• Division of Orthopaedic Oncology / Research

• Results

Division of Orthopaedic Oncology

Bone and soft tissue tumors, particularly malignant diseases, markedly affect patients' lives. Our orthopedic oncology group belongs to four senior staff and three PhD students, treating tumors of the bone and soft tissues arising in the extremities and the trunk. Diagnosis and treatment of bone and soft tissue tumors demand knowledge and expertise due to difficulties in pathological diagnosis, as well as specialized treatments, such as systemic chemotherapy, imaging-based surgical resection, and limb salvage surgery. In these days, the number of cases treated for bone metastasis has increased in our department because overall survival of cancer patients has improved with the development of new therapeutics, such as targeted therapies and immune checkpoint inhibitors. Taking advantage of the multidisciplinary expertise of university hospitals, our goal is to improve treatment outcomes in patients with refractory tumors.

[Clinical Research]

Because bone and soft tissue sarcomas involve various tissue types and are uncommon compared with other cancers, establishing treatment strategies in a single facility with a limited number of patients is challenging. Nationwide clinical studies are necessary to establish standard treatments for bone and soft tissue sarcoma; to this end, we have been participating in the Japan Clinical Oncology Group (JCOG) since September 2014 to conduct clinical trials.

[Basic Research]

Recent advances in diagnostic imaging and surgical margin assessment have improved treatment outcomes in patients, as indicated by the increases in survival and functional preservation. However, because a number of cases are still difficult to treat, a breakthrough in research would significantly improve treatment outcomes in patients. We focus on basic research with the ultimate goal of translating our findings into clinical practice. Our current research interests are in the following areas:

Transcutaneous application of carbon dioxide for treatment of bone and soft tissue sarcomas and metastatic bone tumors
Hypoxia in malignant tumors regulates tumor pathogenesis, disease progression, and metastasis. We previously demonstrated that the transcutaneous application of carbon dioxide reduces hypoxic conditions and enhances therapeutic responses using mouse models of malignant fibrous histiocytoma and lung metastasis in osteosarcoma. We are currently investigating the antitumor effects of the transcutaneous application of carbon dioxide and the underlying inhibitory mechanisms of bone destruction in a mouse model of bone metastasis using breast cancer cell lines.

Antitumor effects of survivin inhibition and smac mimetics in bone and soft tissue sarcoma
Suppression of survivin, which belongs to the inhibitor of apoptosis protein (IAP) family, has been implicated in increased cell death and enhanced chemosensitivity. We are currently investigating the role of survivin in bone and soft tissue sarcoma as a potential therapeutic target. In addition, we are investigating the use of a mimetic of smac, an endogenous antagonist of the IAP family, in bone and soft tissue sarcoma and its synergistic effects with existing chemotherapeutics.

Antitumor effects of AICAR in bone and soft tissue sarcoma
Malignant tumors have long been known to rely on glycolysis for energy metabolism instead of mitochondrial oxidative phosphorylation; however, the underlying mechanisms of the metabolic switch remain unclear. We are currently investigating the antitumor effect of AICAR, an AMPK agonist that promotes mitochondrial proliferation, by regulating mitochondrial biogenesis.

The effect of a novel drug delivery system using Low Adhesive Scaffold Collagen (LASCol) as a drug carrier for the treatment of bone metastasis
This research is conducted in collaboration with the Faculty of Biology-Oriented Science and Technology, Kinki University, where the drug carrier was developed. The ultimate goal of this research is to develop an innovative treatment for bone metastasis using a novel drug delivery system.

• Division of Orthopaedic Oncology / Results

• Research

Original Research Article

1) Yahiro S, Kawamoto T, Fujiwara S, Hara H, Fukase N, Sawada R, Takemori T, Miyamoto T, Mifune Y, Kakutani K, Hoshino Y, Hayashi S, Matsumoto T, Matsushita T, Koyanagi-Aoi M, Aoi T, Kuroda R, Akisue T. Identification and characterization of slow-cycling cells in Ewing sarcoma. Int J Oncol. 2022 ;61(5):138.

