Updated on 2024/10/18

写真a

 
IKUTA Kunihiro
 
Organization
Nagoya University Hospital Orthopedics Lecturer of hospital
Title
Lecturer of hospital

Degree 1

  1. 医学博士 ( 2015.3   名古屋大学 ) 

Research Areas 1

  1. Life Science / Orthopedics

 

Papers 91

  1. High-quality expert annotations enhance artificial intelligence model accuracy for osteosarcoma X-ray diagnosis

    Hasei, J; Nakahara, R; Otsuka, Y; Nakamura, Y; Hironari, T; Kahara, N; Miwa, S; Ohshika, S; Nishimura, S; Ikuta, K; Osaki, S; Yoshida, A; Fujiwara, T; Nakata, E; Kunisada, T; Ozaki, T

    CANCER SCIENCE     2024.9

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    Primary malignant bone tumors, such as osteosarcoma, significantly affect the pediatric and young adult populations, necessitating early diagnosis for effective treatment. This study developed a high-performance artificial intelligence (AI) model to detect osteosarcoma from X-ray images using highly accurate annotated data to improve diagnostic accuracy at initial consultations. Traditional models trained on unannotated data have shown limited success, with sensitivities of approximately 60%–70%. In contrast, our model used a data-centric approach with annotations from an experienced oncologist, achieving a sensitivity of 95.52%, specificity of 96.21%, and an area under the curve of 0.989. The model was trained using 468 X-ray images from 31 osteosarcoma cases and 378 normal knee images with a strategy to maximize diversity in the training and validation sets. It was evaluated using an independent dataset of 268 osteosarcoma and 554 normal knee images to ensure generalizability. By applying the U-net architecture and advanced image processing techniques such as renormalization and affine transformations, our AI model outperforms existing models, reducing missed diagnoses and enhancing patient outcomes by facilitating earlier treatment. This study highlights the importance of high-quality training data and advocates a shift towards data-centric AI development in medical imaging. These insights can be extended to other rare cancers and diseases, underscoring the potential of AI in transforming diagnostic processes in oncology. The integration of this AI model into clinical workflows could support physicians in early osteosarcoma detection, thereby improving diagnostic accuracy and patient care.

    DOI: 10.1111/cas.16330

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  2. Utilizing the Metaverse to Provide Innovative Psychosocial Support for Pediatric, Adolescent, and Young Adult Patients with Rare Cancer

    Hasei, J; Ishida, H; Katayama, H; Maeda, N; Nagano, A; Ochi, M; Okamura, M; Iwata, S; Ikuta, K; Yoshida, S; Fujiwara, T; Nakata, E; Nakahara, R; Kunisada, T; Ozaki, T

    CANCERS   Vol. 16 ( 15 )   2024.8

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    This study investigated the potential of the metaverse in providing psychological support for pediatric and AYA cancer patients, with a focus on those with rare cancers. The research involved ten cancer patients and survivors from four distinct regions in Japan, who participated in metaverse sessions using customizable avatars, facilitating interactions across geographical and temporal barriers. Surveys and qualitative feedback were collected to assess the psychosocial impact of the intervention. The results demonstrated that the metaverse enabled patients to connect with peers, share experiences, and receive emotional support. The anonymity provided by avatars helped reduce appearance-related anxiety and stigma associated with cancer treatment. A case study of a 19-year-old male with spinal Ewing’s sarcoma highlighted the profound emotional relief fostered by metaverse interactions. The findings suggest that integrating virtual spaces into healthcare models can effectively address the unique needs of pediatric and AYA cancer patients, offering a transformative approach to delivering psychosocial support and fostering a global patient community. This innovative intervention has the potential to revolutionize patient care in the digital age.

    DOI: 10.3390/cancers16152617

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  3. Potential drug interactions between pazopanib and proton pump inhibitors/potassium-competitive acid blockers in patients with soft tissue sarcoma

    Liang, Y; Maeda, O; Shimokata, T; Yokota, K; Koike, H; Sakai, T; Ikuta, K; Urakawa, H; Nishida, Y; Akiyama, M; Ando, Y

    INTERNATIONAL CANCER CONFERENCE JOURNAL   Vol. 13 ( 1 ) page: 63 - 67   2024.1

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  4. TWO CASES OF OSTEOSARCOMA WITH FAVORABLE LONG-TERM DISEASE CONTROL WITH GEMCITABINE AND DOCETAXEL COMBINATION THERAPY

    Ichikawa, D; Kikui, H; Sekimizu, M; Hattori, H; Koike, H; Ikuta, K; Nishida, Y; Horibe, K; Maeda, N

    PEDIATRIC BLOOD & CANCER   Vol. 71   page: S35 - S36   2024.1

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  5. A Case of Maffucci Syndrome Reconstructed with Free Fibular Osteocutaneous Flap for Chondrosarcoma in the Upper Arm

    HIGUCHI Shinichi, IKUTA Kunihiro, HASHIKAWA Kazunobu, EBISAWA Katsumi, KAMBE Miki, KAMEI Yuzuru

    Journal of Japanese Society of Reconstructive Microsurgery   Vol. 37 ( 3 ) page: 133 - 136   2024

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    Language:Japanese   Publisher:Japanese Society of Reconstructive Microsurgery  

    <p> A 33-year-old man with Maffucci syndrome developed chondrosarcoma in the left upper arm, which required reconstructive surgery. The left fibula, which had been shortened and underwent bone lengthening in childhood, was not suitable for use as an osteocutaneous flap. Instead, the right fibula, which was free of enchondromas, was considered suitable for use as the donor site for the free-flap reconstruction. One year and three months post-surgery, the transferred bone achieved fusion, and upper limb function was preserved. Maffucci syndrome is characterized by multiple enchondromas and venous malformations due to somatic mosaic mutations in IDH1 and IDH2. Approximately 30% of cases involve malignant transformation of enchondromas. The bone affected by enchondromas is structurally fragile and prone to fractures. In the present study, we used the right fibula, which did not develop enchondromas, as a free flap. The absence of genetic mutations in this bone allowed for normal bone fusion and retention of its strength.</p>

    DOI: 10.11270/jjsrm.37.133

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  6. Development of Therapeutic Agent for Osteoarthritis via Inhibition of KIAA1199 Activity: Effect of Ipriflavone In Vivo

    Zhang Jiarui, Nishida Yoshihiro, Koike Hiroshi, Zhuo Lisheng, Ito Kan, Ikuta Kunihiro, Sakai Tomohisa, Imagama Shiro

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   Vol. 24 ( 15 )   2023.8

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    Language:English   Publisher:International Journal of Molecular Sciences  

    This study aimed to clarify the effects of ipriflavone, which effectively reduces KIAA1199 activity, on osteoarthritis (OA) development and progression in an in vivo OA mouse model. The OA model mice were divided into the ipriflavone (200 mg/kg/day) group and the control group. OA onset and progression were evaluated with the Mankin score, and KIAA1199 expression and hyaluronan (HA) accumulation were analyzed by immunostaining. The molecular weight of HA in the cartilage tissue and serum HA concentration were analyzed by chromatography and competitive HA enzyme-linked immunoassay. The effects of ipriflavone on the bovine cartilage explant culture under the influence of IL-1β were also investigated. In the ipriflavone group, Safranin-O stainability was well-preserved, resulting in significant reduction of the Mankin score (p = 0.027). KIAA1199 staining positivity decreased and HA stainability was preserved in the ipriflavone group. The serum HA concentration decreased, and the molecular weight of HA in the cartilage tissue increased in the ipriflavone group. The results of the cartilage explant culture indicated that ipriflavone could reduce GAG losses and increase the molecular weight of HA. Thus, ipriflavone may have an inhibitory effect on OA development/progression. Ipriflavone could be a therapeutic drug for OA by targeting KIAA1199 activity.

