Noncerebral Rhabdoid Tumors with VIDE. Pediatr Blood Cancer, 63:352-354, 2016

2.Maekawa A, Kohashi K, Kuda M, Iura K, Ishii T, Endo M, Nakatsura T, Iwamoto Y, Oda Y. Prognostic significance of FOXM1 expression and antitumor effect of FOXM1 inhibition in synovial sarcomas. BMC Cancer, 16:511, 2016

3.Hirahata M, Osaki M, Kanda Y, Sugimoto Y, Yoshioka Y, Kosaka N, Takeshita F, Fujiwara T, Kawai A, Ito H, Ochiya T, Okada F. PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma. Cancer Med, 5:892-902, 2016

4.Pan X, Yoshida A, Kawai A, Kondo T. Current status of publicly available sarcoma cell lines for use in proteomic studies. Expert Rev Proteomics, 13:227-240, 2016

5.Bekki H, Fukushi J, Mizu-uchi H, Endo M, Oda Y, Iwamoto Y. Fibromatosis of the soleus muscle presenting as pes equinus: a case report. Foot Ankle Online J, 9:4, 2016

6.Matsunobu T, Bekki H, Harimaya K, Matsumoto Y, Endo M, Yoshitake K, Oda Y, Iwamoto Y. Osteosarcoma of the middle and distal phalanges of the little toe with a cancerous ulcer. Int J Case Rep Images, 7:185-189, 2016

7.Tahara K, Yamashita K, Hiwatashi A, Togao O, Kikuchi K, Endo M, Otsuka H, Oda Y, Honda H. MR Imaging Findings of a Leiomyosarcoma of the Thoracic Spine: A Case Report. Clin Neuroradiol, 26:229-233, 2016

8.Araki N, Takahashi S, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Kawai A. Retrospective inter- and intra-patient evaluation of trabectedin after best supportive care for patients with advanced translocation-related sarcoma after failure of standard chemotherapy. Eur J Cancer, 56:122-130, 2016

9.Fujiki M, Miyamoto S, Kobayashi E, Sakuraba M, Chuman H. Early detection of local recurrence after soft tissue sarcoma resection and flap reconstruction. Int Orthop, 40:1975-1980, 2016

10.Iwata S, Uehara K, Ogura K, Akiyama T, Shinoda Y, Yonemoto T, Kawai A. Reliability and Validity of a Japanese-language and Culturally Adapted Version of the Musculoskeletal Tumor Society Scoring System for the Lower Extremity. Clin Orthop Relat Res, 474:2044-2052, 2016

11.Kato I, Yoshida A, Ikegami M, Okuma T, Tonooka A, Horiguchi S, Funata N, Kawai A, Goto T, Hishima T, Aoki I, Motoi T. FOSL1 immunohistochemistry clarifies the distinction between desmoplastic fibroblastoma and fibroma of tendon sheath. Histopathology, 69:1012-1020, 2016

12.Kawai A, Araki N, Hiraga H, Sugiura H, Matsumine A, Ozaki T, Ueda T, Ishii T, Esaki T, Machida M, Fukasawa N. A randomized, double-blind, placebo-controlled, Phase III study of pazopanib in patients with soft tissue sarcoma: results from the Japanese subgroup. Jpn J Clin Oncol, 46:248-253, 2016

13.Kimura H, Yamamoto N, Shirai T, Nishida H, Hayashi K, Tanzawa Y, Takeuchi A, Miwa S, Tsuchiya H. Clinical Outcome of Reconstruction Using Frozen Autograft for a Humeral Bone Tumor. Anticancer Res, 36:6631-6635, 2016

14.Kim Y, Kobayashi E, Kubota D, Suehara Y, Mukaihara K, Akaike K, Ito A, Kaneko K, Chuman H, Kawai A, Kitano S. Reduced argininosuccinate synthetase expression in refractory sarcomas: Impacts on therapeutic potential and drug resistance. Oncotarget, 7:70832-70844, 2016

15.Miyamoto S, Arikawa M, Fujiki M, Kawai A, Kobayashi E, Sakuraba M. The Superior Rectal Artery as a Recipient Vessel for Free Flap Transfer After Partial Sacrectomy in Patients With Chordoma. Ann Plast Surg, 76:315-317, 2016

16.Miyamoto S, Fujiki M, Sakisaka M, Kawai A. Combined Use of the Latissimus Dorsi Musculocutaneous Flap and the Anterolateral Thigh Flap to Reconstruct an Extensive Shoulder Defect in an NF-1 Patient. Plast Reconstr Surg Glob Open, 4:e670, 2016

17.Miyamoto S, Fujiki M, Setsu N, Kawai A. Simultaneous reconstruction of the bone and vessels for complex femoral defect. World J Surg Oncol, 14:291, 2016