2) Hara H, Kawamoto T, Fukase N, Sawada R, Fujiwara S, Yahiro S, Miyamoto T, Terakawa T, Mifune Y, Hoshino Y, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Kuroda R, Akisue T. Outcomes of palliative surgery for bone metastasis of metastatic renal cell carcinoma in the era of targeted therapy. Eur J Surg Oncol. 2022;25;S0748-7983(22)00822-8.

3) Morii T, Anazawa U, Sato C, Iwata S, Nakagawa M, Endo M, Nakamura T, Ikuta K, Nishida Y, Nakayama R, Udaka T, Kawamoto T, Kito M, Sato K, Imanishi J, Akiyama T, Kobayashi H, Nagano A, Outani H, Toki S, Nishisho T, Sasa K, Suehara Y, Kawano H, Ueda T, Morioka H. Dedifferentiated liposarcoma in the extremity and trunk wall: A multi-institutional study of 132 cases by the Japanese Musculoskeletal Oncology Group (JMOG). Eur J Surg Oncol. 2022;1:S0748-7983(22)00631-X.

4) Fukase N, Duke VR, Lin MC, Stake IK, Huard M, Huard J, Marmor MT, Maharbiz MM, Ehrhart NP, Bahney CS, Herfat ST. Wireless Measurements Using Electrical Impedance Spectroscopy to Monitor Fracture Healing. Sensors (Basel). 2022;19;22(16):6233.

5) Takemori T, Kawamoto T, Hara H, Fukase N, Fujiwara S, Fujita I, Fujimoto T, Morishita M, Kitayama K, Yahiro S, Miyamoto T, Saito M, Sugaya J, Hayashi K, Kawashima H, Torigoe T, Nakamura T, Kondo H, Wakamatsu T, Watanuki M, Kito M, Tsukushi S, Nagano A, Outani H, Toki S, Nishimura S, Kobayashi H, Watanabe I, Demizu Y, Sasaki R, Fukumoto T, Niikura T, Kuroda R, Akisue T. Clinical Outcome of Patients with Pelvic and Retroperitoneal Bone and Soft Tissue Sarcoma: A Retrospective Multicenter Study in Japan. Cancers (Basel). 2022 ;20;14(12):3023.

6) Takemori T, Kawamoto T, Hara H, Fukase N, Fujiwara S, Kitayama K, Yahiro S, Miyamoto T, Mifune Y, Hoshino Y, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Kuroda R, Akisue T. Clinical Outcomes and Prognostic Factors in Soft Tissue Sarcoma Patients After Unplanned Excision. Cancer Manag Res. 2022;25;14:1815-1824.

7) Nakamura T, Matsumine A, Toda Y, Takenaka S, Outani H, Fujiwara T, Nishida Y, Tsukushi S, Tome Y, Kawamoto T, Kito M, Shinohara N, Tomita M, Torigoe T, Sudo A, Kawano H. Long-Term Results of Kyocera Modular Limb Salvage System after Resection of Tumors in the Distal Part of the Femur: Report from Japanese Musculoskeletal Oncology Group Study. Cancers (Basel). 2022 ;10;14(4):870.

8) Hara H, Sakai Y, Kawamoto T, Fukase N, Kawakami Y, Takemori T, Fujiwara S, Kitayama K, Yahiro S, Miyamoto T, Kakutani K, Niikura T, Miyazaki D, Okada T, Sakashita A, Imamura Y, Sasaki R, Kizawa Y, Minami H, Matsumoto T, Matsushita T, Kuroda R, Akisue T. Surgical outcomes of metastatic bone tumors in the extremities (Surgical outcomes of bone metastases). J Bone Oncol. 2021;27:100352.

