Annual Report 2017
Department of Musculoskeletal Oncology and Rehabilitation
Akira Kawai, Fumihiko Nakatani, Eisuke Kobayashi, Shintaro Iwata, Tomoaki Mori, Takeshi Hirose, Takenori Uehara, Yonji Kim
Introduction
Malignant tumors arising from connective tissue are extremely rare, estimated to account for only 1% 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
The Department of Musculoskeletal Oncology and Rehabilitation of the NCCH consists of six staff doctors, three 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 30 patients are hospitalized for operation, chemotherapy, or radiation therapy. Six to 10 major operations are routinely performed every week. In 2017, 479 operations were performed (Table1). Sarcomas in the trunk, including 22 in the thoracic wall, six in the retroperitoneal space and 20 abdominal wall lesions were excised in cooperation with thoracic, general or urological surgeons. A total of 70 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 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.
Table 1. Type of surgical procedure (2017)
Table 2. Collaborative surgery (2017
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 2002, we have been collaborating with the NCC Research Institute (NCCRI) 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 tumor samples or serum samples from patients with various types of bone 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 chemotherapeutic agents. We also have been developing a mouse xenograft model of sarcoma using clinical samples of biopsied or resected tumors with the aim of creating novel molecular targeted therapies or biomarkers. Moreover, we have been investigating on the prognostic impact of immunological status of peripheral blood in bone and soft-tissue sarcoma patients.
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 multi-institutional phase III clinical trial of preoperative denosumab for giant cell tumor (JCOG 1610) since 2017
Education
Each resident performs 60 to70 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 January 2017 - March 2018
Journal
1.Ogura K, Higashi T, Kawai A. Statistics of soft-tissue sarcoma in Japan: Report from the Bone and Soft Tissue Tumor Registry in Japan. J Orthop Sci, 22:755-764, 2017
2.Tsuda Y, Ogura K, Hakozaki M, Kikuta K, Ae K, Tsuchiya H, Iwata S, Ueda T, Kawano H, Kawai A. Mesenchymal chondrosarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study on 57 patients. J Surg Oncol, 115:760-767, 2017
3.Okada E M D, Matsumoto M M D, Nishida M, Iga T, Morishita M, Tezuka M, Mukai K, Kobayashi E, Watanabe K. Epithelioid Hemangioma of the Thoracic Spine: A Case Report and Review of the Literature. J Spinal Cord Med, 1-6, 2017
4.Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, Furusawa Y, Hase K, Sasaki A, Udono H. Attenuation of CD4+CD25+ Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug. EBioMedicine, 25:154-164, 2017
5.Yoshida A, Kobayashi E, Kubo T, Kodaira M, Motoi T, Motoi N, Yonemori K, Ohe Y, Watanabe SI, Kawai A, Kohno T, Kishimoto H, Ichikawa H, Hiraoka N. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol, 30:797-809, 2017
6.Asano N, Yoshida A, Ichikawa H, Mori T, Nakamura M, Kawai A, Hiraoka N. Immunohistochemistry for trimethylated H3K27 in the diagnosis of malignant peripheral nerve sheath tumours. Histopathology, 70:385-393, 2017
7.Uotani K, Fujiwara T, Yoshida A, Iwata S, Morita T, Kiyono M, Yokoo S, Kunisada T, Takeda K, Hasei J, Numoto K, Nezu Y, Yonemoto T, Ishii T, Kawai A, Ochiya T, Ozaki T. Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma. Sci Rep, 7:14634, 2017
8.Makise N, Yoshida A, Komiyama M, Nakatani F, Yonemori K, Kawai A, Fukayama M, Hiraoka N. Dedifferentiated Liposarcoma With Epithelioid/Epithelial Features. Am J Surg Pathol, 41:1523-1531, 2017
9.Fujiwara T, Uotani K, Yoshida A, Morita T, Nezu Y, Kobayashi E, Uehara T, Omori T, Sugiu K, Komatsubara T, Takeda K, Kunisada T, Kawamura M, Kawai A, Ochiya T, Ozaki T. Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma. Oncotarget, 8:33375-33392, 2017
10.Fujiwara T, Oda M, Yoshida A, Ogura K, Chuman H, Kusumoto M, Kawai A. Atypical manifestation of lung metastasis 17 years after initial diagnosis of low-grade central osteosarcoma. J Orthop Sci, 22:357-361, 2017