    DOI: 10.3390/ijms241512422

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  7. The current management of clear cell sarcoma

    Ikuta Kunihiro, Nishida Yoshihiro, Imagama Shiro, Tanaka Kazuhiro, Ozaki Toshifumi

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY     2023.7

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  8. 特集 脊髄および末梢神経鞘腫瘍のすべて -神経鞘腫瘍の手術:末梢神経鞘腫瘍-悪性末梢神経鞘腫瘍

    西田 佳弘, 浦川 浩, 生田 国大, 酒井 智久, 小池 宏, 藤戸 健雄

    脊椎脊髄ジャーナル   Vol. 36 ( 5 ) page: 351 - 355   2023.6

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    Publisher:三輪書店  

    DOI: 10.11477/mf.5002202087

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  9. Clinical Outcome of Low-Grade Myofibroblastic Sarcoma in Japan: A Multicenter Study from the Japanese Musculoskeletal Oncology Group

    Kito Munehisa, Ae Keisuke, Okamoto Masanori, Endo Makoto, Ikuta Kunihiro, Takeuchi Akihiko, Yasuda Naohiro, Yasuda Taketoshi, Imura Yoshinori, Morii Takeshi, Kikuta Kazutaka, Kawamoto Teruya, Nezu Yutaka, Baba Ichiro, Ohshika Shusa, Uehara Takeshi, Ueda Takafumi, Takahashi Jun, Kawano Hirotaka

    CANCERS   Vol. 15 ( 8 )   2023.4

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    Language:English   Publisher:Cancers  

    This retrospective multicenter study aimed to analyze the clinical features and prognosis of 24 patients diagnosed with LGMS between 2002 and 2019 in the Japanese sarcoma network. Twenty-two cases were surgically treated and two cases were treated with radical radiotherapy (RT). The pathological margin was R0 in 14 cases, R1 in 7 cases, and R2 in 1 case. The best overall response in the two patients who underwent radical RT was one complete response and one partial response. Local relapse occurred in 20.8% of patients. Local relapse-free survival (LRFS) was 91.3% at 2 years and 75.4% at 5 years. In univariate analysis, tumors of 5 cm or more were significantly more likely to cause local relapse (p < 0.01). In terms of the treatment of relapsed tumors, surgery was performed in two cases and radical RT was performed in three cases. None of the patients experienced a second local relapse. Disease-specific survival was 100% at 5 years. A wide excision aimed at the microscopically R0 margin is considered the standard treatment for LGMS. However, RT may be a viable option in unresectable cases or in cases where surgery is expected to cause significant functional impairment.

    DOI: 10.3390/cancers15082314

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  10. Clinical results of active surveillance for extra-abdominal desmoid-type fibromatosis Reviewed

    Sakai Tomohisa, Nishida Yoshihiro, Ito Kan, Ikuta Kunihiro, Urakawa Hiroshi, Koike Hiroshi, Imagama Shiro

    CANCER MEDICINE   Vol. 12 ( 5 ) page: 5245 - 5254   2023.3

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    DOI: 10.1002/cam4.5329

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  11. Dedifferentiated liposarcoma in the extremity and trunk wall: A multi-institutional study of 132 cases by the Japanese Musculoskeletal Oncology Group (JMOG). Reviewed

    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

    European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology   Vol. 49 ( 2 ) page: 353 - 361   2023.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.ejso.2022.08.024

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  12. Short-term clinical outcomes of Kyocera Modular Limb Salvage System designed cementless stems for the endoprosthetic reconstruction of lower extremities: a Japanese Musculoskeletal Oncology Group multi-institutional study Reviewed

    Tsukushi S., Nishida Y., Hirose T., Nakata E., Nakagawa R., Nakamura T., Imanishi J., Nagano A., Tamiya H., Ueda T., Tsukushi S., Ikuta K., Kawai A., Kunisada T., Nakayama R., Torigoe T., Takenaka S., Kakunaga S., Kawano H., Shirai T., Terauchi R., Outani H., Nishimura S., Honoki K.

    BMC Cancer   Vol. 22 ( 1 )   2022.12

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1186/s12885-022-09873-x

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  13. Surgical Treatment and Complications of Deep-Seated Nodular Plexiform Neurofibromas Associated with Neurofibromatosis Type 1 Reviewed

    Ikuta Kunihiro, Nishida Yoshihiro, Sakai Tomohisa, Koike Hiroshi, Ito Kan, Urakawa Hiroshi, Imagama Shiro

    JOURNAL OF CLINICAL MEDICINE   Vol. 11 ( 19 )   2022.9

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3390/jcm11195695

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  14. A clinical trial of a unidirectional porous tricalcium phosphate filling for defects after resection of benign bone lesions: a prospective multicenter study Reviewed

    Ikuta Kunihiro, Nishida Yoshihiro, Ota Takehiro, Tsukushi Satoshi, Kozawa Eiji, Nakashima Hiroatsu, Yamada Kenji, Yamashita Satoshi, Imagama Shiro

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 16060   2022.9

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s41598-022-20359-5

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  15. S100-negative epithelioid malignant peripheral nerve sheath tumor with possible perineurial differentiation Reviewed

    Yamashita Kyoko, Funauchi Yuki, Hayakawa Keiko, Ae Keisuke, Matsumoto Seiichi, Ikuta Kunihiro, Nishida Yoshihiro, Ueno Teruko, Shimoyama Yoshie, Hiruta Nobuyuki, Machinami Rikuo, Kawachi Hiroshi, Takeuchi Kengo

    VIRCHOWS ARCHIV   Vol. 480 ( 6 ) page: 1269 - 1275   2022.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1007/s00428-021-03218-y

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  16. Diffusion-Weighted Magnetic Resonance Imaging Improves the Accuracy of Differentiation of Benign from Malignant Peripheral Nerve Sheath Tumors Reviewed

    Koike Hiroshi, Nishida Yoshihiro, Ito Shinji, Shimoyama Yoshie, Ikuta Kunihiro, Urakawa Hiroshi, Sakai Tomohisa, Shimizu Koki, Ito Kan, Imagama Shiro

    WORLD NEUROSURGERY   Vol. 157   page: E207 - E214   2022.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.wneu.2021.09.130

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  17. 後腹膜発生軟部肉腫に対する治療戦略 Reviewed

    生田 国大, 西田 佳弘

    整形・災害外科   Vol. 65   page: 289 - 294   2022

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  18. 薬物療法の適応と限界1・2 デスモイドに対する薬物治療 Reviewed

    西田 佳弘, 酒井 智久, 生田 国大, 小池 宏

    日本整形外科学会雑誌   Vol. 96   page: 488 - 493   2022

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  19. 整形外科画像診断・評価の進歩】MRI 骨肉腫の術前化学療法評価における拡散強調画像の有用性 Reviewed

    小池 宏, 生田 国大, 酒井 智久

    整形外科   Vol. 73   page: 601 - 604   2022

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  20. Successful treatment with denosumab for pelvic fibrous dysplasia A case report and review of the literature