9) Kitayama K, Kawamoto T, Kawakami Y, Hara H, Takemori T, Fujiwara S, Yahiro S, Miyamoto T, Mifune Y, Hoshino Y, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Kuorada R, Akisue T. Regulatory roles of miRNAs 16, 133a, and 223 on osteoclastic bone destruction caused by breast cancer metastasis. Int J Oncol. 2021;59(5):97.

10) Takemori T, Kawamoto T, Morishita M, Hara H, Fukase N, Kawakami Y, Fujiwara S, Kitayama K, Yahiro S, Miyamoto T, Fujimoto T, Fujita I, Mifune Y, Hoshino Y, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Kuroda R, Akisue T. Clinical Outcome of the Patients With Brain Metastasis from Soft Tissue Sarcomas. Anticancer Res. 2021;41(2):1027-1034.

11) Fujimoto T, Suzuki M, Kuratsu S, Fujita I, Morishita M, Sudo T, Sakuma T, Nakamatsu Y, Sakurai Y, Takata T, Tamari Y, Tanaka H, Masunaga SI, Kinashi Y, Kondo N, Sakakibara S, Igaki H, Andoh T, Sakamoto S, Kawamoto T, Watabe T, Hara H, Fukase N, Kawakami Y, Matsumoto T, Akisue T, Ono K, Ichikawa H, Kuroda R, Hirose T. BNCT for primary synovial sarcoma. Appl Radiat Isot. 2021;169:109407.

12) Kawakami Y, Nonaka K, Fukase N, Amore A, Murata Y, Quinn P, Luketich S, Takayama K, Patel KG, Matsumoto T, Cummins JH, Kurosaka M, Kuroda R, Wagner WR, Fu FH, Huard J. A Cell-free Biodegradable Synthetic Artificial Ligament for the Reconstruction of Anterior Cruciate Ligament in a Rat Model. Acta Biomater. 2021;121:275-287.

13) Kohsaka S, Hirata M, Ikegami M, Ueno T, Kojima S, Sakai T, Ito K, Naka N, Ogura K, Kawai A, Iwata S, Okuma T, Yonemoto T, Kobayashi H, Suehara Y, Hiraga H, Kawamoto T, Motoi T, Oda Y, Matsubara D, Matsuda K, Nishida Y, Mano H. Comprehensive molecular and clinicopathological profiling of desmoid tumours. Eur H Cancer. 2021;145:109-120.

14) Fujiwara S, Kawamoto T, Kawakami Y, Koterazawa Y, Hara H, Takemori T, Kitayama K, Yahiro S, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Koyanagi-Aoi M, Aoi T, Kuroda R, Akisue T. Acquisition of cancer stem cell properties in osteosarcoma cells by defined factors. Stem Cell Res Ther. 2020;11(1):429.

15) Kawamoto T, Hara H, Morishita M, Fukase N, Kawakami Y, Takemori T, Fujiwara S, Kitayama K, Yahiro S, Miyamoto T, Fujimoto T, Fujita I, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Kuroda R, Akisue T. Prognostic influence of the treatment approach for pulmonary metastasis in patients with soft tissue sarcoma. Clin Exp metastasis. 2020;37(4):509-517.

16) Fujimoto T, Suzuki M, Sudo T, Fujita I, Sakuma T, Sakurai Y, Hirose T, Morishita M, Takata T, Tamari Y, Tanaka H, Andoh T, Kawamoto T, Hara H, Fukase N, kawakami Y, Shigemoto R, Matsumoto T, Ichikawa H, Ono K, Kuroda R, Akisue T. Boron neutron capture therapy for clear cell sarcoma. Appl Radiat Isot. 2020;166:109324.

17) Uemura S, Mori T, Ishiko S, Takafuji S, Nino N, Yamamoto N, Hayakawa A, Nishimura N, Hara H, Kawamoto T, Akisue T, Iijima K. Retrospective analysis of high-dose chemotherapy followed by autologous stem cell transplantation for high-risk pediatric osteosarcoma. Pediatr hematol Oncol. 2020;37(4):337-343.