11.Akiyama T, Uehara K, Ogura K, Shinoda Y, Iwata S, Saita K, Tanzawa Y, Nakatani F, Yonemoto T, Kawano 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 upper extremities. J Orthop Sci, 22:127-132, 2017
12.Miyamoto S, Fujiki M, Nakatani F, Kobayashi E, Sakisaka M, Sakuraba M. Reconstruction of Complex Groin Defects After Sarcoma Resection. Ann Plast Surg, 78:443-447, 2017
13.Yoshiyama A, Morii T, Susa M, Morioka H, Kobayashi E, Asano N, Mori T, Anazawa U, Watanabe I, Takeuchi K, Kushima Y, Aoyagi T, Ichimura S. Preoperative evaluation of renal cell carcinoma patients with bone metastases on risks for blood loss, performance status and lethal event. J Orthop Sci, 22:924-930, 2017
14.Nagano A, Ishimaru D, Nishimoto Y, Akiyama H, Kawai A. Primary bone sarcomas in patients over 40 years of age: A retrospective study using data from the Bone Tumor Registry of Japan. J Orthop Sci, 22:749-754, 2017
15.Ogura K, Higashi T, Kawai A. Statistics of bone sarcoma in Japan: Report from the Bone and Soft Tissue Tumor Registry in Japan. J Orthop Sci, 22:133-143, 2017
16.Tsuneki M, Kinjo T, Mori T, Yoshida A, Kuyama K, Ohira A, Miyagi T, Takahashi K, Kawai A, Chuman H, Yamazaki N, Masuzawa M, Arakawa H. Survivin: A novel marker and potential therapeutic target for human angiosarcoma. Cancer Sci, 108:2295-2305, 2017
17.Kikuta K, Nakayama R, Yoshida A, Sasaki A, Kameyama K, Chuman H, Kawai A, Nakamura M, Matsumoto M, Morioka H. A histological positive margin after surgery is correlated with high local re-recurrence rate in patients with recurrent myxofibrosarcoma. Jpn J Clin Oncol, 47:334-341, 2017
18.Araki Y, Yoshida A, Chuman H, Tanzawa Y, Endo M, Kawai A, Kobayashi E. Angioleiomyoma mimicking pes anserinus bursitis: A case report. J Dermatol, 44:e194-e195, 2017
19.Saito K, Kobayashi E, Yoshida A, Araki Y, Kubota D, Tanzawa Y, Kawai A, Yanagawa T, Takagishi K, Chuman H. Angiomatoid fibrous histiocytoma: a series of seven cases including genetically confirmed aggressive cases and a literature review. BMC Musculoskelet Disord, 18:31, 2017
20.Yoshida A, Arai Y, Kobayashi E, Yonemori K, Ogura K, Hama N, Mukai W, Motoi T, Kawai A, Shibata T, Hiraoka N. CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study. Histopathology, 71:461-469, 2017
21.Sugawara M, Kobayashi E, Asano N, Yoshida A, Kawai A. Malignant Peripheral Nerve Sheath Tumor of the Femur: A Rare Diagnosis Supported by Complete Immunohistochemical Loss of H3K27me3. Int J Surg Pathol, 25:629-634, 2017
22.Takahashi M, Takahashi S, Araki N, Sugiura H, Ueda T, Yonemoto T, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Shimura M, Kawai A. Efficacy of Trabectedin in Patients with Advanced Translocation-Related Sarcomas: Pooled Analysis of Two Phase II Studies. Oncologist, 22:979-988, 2017
23.Mukaihara K, Tanabe Y, Kubota D, Akaike K, Hayashi T, Mogushi K, Hosoya M, Sato S, Kobayashi E, Okubo T, Kim Y, Kohsaka S, Saito T, Kaneko K, Suehara Y. Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma. PLoS One, 12:e0185321, 2017
24.Kawai A, Araki N, Naito Y, Ozaki T, Sugiura H, Yazawa Y, Morioka H, Matsumine A, Saito K, Asami S, Isu K. Phase 2 study of eribulin in patients with previously treated advanced or metastatic soft tissue sarcoma. Jpn J Clin Oncol, 47:137-144, 2017
25.Sakumoto M, Takahashi M, Oyama R, Takai Y, Kito F, Shiozawa K, Qiao Z, Yoshida A, Endo M, Kawai A, Kondo T. Establishment and proteomic characterization of NCC-LMS1-C1, a novel cell line of primary leiomyosarcoma of the bone. Jpn J Clin Oncol, 47:954-961, 2017
26.Kikuta K, Kubota D, Yoshida A, Qiao Z, Morioka H, Nakamura M, Matsumoto M, Chuman H, Kawai A, Kondo T. Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is a novel biomarker of myxofibrosarcoma invasion identified by global protein expression profiling. Biochim Biophys Acta, 1865:1160-1166, 2017
27.Oyama R, Takahashi M, Yoshida A, Sakumoto M, Takai Y, Kito F, Shiozawa K, Qiao Z, Arai Y, Shibata T, Araki Y, Endo M, Kawai A, Kondo T. Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines. Sci Rep, 7:4712, 2017