    Ikuta Kunihiro, Sakai Tomohisa, Koike Hiroshi, Ito Kan, Imagama Shiro, Nishida Yoshihiro

    MEDICINE   Vol. 100 ( 49 ) page: e28138   2021.12

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    Language:Japanese   Publisher:Medicine (United States)  

    Rationale:Fibrous dysplasia is a rare disorder that results in fractures, pain, and disability and can affect any bone in the body. The treatment of symptomatic fibrous dysplasia is determined based on the affected bones. Although some lesions are often too extensive for surgical procedures, there are currently no effective or recommended medical treatments available for them.Patient concerns:A 27-year-old woman developed right buttock pain and was diagnosed with a bone tumor in the right ilium. Clinical images revealed an expansive osteolytic lesion with thinning of the cortex and cystic change from the acetabulum to the sacroiliac joint.Diagnosis:An incisional biopsy was performed, and the lesion was diagnosed as cystic fibrous dysplasia. Occasional osteoclast-like giant cells and woven bone were observed. The patient had no evidence of polyostotic lesions or findings of McCune-Albright syndrome. Biochemical blood test results showed no obvious abnormal values, except for an increase in serum tartrate-resistant acid phosphatase 5b to 459 mU/dL.Interventions:Since surgical treatment appeared to be challenging, she was treated with denosumab with decreased dose-intensity schedules.Outcomes:The administration of denosumab caused osteosclerosis within the lesion, resulting in the elimination of bone pain. The patient received denosumab treatment for 18 months. Pain relief and lesion radiodensity were maintained for 9 months after denosumab discontinuation. The serum level of tartrate-resistant acid phosphatase 5b was measured to monitor the response to denosumab, which was suppressed during denosumab treatment.Lessons:We described successful denosumab treatment in a patient with cystic fibrous dysplasia (FD) who maintained efficacy for 9 months after treatment. Although the use of denosumab in fibrous dysplasia is currently off-label, our experience with this patient supports the potential of denosumab therapy for patients for whom surgical treatment is challenging.

    DOI: 10.1097/MD.0000000000028138

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  21. Reconstruction of the extensor mechanism augmented with reverse transferred iliotibial band after proximal tibia tumor resection and mega-prosthetic replacement Reviewed

    Ikuta Kunihiro, Nishida Yoshihiro, Tsukushi Satoshi, Sakai Tomohisa, Koike Hiroshi, Imagama Shiro

    KNEE   Vol. 33   page: 102 - 109   2021.12

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.knee.2021.09.006

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  22. Effect of hydroxyapatite tubes on the lag screw intraoperative insertion torque for the treatment of intertrochanteric femoral fractures Reviewed

    Iwata H., Takada N., Kuroyanagi G., Ikuta K., Usami T., Sekiya I., Murakami H.

    Injury   Vol. 52 ( 11 ) page: 3377 - 3381   2021.11

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    DOI: 10.1016/j.injury.2021.07.032

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  23. Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990-2019, for 204 countries and territories: the Global Burden of Diseases Study 2019 Reviewed