18.Miyamoto S, Kagaya Y, Arikawa M, Kobayashi E. Combined Use of an Anterolateral Thigh Flap and Superficial Inferior Epigastric Artery Flap for Reconstruction of an Extensive Abdominal Wall Defect. Plast Reconstr Surg Glob Open, 4:e1121, 2016

19.Mori T, Nakayama R, Endo M, Hiraga H, Tomita M, Fukase N, Kobayashi E, Kawai A, Ueda T, Morioka H. Forty-eight cases of leiomyosarcoma of bone in Japan: A multicenter study from the Japanese musculoskeletal oncology group. J Surg Oncol, 114:495-500, 2016

20.Miyamoto S, Fujiki M, Kawai A, Chuman H, Sakuraba M. Anterolateral thigh flap for axillary reconstruction after sarcoma resection. Microsurgery, 36:378-383, 2016

21.Morioka H, Takahashi S, Araki N, Sugiura H, Ueda T, Takahashi M, Yonemoto T, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Susa M, Nakayama R, Nishimoto K, Kikuta K, Horiuchi K, Kawai A. Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma. BMC Cancer, 16:479, 2016

22.Yoshida A, Goto K, Kodaira M, Kobayashi E, Kawamoto H, Mori T, Yoshimoto S, Endo O, Kodama N, Kushima R, Hiraoka N, Motoi T, Kawai A. CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas. Am J Surg Pathol, 40:313-323, 2016

23.Mukaihara K, Suehara Y, Kohsaka S, Kubota D, Toda-Ishii M, Akaike K, Fujimura T, Kobayashi E, Yao T, Ladanyi M, Kaneko K, Saito T. Expression of F-actin-capping protein subunit beta, CAPZB, is associated with cell growth and motility in epithelioid sarcoma. BMC Cancer, 16:206, 2016

24.Setsu N, Kobayashi E, Asano N, Yasui N, Kawamoto H, Kawai A, Horiuchi K. Severe hypercalcemia following denosumab treatment in a juvenile patient. J Bone Miner Metab, 34:118-122, 2016

25.Ito J, Asano N, Kawai A, Yoshida A. The diagnostic utility of reduced immunohistochemical expression of SMARCB1 in synovial sarcomas: a validation study. Hum Pathol, 47:32-37, 2016

26.Akiyama T, Saita K, Ogura K, Kawai A, Imanishi J, Yazawa Y, Kawashima N, Ogata T. The effect of an external hip joint stabiliser on gait function after surgery for tumours located around the circumference of the pelvis: analysis of seven cases of internal hemipelvectomy or proximal femur resection. Int Orthop, 40:561-567, 2016

27.Nakamura T, Matsumine A, Kawai A, Araki N, Goto T, Yonemoto T, Sugiura H, Nishida Y, Hiraga H, Honoki K, Yasuda T, Boku S, Sudo A, Ueda T. The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study. Cancer, 122:1408-1416, 2016

28.Nezu Y, Hagiwara K, Yamamoto Y, Fujiwara T, Matsuo K, Yoshida A, Kawai A, Saito T, Ochiya T. miR-135b, a key regulator of malignancy, is linked to poor prognosis in human myxoid liposarcoma. Oncogene, 35:6177-6188, 2016

29.Setsu N, Miyake M, Wakai S, Nakatani F, Kobayashi E, Chuman H, Hiraoka N, Kawai A, Yoshida A. Primary Retroperitoneal Myxoid Liposarcomas. Am J Surg Pathol, 40:1286-1290, 2016

30.Shibata H, Kato S, Sekine I, Abe K, Araki N, Iguchi H, Izumi T, Inaba Y, Osaka I, Kawai A, Kinuya S, Kodaira M, Kobayashi E, Kobayashi T, Sato J, Shinohara N, Takahashi S, Takamatsu Y, Takayama K, Tateishi U, Nagakura H, Hosaka M, Morioka H, Moriya T, Yuasa T, Yurikusa T, Yomiya K, Yoshida M. Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology. ESMO Open, 1:e000037, 2016

31.Takeuchi A, Tsuchiya H, Ishii T, Nishida Y, Abe S, Matsumine A, Kawai A, Yoshimura K, Ueda T. Clinical outcome of recurrent giant cell tumor of the extremity in the era before molecular target therapy: the Japanese Musculoskeletal Oncology Group study. BMC Musculoskelet Disord, 17:306, 2016

32.Kubota D, Kosaka N, Fujiwara T, Yoshida A, Arai Y, Qiao Z, Takeshita F, Ochiya T, Kawai A, Kondo T. miR-125b and miR-100 Are Predictive Biomarkers of Response to Induction Chemotherapy in Osteosarcoma. Sarcoma, 2016:1390571, 2016