18) Nagano A, Matsumoto S, Kawai A, Okuma T, Hiraga H, Matsumoto Y, Nishida Y, Yonemoto T, Hosaka M, Takahashi M, Yoshikawa H, Kunisada T, Asamura K, naka N, Emori M, Kubo T, Kawashima H, Kawamoto T, Yokoyama R, Tsukushi S, Sato K, Okamoto T, Hiraoka K, Morioka H, Tanaka K, Takagi T, Iwamoto Y, Ozaki T. Osteosarcoma in patients over 50 years of age: Multi-institutional retrospective analysis of 104 patients. J Orthop Sci. 2020;25(2):319-323.

19) Kanda Y, Kakutani K, Yurube T, Zhang Z, Miyazaki S, Kakiuchi Y, Takeoka Y, Tsujimoto R, Miyazaki K, Kawamoto T, Takada T, Hoshino Y, Tabata Y, Kuroda R. A novel topical treatment for bone metastases using a gelatin hydrogel incorporating cisplatin as a sustained release system. J Orthop Res. 2020;39(3):525-535.

20) Heng M, Gupta A, Chung PW, Healey JH, Vaynrub M, Rose PS, Houdek MT, Lin PP, Bishop AJ, Hornicek FJ, Chen YL, Lozano-Calderon S, Holt GE, Han I, Biau D, Niu X, Bernthal NM, Ferguson PC, Wunder JS; Japanese Musculoskeletal Oncology Group (JMOG); Soft Tissue Osteosarcoma International Collaborative (STOIC). The role of chemotherapy and radiotherapy in localized extraskeletal osteosarcoma. Eur J Cancer. 2020;125:130-141.

21) Hara H, Kawamoto T, Fukase N, Kawakami Y, Takemori T, Fujiwara S, Kitayama K, Nishida K, Kuroda R, Akisue T. Gemcitabine and docetaxel combination chemotherapy for advanced bone and soft tissue sarcomas: protocol for an open-label, non-randomised, Phase 2 study. BMC Cancer. 2019;19(1):725.

22) Sekimizu M, Yoshida A, Mitani S, Asano N, Hirata M, Kubo T, Yamazaki F, Sakamoto H, Kato M, Makise N, Mori T, Yamazaki N, Sekine S, Oda I, Watanabe SI, Hiraga H, Yonemoto T, Kawamoto T, Naka N, Funauchi Y, Nishida Y, Honoki K, Kawano H, Tsuchiya H, Kunisada T, Matsuda K, Inagaki K, Kawai A, Ichikawa H. Frequent mutations of genes encoding vacuolar H+-ATPase components in granular cell tumors. Genes Chromosomes Cancer. 2019;58(6):373-380.

23) Takemori T, Kawamoto T, Ueha T, Toda M, Morishita M, Kamata E, Fukase N, Hara H, Fujiwara S, Niikura T, Kuroda R, Akisue T. Transcutaneous carbon dioxide application suppresses bone destruction caused by breast cancer metastasis. Oncol Rep. 2018;40(4):2079-2087.

24) Urakawa H, Yonemoto T, Matsumoto S, Takagi T, Asanuma K, Watanuki M, Takemoto A, Naka N, Matsumoto Y, Kawai A, Kunisada T, Kubo T, Emori M, Hiraga H, Hatano H, Tsukushi S, Nishida Y, Akisue T, Morii T, Takahashi M, Nagano A, Yoshikawa H, Sato K, Kawano M, Hiraoka K, Tanaka K, Iwamoto Y, Ozaki T. Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study. World J Surg Oncol. 2018;16(1):160.

25) Iwata E, Hasegawa T, Ueha T, Takeda D, Saito I, Kawamoto T, Akisue T, Sakai Y, Sasaki R, Kuroda R, Komori T. Transcutaneous carbon dioxide enhances the antitumor effect of radiotherapy on oral squamous cell carcinoma. Oncol Rep. 2018;40(1):434-442.