    Jahagirdar Deepa, Walters Magdalene K., Novotney Amanda, Brewer Edmond D., Frank Tahvi D., Carter Austin, Biehl Molly H., Abbastabar Hedayat, Abhilash E. S., Abu-Gharbieh Eman, Abu-Raddad Laith Jamal, Adekanmbi Victor, Adeyinka Daniel Adedayo, Adnani Qorinah Estiningtyas Sakilah, Afzal Saira, Aghababaei Soodabeh, Ahinkorah Bright Opoku, Ahmad Sajjad, Ahmadi Keivan, Ahmadi Sepideh, Ahmadpour Ehsan, Ahmed Muktar Beshir, Rashid Tarik Ahmed, Salih Yusra Ahmed, Aklilu Addis, Akram Tayyaba, Akunna Chisom Joyqueenet, Al Hamad Hanadi, Alahdab Fares, Alanezi Fahad Mashhour, Aleksandrova Ekaterina A., Alene Kefyalew Addis, Ali Liaqat, Alipour Vahid, Almustanyir Sami, Alvis-Guzman Nelson, Ameyaw Edward Kwabena, Amu Hubert, Andrei Catalina Liliana, Andrei Tudorel, Anvari Davood, Arabloo Jalal, Aremu Olatunde, Arulappan Judie, Atnafu Desta Debalkie, Quintanilla Beatriz Paulina Ayala, Ayza Muluken Altaye, Azari Samad, Darshan B. B., Banach Maciej, Barnighausen Till Winfried, Barra Fabio, Barrow Amadou, Basu Sanjay, Bazargan-Hejazi Shahrzad, Belay Habtamu Gebrehana, Berheto Tezera Moshago, Bezabhe Woldesellassie Mequanint, Bezabih Yihienew Mequanint, Bhagavathula Akshaya Srikanth, Bhardwaj Nikha, Bhardwaj Pankaj, Bhattacharyya Krittika, Bibi Sadia, Bijani Ali, Bisignano Catherine, Bolarinwa Obasanjo Afolabi, Boloor Archith, Boltaev Azizbek A., Briko Nikolay Ivanovich, Buonsenso Danilo, Burkart Katrin, Butt Zahid A., Cao Chao, Charan Jaykaran, Chatterjee Souranshu, Chattu Soosanna Kumary, Chattu Vijay Kumar, Choudhari Sonali Gajanan, Dinh-Toi Chu, Couto Rosa A. S., Cowden Richard G., Dachew Berihun Assefa, Dadras Omid, Dagnew Amare Belachew, Dahlawi Saad M. A., Dai Xiaochen, Dandona Lalit, Dandona Rakhi, das Neves Jose, Degenhardt Louisa, Demeke Feleke Mekonnen, Desta Abebaw Alemayehu, Deuba Keshab, Dhamnetiya Deepak, Dhungana Govinda Prasad, Dianatinasab Mostafa, Diaz Daniel, Djalalinia Shirin, Linh Phuong Doan, Dorostkar Fariba, Edinur Hisham Atan, Effiong Andem, Eftekharzadeh Sahar, Zaki Maysaa El Sayed, Elayedath Rajesh, Elhadi Muhammed, El-Jaafary Shaimaa I, El-Khatib Ziad, Elsharkawy Aisha, Endalamaw Aklilu, Endries Aman Yesuf, Eskandarieh Sharareh, Ezeonwumelu Ifeanyi Jude, Ezzikouri Sayeh, Farahmand Mohammad, Faraon Emerito Jose A., Fasanmi Abidemi Omolara, Ferrero Simone, Desideri Lorenzo Ferro, Filip Irina, Fischer Florian, Folayan Morenike Oluwatoyin, Foroutan Masoud, Fukumoto Takeshi, Gad Mohamed M., Gadanya Muktar A., Gaidhane Abhay Motiramji, Garg Tushar, Gayesa Reta Tsegaye, Gebreyohannes Eyob Alemayehu, Gesesew Hailay Abrha, Obsa Abera Getachew, Ghadiri Keyghobad, Ghashghaee Ahmad, Gilani Syed Amir, Ginindza Themba G., Glavan Ionela-Roxana, Glushkova Ekaterina Vladimirovna, Golechha Mahaveer, Gugnani Harish Chander, Gupta Bhawna, Gupta Sapna, Gupta Veer Bala, Gupta Vivek Kumar, Hamidi Samer, Handanagic Senad, Haque Shafiul, Harapan Harapan, Hargono Arief, Hasaballah Ahmed I, Hashi Abdiwahab, Hassan Shoaib, Hassanipour Soheil, Hayat Khezar, Heredia-Pi Ileana, Hezam Kamal, Holla Ramesh, Hoogar Praveen, Hoque Mohammad Enamul, Hosseini Mostafa, Hosseinzadeh Mehdi, Hsairi Mohamed, Hussain Rabia, Ibitoye Segun Emmanuel, Idrisov Bulat, Ikuta Kevin S., Ilesanmi Olayinka Stephen, Ilic Irena M., Ilic Milena D., Irvani Seyed Sina Naghibi, Islam M. Mofizul, Ismail Nahlah Elkudssiah, Itumalla Ramaiah, Iyamu Ihoghosa Osamuyi, Jabbarinejad Roxana, Jain Vardhmaan, Jayawardena Ranil, Jha Ravi Prakash, Joseph Nitin, Kabir Ali, Kabir Zubair, Kalhor Rohollah, Kaliyadan Feroze, Kamath Ashwin, Kanchan Tanuj, Kandel Himal, Kassahun Getinet, Katoto Patrick Dmc, Kayode Gbenga A., Kebede Ermiyas Mulu, Kebede Hafte Kahsay, Khajuria Himanshu, Khalid Nauman, Khan Ejaz Ahmad, Khan Gulfaraz, Khatab Khaled, Kim Min Seo, Kim Yun Jin, Kisa Adnan, Kisa Sezer, Kochhar Sonali, Korshunov Vladimir Andreevich, Koul Parvaiz A., Laxminarayana Sindhura Lakshmi Koulmane, Koyanagi Ai, Krishan Kewal, Defo Barthelemy Kuate, Kumar G. Anil, Kumar Manasi, Kumar Nithin, Kwarteng Alexander, Lal Dharmesh Kumar, Landires Ivan, Lasrado Savita, Lassi Zohra S., Lazarus Jeffrey V, Lee Jane Jean-Hee, Lee Yeong Yeh, LeGrand Kate E., Lin Christine, Liu Xuefeng, Maddison Emilie R., Abd El Razek Hassan Magdy, Mahasha Phetole Walter, Majeed Azeem, Makki Alaa, Malik Ahmad Azam, Manamo Wondimu Ayele, Mansournia Mohammad Ali, Martins-Melo Francisco Rogerlandio, Masoumi Seyedeh Zahra, Memish Ziad A., Menezes Ritesh G., Mengesha Endalkachew Worku, Merie Hayimro Edemealem, Mersha Amanual Getnet, Mestrovic Tomislav, Meylakhs Peter, Mheidly Nour, Miller Ted R., Mirica Andreea, Moazen Babak, Mohammad Yousef, Mohammadi Mokhtar, Mohammed Arif, Mohammed Salahuddin, Mohammed Shafiu, Moitra Modhurima, Mokdad Ali H., Molokhia Mariam, Moni Mohammad Ali, Moradi Ghobad, Moradi Yousef, Mpundu-Kaambwa Christine, Mubarik Sumaira, Munro Sandra B., Mwanri Lillian, Nachega Jean B., Nagarajan Ahamarshan Jayaraman, Narayana Aparna Ichalangod, Naveed Muhammad, Nayak Biswa Prakash, Nduaguba Sabina O., Kandel Sandhya Neupane, Nguefack-Tsague Georges, Trang Huyen Nguyen, Nixon Molly R., Nnaji Chukwudi A., Noubiap Jean Jacques, Nunez-Samudio Virginia, Nyirenda Thomas Elliot, Oghenetega Onome Bright, Olagunju Andrew T., Olakunde Babayemi Oluwaseun, Owopetu Oluwatomi Funbi, Mahesh P. A., Padubidri Jagadish Rao, Pakhale Smita, Parekh Tarang, Kan Fatemeh Pashazadeh, Pawar Shrikant, Filipino Pepito Veincent Christian, Peprah Emmanuel K., Pinheiro Marina, Pokhrel Khem Narayan, Polibin Roman V, Pollok Richard Charles G., Postma Maarten J., Syed Zahiruddin Quazi, Radfar Amir, Radhakrishnan Raghu Anekal, Rahim Fakher, Rahimi-Movaghar Vafa, Rahimzadeh Shadi, Rahman Mosiur, Rahmani Amir Masoud, Ram Pradhum, Ranabhat Chhabi Lal, Ranasinghe Priyanga, Rao Chythra R., Rao Sowmya J., Rathi Priya, Rawaf David Laith, Rawaf Salman, Regassa Lemma Demissie, Rehman Inayat Ur, Renzaho Andre M. N., Rezaei Nima, Rezahosseini Omid, Rezai Mohammad Sadegh, Rezapour Aziz, Ripon Rezaul Karim, Rodrigues Voilet, Roshchin Denis O., Rwegerera Godfrey M., Saeed Umar, Moghaddam Sahar Saeedi, Sagar Rajesh, Saif-Ur-Rahman K. M., Salem Marwa Rashad, Samaei Mehrnoosh, Samy Abdallah M., Santric-Milicevic Milena M., Saroshe Satish, Sathian Brijesh, Satpathy Maheswar, Sawhney Monika, Schutte Aletta Elisabeth, Seylani Allen, Shaikh Masood Ali, Shaka Mohammed Feyisso, Shamshad Hina, Shamsizadeh Morteza, Shannawaz Mohammed, Shetty Adithi, Il Shin Jae, Shivakumar K. M., Singh Jasvinder A., Skryabin Valentin Yurievich, Skryabina Anna Aleksandrovna, Somayaji Ranjani, Soshnikov Sergey, Spurlock Emma Elizabeth, Stein Dan J., Sufiyan Mu'awiyyah Babale, Tadbiri Hooman, Tadesse Birkneh Tilahun, Tadesse Eyayou Girma, Tamiru Animut Tagele, Tarkang Elvis Enowbeyang, Taveira Nuno, Tekalegn Yohannes, Tesfay Fisaha Haile, Tessema Gizachew Assefa, Thapar Rekha, Tovani-Palone Marcos Roberto, Traini Eugenio, Bach Xuan Tran, Tsai Alexander C., Tusa Biruk Shalmeno, Ullah Saif, Umeokonkwo Chukwuma David, Unnikrishnan Bhaskaran, Tahbaz Sahel Valadan, Villafane Jorge Hugo, Vladimirov Sergey Konstantinovitch, Bay Vo, Vongpradith Avina, Giang Thu Vu, Waheed Yasir, Wamai Richard G., Wang Guan, Wang Yanzhong, Ward Paul, Westerman Ronny, Winkler Andrea Sylvia, Yadav Lalit, Jabbari Seyed Hossein Yahyazadeh, Yazie Taklo Simeneh, Yi Siyan, Yigit Vahit, Yirdaw Birhanu Wubale, Yonemoto Naohiro, Yu Chuanhua, Yunusa Ismaeel, Zastrozhin Mikhail Sergeevich, Zastrozhina Anasthasia, Zhang Zhi-Jiang, Zumla Alimuddin, Salomon Joshua A., Eaton Jeffrey W., Naghavi Mohsen, Dwyer-Lindgren Laura, Wang Haidong, Lim Stephen S., Hay Simon I, Murray Christopher J. L., Kyu Hmwe H.