28.Stacchiotti S, Gronchi A, Fossati P, Akiyama T, Alapetite C, Baumann M, Blay JY, Bolle S, Boriani S, Bruzzi P, Capanna R, Caraceni A, Casadei R, Colia V, Debus J, Delaney T, Desai A, Dileo P, Dijkstra S, Doglietto F, Flanagan A, Froelich S, Gardner PA, Gelderblom H, Gokaslan ZL, Haas R, Heery C, Hindi N, Hohenberger P, Hornicek F, Imai R, Jeys L, Jones RL, Kasper B, Kawai A, Krengli M, Leithner A, Logowska I, Martin Broto J, Mazzatenta D, Morosi C, Nicolai P, Norum OJ, Patel S, Penel N, Picci P, Pilotti S, Radaelli S, Ricchini F, Rutkowski P, Scheipl S, Sen C, Tamborini E, Thornton KA, Timmermann B, Torri V, Tunn PU, Uhl M, Yamada Y, Weber DC, Vanel D, Varga PP, Vleggeert-Lankamp CLA, Casali PG, Sommer J. Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group. Ann Oncol, 28:1230-1242, 2017
29.Asano N, Yoshida A, Mitani S, Kobayashi E, Shiotani B, Komiyama M, Fujimoto H, Chuman H, Morioka H, Matsumoto M, Nakamura M, Kubo T, Kato M, Kohno T, Kawai A, Kondo T, Ichikawa H. Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. Oncotarget, 8:12941-12952, 2017
30.Katanoda K, Shibata A, Matsuda T, Hori M, Nakata K, Narita Y, Ogawa C, Munakata W, Kawai A, Nishimoto H. Childhood, adolescent and young adult cancer incidence in Japan in 2009-2011. Jpn J Clin Oncol, 47:762-771, 2017
31.Ogura K, Hosoda F, Nakamura H, Hama N, Totoki Y, Yoshida A, Ohashi S, Rokutan H, Takai E, Yachida S, Kawai A, Tanaka S, Shibata T. Highly recurrent H3F3A mutations with additional epigenetic regulator alterations in giant cell tumor of bone. Genes Chromosomes Cancer, 56:711-718, 2017
32.Nakamura T, Kawai A, Sudo A. Analysis of the patients with soft tissue sarcoma who received additional excision after unplanned excision: report from the Bone and Soft Tissue Tumor Registry in Japan. Jpn J Clin Oncol, 47:1055-1059, 2017
33.Kawai A, Yonemori K, Takahashi S, Araki N, Ueda T. Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin. Adv Ther, 34:1556-1571, 2017
34.Uehara K, Ogura K, Akiyama T, Shinoda Y, Iwata S, Kobayashi E, Tanzawa Y, Yonemoto T, Kawano H, Kawai A. Reliability and Validity of the Musculoskeletal Tumor Society Scoring System for the Upper Extremity in Japanese Patients. Clin Orthop Relat Res, 475:2253-2259, 2017
35.Ogura K, Gokita T, Shinoda Y, Kawano H, Takagi T, Ae K, Kawai A, Wedin R, Forsberg JA. Can A Multivariate Model for Survival Estimation in Skeletal Metastases (PATHFx) Be Externally Validated Using Japanese Patients? Clin Orthop Relat Res, 475:2263-2270, 2017
36.Tsuda Y, Ogura K, Kobayashi E, Hiruma T, Iwata S, Asano N, Kawai A, Chuman H, Ishii T, Morioka H, Kobayashi H, Kawano H. Impact of geriatric factors on surgical and prognostic outcomes in elderly patients with soft-tissue sarcoma. Jpn J Clin Oncol, 47:422-429, 2017
37.Maeda K, Setsu N, Kato Y, Kawai A, Kobayashi E. Fibroma of Tendon Sheath Presenting Limited Flexion of the Fingers. Case reports in orthopedics, 2017:4129714, 2017
38.Araki Y, Yoshida A, Tanzawa Y, Endo M, Kobayashi E, Kawai A. Reconstruction of the Shoulder Joint with a Custom-Made Ceramic Implant After a Total Scapulectomy: A Case Report. JBJS Case Connect, 8:e12, 2018
39.Toki S, Motoi T, Miyake M, Kobayashi E, Kawai A, Yoshida A. Minute Mesenchymal Chondrosarcoma within Osteochondroma: An Unexpected Diagnosis Confirmed by HEY1-NCOA2 Fusion. Hum Pathol, 2018
40.Minami Y, Kobayashi E, Kawai A. Unusual subcutaneous invasion of myxoid liposarcoma. J Dermatol, 45:e130-e131, 2018
41.Sakumoto M, Oyama R, Takahashi M, Takai Y, Kito F, Shiozawa K, Qiao Z, Endo M, Yoshida A, Kawai A, Kondo T. Establishment and proteomic characterization of patient-derived clear cell sarcoma xenografts and cell lines. In Vitro Cell Dev Biol Anim, 54:163-176, 2018
42.Crompton JG, Ogura K, Bernthal NM, Kawai A, Eilber FC. Local Control of Soft Tissue and Bone Sarcomas. J Clin Oncol, 36:111-117, 2018
43.Oyama R, Kito F, Sakumoto M, Shiozawa K, Toki S, Yoshida A, Kawai A, Kondo T. Establishment and proteomic characterization of a novel cell line, NCC-UPS2-C1, derived from a patient with undifferentiated pleomorphic sarcoma. In Vitro Cell Dev Biol Anim, 54:257-263, 2018
Book
1.Kitano S, Ito A, Kim Y. 12 Immunotherapy for Renal Cell Cancer. In: Mototsugu Oya (ed), Renal Cell Carcinoma: Molecular Features and Treatment Updates, pp 295-318, 2017