    LANCET HIV   Vol. 8 ( 10 ) page: E633 - E651   2021.10

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  24. Less-invasive fascia-preserving surgery for abdominal wall desmoid Reviewed

    Nishida Yoshihiro, Hamada Shunsuke, Sakai Tomohisa, Ito Kan, Ikuta Kunihiro, Urakawa Hiroshi, Koike Hiroshi, Imagama Shiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 19379   2021.9

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    DOI: 10.1038/s41598-021-98775-2

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  25. Tumor location and type affect local recurrence and joint damage in tenosynovial giant cell tumor: a multi-center study Reviewed

    Ota Takehiro, Nishida Yoshihiro, Ikuta Kunihiro, Tsukushi Satoshi, Yamada Kenji, Kozawa Eiji, Urakawa Hiroshi, Imagama Shiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 17384   2021.8

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    DOI: 10.1038/s41598-021-96795-6

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  26. Spontaneous Regression of Brown Tumor in a Patient Treated With Peritoneal Dialysis Reviewed

    Ito Kan, Ikuta Kunihiro, Nishida Yoshihiro, Sakai Tomohisa, Imagama Shiro

    CUREUS   Vol. 13 ( 8 ) page: e17078   2021.8

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  27. Overexpression of KIAA1199, a novel strong hyaluronidase, is a poor prognostic factor in patients with osteosarcoma Reviewed

    Ito Kan, Nishida Yoshihiro, Ikuta Kunihiro, Urakawa Hiroshi, Koike Hiroshi, Sakai Tomohisa, Zhang Jiarui, Shimoyama Yoshie, Imagama Shiro

    JOURNAL OF ORTHOPAEDIC SURGERY AND RESEARCH   Vol. 16 ( 1 ) page: 439   2021.7

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    DOI: 10.1186/s13018-021-02590-4

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  28. Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital Reviewed

    Nishida Yoshihiro, Ikuta Kunihiro, Natsume Atsushi, Ishihara Naoko, Morikawa Maki, Kidokoro Hiroyuki, Muramatsu Yukako, Nonobe Norie, Ishizuka Kanako, Takeichi Takuya, Kanbe Miki, Mizuno Seiji, Imagama Shiro, Ozaki Norio

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 11933   2021.6

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    DOI: 10.1038/s41598-021-91345-6

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  29. Short-range UV-LED irradiation in postmenopausal osteoporosis using ovariectomized mice Reviewed

    Ochiai Satoshi, Nishida Yoshihiro, Higuchi Yoshitoshi, Morita Daigo, Makida Kazuya, Seki Taisuke, Ikuta Kunihiro, Imagama Shiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 7875   2021.4

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    DOI: 10.1038/s41598-021-86730-0

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  30. Limitations and benefits of FDG-PET/CT in NF1 patients with nerve sheath tumors: A cross-sectional/longitudinal study Reviewed

    Nishida Yoshihiro, Ikuta Kunihiro, Ito Shinji, Urakawa Hiroshi, Sakai Tomohisa, Koike Hiroshi, Ito Kan, Imagama Shiro

    CANCER SCIENCE   Vol. 112 ( 3 ) page: 1114 - 1122   2021.3

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    DOI: 10.1111/cas.14802

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  31. Bone fragility of a school child during COVID-19 Reviewed

    Nishida Yoshihiro, Ikuta Kunihiro

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 83 ( 1 ) page: 217 - 218   2021.2

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    DOI: 10.18999/nagjms.83.1.217

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  32. 【骨・軟部腫瘍のマネジメント(その1)】診断 組織・遺伝子診断 デスモイド型線維腫症の病理組織診断におけるピットフォール CTNNB1遺伝子変異解析の有用性 Reviewed

    酒井 智久, 西田 佳弘, 生田 国大, 小池 宏, 伊藤 鑑, 今釜 史郎

    別冊整形外科   Vol. -   page: 55 - 57   2021

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  33. 【骨・軟部腫瘍のマネジメント(その2)】良性骨腫瘍・腫瘍類似疾患の治療 類骨骨腫 類骨骨腫に対するO-armガイド下手術の有用性 Reviewed

    小池 宏, 西田 佳弘, 生田 国大, 酒井 智久, 伊藤 鑑, 今釜 史郎

    別冊整形外科   Vol. -   page: 71 - 73   2021

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  34. 【骨・軟部腫瘍のマネジメント(その2)】再建法、その他 骨欠損への対応 悪性骨・軟部腫瘍切除後の骨性再建における自家加温処理骨の長期成績 Reviewed

    生田 国大, 西田 佳弘, 杉浦 英志, 今釜 史郎

    別冊整形外科   Vol. -   page: 113 - 116   2021

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  35. Desmoid with biweekly methotrexate and vinblastine shows similar effects to weekly administration: A phase II clinical trial Reviewed

    Nishida Yoshihiro, Hamada Shunsuke, Urakawa Hiroshi, Ikuta Kunihiro, Sakai Tomohisa, Koike Hiroshi, Ito Kan, Emoto Ryo, Ando Yuichi, Matsui Shigeyuki

    CANCER SCIENCE   Vol. 111 ( 11 ) page: 4187 - 4194   2020.11

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    DOI: 10.1111/cas.14626

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  36. Forced expression of KIAA1199, a novel hyaluronidase, inhibits tumorigenicity of low-grade chondrosarcoma Reviewed

    Koike Hiroshi, Nishida Yoshihiro, Shinomura Tamayuki, Zhuo Lisheng, Hamada Shunsuke, Ikuta Kunihiro, Ito Kan, Kimata Koji, Ushida Takahiro, Ishiguro Naoki

    JOURNAL OF ORTHOPAEDIC RESEARCH   Vol. 38 ( 9 ) page: 1942 - 1951   2020.9

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    DOI: 10.1002/jor.24629

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  37. Low energy irradiation of narrow-range UV-LED prevents osteosarcopenia associated with vitamin D deficiency in senescence-accelerated mouse prone 6 Reviewed

    Makida Kazuya, Nishida Yoshihiro, Morita Daigo, Ochiai Satoshi, Higuchi Yoshitoshi, Seki Taisuke, Ikuta Kunihiro, Ishiguro Naoki

    SCIENTIFIC REPORTS   Vol. 10 ( 1 ) page: 11892   2020.7

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    DOI: 10.1038/s41598-020-68641-8

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  38. Functional evaluation following deltoid muscle resection in patients with soft tissue sarcoma Reviewed

    Hamada Shunsuke, Nishida Yoshihiro, Takanari Keisuke, Ota Takehiro, Urakawa Hiroshi, Ikuta Kunihiro, Sakai Tomohisa, Tsukushi Satoshi, Kamei Yuzuru, Ishiguro Naoki

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   Vol. 50 ( 7 ) page: 772 - 778   2020.7

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  39. Glomus Tumor Arising from the Surface of a Proximal Humerus : Case Report Reviewed

      Vol. 55 ( 4 ) page: 385 - 388   2020.4

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    DOI: 10.11477/mf.1408201651

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  40. Effects of ultraviolet irradiation with a LED device on bone metabolism associated with vitamin D deficiency in senescence-accelerated mouse P6 Reviewed

    Morita Daigo, Higuchi Yoshitoshi, Makida Kazuya, Seki Taisuke, Ikuta Kunihiro, Ishiguro Naoki, Nishida Yoshihiro

    HELIYON   Vol. 6 ( 2 ) page: e03499   2020.2

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  41. Treatment of tenosynovial giant-cell tumour types Reviewed

    Nishida Yoshihiro, Ikuta Kunihiro

    LANCET ONCOLOGY   Vol. 20 ( 8 ) page: E399 - E399   2019.8

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  42. 誌上シンポジウム 骨軟部腫瘍の薬物治療アップデート 骨巨細胞腫に対するデノスマブ治療 Reviewed

    浦川 浩, 新井 英介, 生田 国大, 大田 剛広, 酒井 智久, 西田 佳弘

    臨床整形外科   Vol. 54 ( 7 ) page: 665 - 670   2019.7

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    DOI: 10.11477/mf.1408201410

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  43. Low-dose chemotherapy with methotrexate and vinblastine for patients with refractory desmoid tumors: A second report of relationship between efficacy and various factors. Reviewed

    Nishida Yoshihiro, Sakai Tomohisa, Shimizu Koki, Urakawa Hiroshi, Arai Eisuke, Ikuta Kunihiro, Ando Yuichi, Ishiguro Naoki

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 37 ( 15 )   2019.5

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  44. 膝関節周囲軟部肉腫術後の膝関節機能の検討

    小池 宏, 永野 昭仁, 相羽 久輝, 淺沼 邦洋, 筑紫 聡, 小澤 英史, 河南 勝久, 生田 国大, 西田 佳弘, 今釜 史郎

    日本整形外科学会雑誌   Vol. 98 ( 6 ) page: S1607 - S1607   2024.6

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  45. 叢状神経線維腫に対するMEK阻害剤セルメチニブの期待と注意事項

    西田 佳弘, 野々部 典枝, 城所 博之, 加藤 太一, 武市 拓也, 生田 国大, 今釜 史郎

    日本整形外科学会雑誌   Vol. 97 ( 6 ) page: S1427 - S1427   2023.6

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  46. 叢状神経線維腫に対するMEK阻害剤セルメチニブの期待と注意事項

    西田 佳弘, 野々部 典枝, 城所 博之, 加藤 太一, 武市 拓也, 生田 国大, 今釜 史郎

    日本整形外科学会雑誌   Vol. 97 ( 6 ) page: S1427 - S1427   2023.6

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  47. 骨形成促進と腫瘍抑制効果を有する骨転移新規治療法開発に向けた臨床研究 Bench to bedside approach

    西田 佳弘, 小池 宏, 木村 浩明, 生田 国大, 相羽 久輝, 浦川 浩, 酒井 智久, 伊藤 鑑, 村上 英樹, 今釜 史郎

    日本整形外科学会雑誌   Vol. 97 ( 3 ) page: S620 - S620   2023.3

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  48. Hyaluronan in articular cartilage: Analysis of hip osteoarthritis and osteonecrosis of femoral head. Reviewed International journal

    Jiarui Zhang, Yoshihiro Nishida, Hiroshi Koike, Kan Ito, Lisheng Zhuo, Kazuki Nishida, Koji Kimata, Kunihiro Ikuta, Tomohisa Sakai, Hiroshi Urakawa, Taisuke Seki, Shiro Imagama

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   Vol. 41 ( 2 ) page: 307 - 315   2023.2

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    Hyaluronan (HA) plays crucial roles in the maintenance of high-quality cartilage extracellular matrix. Several studies have reported the HA in synovial fluid in patients with osteoarthritis (OA), but few have described the changes of HA in articular cartilage of OA or idiopathic osteonecrosis of the femoral head (ONFH). KIAA1199 was recently reported to have strong hyaluronidase activity. The aim of this study was to clarify the HA metabolism in OA and ONFH, particularly the involvement of KIAA1199. Immunohistochemical analysis of KIAA1199 and HA deposition was performed for human OA (n = 10), ONFH (n = 10), and control cartilage (n = 7). The concentration and molecular weight (MW) of HA were determined by competitive HA ELISA and Chromatography, respectively. Regarding HA metabolism-related molecules, HAS1, HAS2, HAS3, HYAL1, HYAL2, and KIAA1199 gene expression was assessed by reverse transcriptase polymerase chain reaction. Histological analysis showed the overexpression of KIAA1199 in OA cartilage, which was accompanied by decreased hyaluronic acid binding protein (HABP) staining compared with ONFH and control. Little KIAA1199 expression was observed in cartilage at the collapsed area of ONFH, which was accompanied by a slight decrease in HABP staining. The messenger RNA (​​​​​mRNA) expression of HAS2 and KIAA1199 was upregulated in OA cartilage, while the mRNA expression of genes related to HA catabolism in ONFH cartilage showed mostly a downward trend. The MW of HA in OA cartilage increased while that in ONFH cartilage decreased. HA metabolism in ONFH is suggested to be generally indolent, and is activated in OA including high expression of KIAA1199. Interestingly, MW of HA in OA cartilage was not reduced.

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  49. Efficacy of auranofin as an inhibitor of desmoid progression. Reviewed International journal

    Kan Ito, Yoshihiro Nishida, Shunsuke Hamada, Koki Shimizu, Tomohisa Sakai, Bisei Ohkawara, Benjamin A Alman, Atsushi Enomoto, Kunihiro Ikuta, Hiroshi Koike, Jiarui Zhang, Kinji Ohno, Shiro Imagama

    Scientific reports   Vol. 12 ( 1 ) page: 11918 - 11918   2022.7

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    Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.

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  50. Tail-like lesionを有する悪性軟部腫瘍に対する術前療法の効果に関する検討 東海骨軟部腫瘍コンソーシアム多施設共同研究

    相羽 久輝, 生田 国大, 淺沼 邦洋, 河南 勝久, 筑紫 聡, 松峯 昭彦, 石村 大輔, 永野 昭仁, 紫藤 洋二, 小澤 英史, 山田 健志, 和佐 潤志, 木村 浩明, 酒井 貴央, 村上 英樹, 酒井 智久, 中村 知樹, 西田 佳弘

    日本整形外科学会雑誌   Vol. 96 ( 6 ) page: S1364 - S1364   2022.6

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  51. 転移性骨腫瘍の新たな展開 デュアルコンセプトの骨転移治療法開発 抗腫瘍と骨形成促進効果

    西田 佳弘, 大田 剛広, 生田 国大, 鈴木 喜貴, 小池 宏, 相羽 久輝, 木村 浩明, 酒井 智久, 伊藤 鑑, 村上 英樹, 今釜 史郎

    日本整形外科学会雑誌   Vol. 96 ( 6 ) page: S1275 - S1275   2022.6

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  52. NF1関連悪性末梢神経鞘腫瘍の予後改善をめざした科横断的診療体制の確立と運用 Reviewed

    西田 佳弘, 生田 国大, 夏目 敦至, 森川 真紀, 城所 博之, 野々部 典枝, 武市 拓也, 神戸 未来, 尾崎 紀夫, 今釜 史郎

    日本整形外科学会雑誌   Vol. 96 ( 3 ) page: S602 - S602   2022.3

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  53. 転移性骨腫瘍に対するデノスマブ長期使用により非定型大腿骨骨折を生じた1例 Reviewed

    家﨑雄介、生田国大、酒井智久、小池宏、今釜史郎、西田佳弘

    整形・災害外科   Vol. 64 ( 9 ) page: 1151 - 1154   2021.8

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  54. Effect of Neoadjuvant Therapies on Soft Tissue Sarcomas with Tail-like Lesions: A Multicenter Retrospective Study. International journal

    Hisaki Aiba, Kunihiro Ikuta, Kunihiro Asanuma, Katsuhisa Kawanami, Satoshi Tsukushi, Akihiko Matsumine, Daisuke Ishimura, Akihito Nagano, Yoji Shido, Eiji Kozawa, Kenji Yamada, Junji Wasa, Hiroaki Kimura, Takao Sakai, Hideki Murakami, Tomohisa Sakai, Tomoki Nakamura, Yoshihiro Nishida

    Cancers   Vol. 13 ( 15 )   2021.8

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    Several types of soft tissue sarcomas have peripheral infiltrative growth characteristics called tail-like lesions. The efficacy of neoadjuvant therapy for tumors with tail-like lesions has not been elucidated. From 2012 to 2019, we analyzed 36 patients with soft tissue sarcoma with tail-like lesions treated with neoadjuvant therapy, including chemotherapy, radiotherapy, or both. The effect of neoadjuvant therapy on the tail sign was investigated by analyzing the change in tail-like lesions during neoadjuvant therapy and histological responses. The median length of the tail-like lesion reduced from 29.5 mm at initiation to 19.5 mm after neoadjuvant therapy. The extent of shrinkage in tail-like lesions was related to the histopathological responses in the main part of the tumor. Complete disappearance of the tail-like lesion was observed in 12 patients; however, it was not related to achieving a microscopically negative margin. The oncologic outcomes did not significantly differ between cases with and without the complete disappearance of tail-like lesions. This study indicated that the shrinkage of tail-like lesions did not have a significant effect on complete resection or improvements of clinical outcomes. A more comprehensive evaluation is needed to elaborate on the surgical strategy.

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  55. KMLS新セメントレスステムの短期成績調査JMOG多施設共同研究

    筑紫 聡, 西田 佳弘, 廣瀬 毅, 中田 英二, 中川 瑠美, 今西 淳悟, 中村 知樹, 永野 昭仁, 田宮 大也, 角永 茂樹, 朴木 寛弥, 寺内 竜, 王谷 英達, 西村 俊司, 生田 国大, 上田 孝文

    日本整形外科学会雑誌   Vol. 95 ( 6 ) page: S1349 - S1349   2021.6

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  56. 腹壁原発C/C-rearranged sarcomaの1例 Reviewed

    加藤 万結, 服部 浩佳, 川田 しお梨, 秋田 直洋, 関水 匡大, 小野 学, 二村 昌樹, 後藤 雅彦, 堀部 敬三, 生田 国大, 新井 英介, 西田 佳弘, 前田 尚子

    日本小児血液・がん学会雑誌   Vol. 57 ( 5 ) page: 414 - 414   2021.2

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  57. Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma. International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Shinya Akatsuka, Kunihiro Ikuta, Yoshihiro Nishida, Shinya Toyokuni, Yoshinao Oda

    Genes, chromosomes & cancer   Vol. 60 ( 1 ) page: 26 - 37   2021.1

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    Dedifferentiated liposarcoma (DDLPS) is a relatively common soft tissue sarcoma that results from the progression of well-differentiated liposarcoma (WDLPS). This study aimed to investigate the progression process and to clarify the pathological and genetic factors related to poor prognosis in DDLPS. In 32 DDLPS cases and five WDLPS cases, genetic factors were analyzed by custom comparative genomic hybridization (CGH) array, which was designed to densely cover gene regions known to be frequently amplified in WD/DDLPS. The analyses comparing primary and metastatic lesions and those comparing histologically different areas in the same tumor revealed intra-tumoral genetic heterogeneity and progression. According to a prognostic analysis comparing the good-prognosis and the poor-prognosis groups, we selected MDM2 and HMGA2 as candidate genes associated with poor and good prognosis, respectively. The ratios of the amplification or gain levels of MDM2 and HMGA2 expressed in log ratios (log[MDM2/HMGA2] = log[MDM2]-log[HMGA2]) were significantly associated with prognosis. An amplification or gain level of MDM2 that was more than twice that of HMGA2 (MDM2/HMGA2 > 2, log[MDM2/HMGA2] > 1) was strongly related to poor OS (P < .001) and poor distant metastasis-free survival (DMFS) (P < .001). In the pathological analysis of 44 cases of DDLPS, histological tumor grade, cellular atypia, and MDM2 immunoreactivity were related to overall survival (OS), while HMGA2 immunoreactivity tended to be associated with OS. Cellular atypia was also associated with DMFS. In conclusion, histological grade and MDM2 expression were determined to be prognostically important, and the MDM2/HMGA2 amplification or gain ratio was found to have significant prognostic value by the custom CGH array analysis.

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  58. Cardiac metastases from primary myxoid liposarcoma of the thigh: a case report. International journal

    Kunihiro Ikuta, Tomohisa Sakai, Hiroshi Koike, Tohru Okada, Shiro Imagama, Yoshihiro Nishida

    World journal of surgical oncology   Vol. 18 ( 1 ) page: 227 - 227   2020.8

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    BACKGROUND: Myxoid liposarcoma is well known to have an unusual proclivity for extrapulmonary metastasis. However, cardiac metastasis of myxoid liposarcoma is very rare, even in patients with advanced disease. CASE PRESENTATION: A 40-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two years after the surgery, a low-density area in the left ventricle was found on follow-up chest computed tomography, and was suspected of being metastatic disease. He underwent surgical treatment, and the lesion was pathologically confirmed as metastasis of myxoid liposarcoma. Fifteen months later, he complained of slight dyspnea and developed metastatic disease in the right atrium. He was treated with surgical excision, followed by radiotherapy. Although there was no recurrence in the heart since the second cardiac metastasectomy, multiple metastases occurred in the abdominal cavity, lungs, and muscles. He finally died of the disease 2 years after the second cardiac metastasectomy. CONCLUSION: We experienced a case of primary myxoid liposarcoma in the thigh, accompanied by ectopic and metachronous cardiac metastases. Although this condition is rare, we should follow-up patients with myxoid liposarcoma, considering the possibility of cardiac metastasis.

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  59. Clinical value of serum bone resorption markers for predicting clinical outcomes after use of bone modifying agents in metastatic bone tumors: A prospective cohort study Reviewed

    Hiroshi Urakawa, Yuichi Ando, Tetsunari Hase, Toyone Kikumori, Eisuke Arai, Osamu Maeda, Ayako Mitsuma, Mihoko Sugishita, Tomoya Shimokata, Kunihiro Ikuta, Naoki Ishiguro, Yoshihiro Nishida

    International Journal of Cancer   Vol. 146 ( 12 ) page: 3504 - 3515   2020.6

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  60. A case of retroperitoneal dedifferentiated liposarcoma successfully treated by neoadjuvant chemotherapy and subsequent surgery

    Yokoyama Yukihiro, Nishida Yoshihiro, Ikuta Kunihiro, Nagino Masato

    SURGICAL CASE REPORTS   Vol. 6 ( 1 ) page: 105   2020.5

  61. 上腕骨近位部の骨表面に発生したグロムス腫瘍の1例 Reviewed

    杉浦 喬也, 生田 国大, 新井 英介, 酒井 智久, 小池 宏, 西田 佳弘

    臨床整形外科   Vol. 55 ( 4 ) page: 385 - 388   2020.4

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  62. MRI characteristics predict the efficacy of meloxicam treatment in patients with desmoid-type fibromatosis Reviewed

    Shimizu Koki, Hamada Shunsuke, Sakai Tomohisa, Ito Shinji, Urakawa Hiroshi, Arai Eisuke, Ikuta Kunihiro, Koike Hiroshi, Ishiguro Naoki, Nishida Yoshihiro

    JOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY   Vol. 63 ( 6 ) page: 751 - 757   2019.12

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  63. The clinical outcome of eribulin treatment in Japanese patients with advanced soft tissue sarcoma: a Tokai Musculoskeletal Oncology Consortium study Reviewed International journal

    Nakamura Tomoki, Tsukushi Satoshi, Asanuma Kunihiro, Katagiri Hirohisa, Ikuta Kunihiro, Nagano Akihito, Kozawa Eiji, Yamada Satoshi, Shido Yoji, Yamada Kenji, Kawanami Katsuhisa, Ishimura Daisuke, Sudo Akihiro, Nishida Yoshihiro

    CLINICAL & EXPERIMENTAL METASTASIS   Vol. 36 ( 4 ) page: 343 - 350   2019.8

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    The efficacy and safety of eribulin in Japanese patients with advanced soft-tissue sarcomas (STS) have not been evaluated in a large-scale cohort study. Thus, we aimed to investigate the clinical outcome of 82 Japanese patients with STS receiving eribulin across multiple study centers retrospectively. Of 82 STS patients receiving eribulin treatment, 13 were treated for locally unresectable tumor, 46 for metastasis, and 23 for both. The primary endpoint of this study was to evaluate the efficacy of eribulin against STS. The median age was 60 years. Thirty-seven were diagnosed with L-sarcoma (leiomyosarcoma or liposarcoma) and 45 had non-L-sarcoma. The median progression-free survival (PFS) for all patients was 2.7 months, with 3.4 months in those with L-sarcoma and 2.2 months in those with non-L-sarcoma. Patients with L-sarcoma showed a better PFS than those with non-L-sarcoma. Overall, the median survival time was 11.1 months, and 12.3 months and 7.9 months in patients with L-sarcoma and non-L-sarcoma, respectively; however, there was no significant differences between the groups. The prognostic significance of PS = 0 and both existence of local and metastatic STS was evaluated by multivariate analysis. We also evaluated the overall survival (OS) in patients with undifferentiated pleomorphic sarcoma (UPS) and other non-L-sarcomas. Patients with UPS had better OS than those with the other non-L-sarcomas. In conclusion, there was a significant difference in PFS between patients with L-sarcoma and non-L-sarcoma following treatment with eribulin. The anti-tumor potential of eribulin was evident in patients with UPS.

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  64. Treatment of tenosynovial giant-cell tumour types. Reviewed

    Nishida Y, Ikuta K

    The Lancet. Oncology   Vol. 20 ( 8 ) page: e399   2019.8

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    DOI: 10.1016/S1470-2045(19)30398-5

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  65. エリブリンを用いた進行期軟部肉腫の治療成績 東海骨軟部腫瘍コンソーシアム共同研究

    中村 知樹, 筑紫 聡, 淺沼 邦洋, 片桐 浩久, 生田 国大, 永野 昭仁, 小澤 英史, 山田 聡, 紫藤 洋二, 石村 大輔, 山田 健志, 河南 勝久, 須藤 啓広, 西田 佳弘

    日本整形外科学会雑誌   Vol. 93 ( 6 ) page: S1390 - S1390   2019.6

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  66. Outpatient chemotherapy for patients with unresectable or metastatic bone sarcomas

    Urakawa Hiroshi, Nishida Yoshihiro, Mitsuma Ayako, Maeda Osamu, Sugishita Mihoko, Shimokata Tomoya, Mizutani Takeshi, Arai Eisuke, Ikuta Kunihiro, Hamada Shunsuke, Ota Takehiro, Ishiguro Naoki, Ando Yuichi

    ANNALS OF ONCOLOGY   Vol. 29   2018.10

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  67. Predictors of complications in heat-treated autograft reconstruction after intercalary resection for malignant musculoskeletal tumors of the extremity. Reviewed

    Ikuta K, Nishida Y, Sugiura H, Tsukushi S, Yamada K, Urakawa H, Arai E, Hamada S, Ishiguro N

    Journal of surgical oncology   Vol. 117 ( 7 ) page: 1469 - 1478   2018.6

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  68. Suppression of hyaluronan synthesis attenuates the tumorigenicity of low-grade chondrosarcoma. Reviewed International journal

    Shunsuke Hamada, Yoshihiro Nishida, Lisheng Zhuo, Tamayuki Shinomura, Kunihiro Ikuta, Eisuke Arai, Hiroshi Koike, Koji Kimata, Takahiro Ushida, Naoki Ishiguro

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   Vol. 36 ( 6 ) page: 1573 - 1580   2018.6

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    Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Chondrosarcoma, particularly when low-grade, is characterized by the formation of an extracellular matrix (ECM) containing abundant HA, and its drug/radiation resistance has become a clinically relevant problem. This study aimed to evaluate the effects of an HA synthesis inhibitor, 4-methylumbelliferone (MU), on ECM formation as well as antitumor effects in chondrosarcoma. We investigated the effects of MU on rat chondrosarcoma (RCS) cells with a grade I histological malignancy in vitro and in vivo grafted model. HA binding protein (HABP) stainability on and around the RCS cells was effectively reduced with treatment of MU. ECM formation was markedly suppressed by MU at a dose of 1.0 mM. Cell proliferation was significantly reduced by MU at 24 h. Cell motility and invasion were suppressed in a dose-dependent manner by MU. No significant changes in mRNA expression of Has1-3 were observed. Furthermore, MU inhibited the growth of grafted tumors in vivo. Histologically, chondrosarcoma cells of control tumors showed a cell-clustering structure. HABP stainability was markedly decreased in the MU-treated group. These results suggest that MU exhibits antitumor effects on low-grade chondrosarcoma, via inhibition of HA accumulation and ECM formation. MU, which is an approved drug in bile therapy, could be a new off-label medication for chondrosarcomas. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1573-1580, 2018.

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  69. Mithramycin has inhibitory effects on gliostatin and matrix metalloproteinase expression induced by gliostatin in rheumatoid fibroblast-like synoviocytes

    Tatematsu N., Waguri-Nagaya Y., Kawaguchi Y., Oguri Y., Ikuta K., Kobayashi M., Nozaki M., Asai K., Aoyama M., Otsuka T.

    Modern Rheumatology   Vol. 28 ( 3 ) page: 495 - 505   2018.5

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    Objectives: Gliostatin (GLS) has angiogenic and arthritogenic activities and enzymatic activity as thymidine phosphorylase. Aberrant GLS production has been observed in the synovial membranes of patients with rheumatoid arthritis (RA). Matrix metalloproteinases (MMPs) are involved in joint destruction. Promoters of GLS and some MMP genes contain Sp1 binding sites. We examined the inhibitory effect of the Sp1 inhibitor mithramycin on GLS-induced GLS and MMP expression in cultured fibroblast-like synoviocytes (FLSs). Methods: Synovial tissue samples were obtained from patients with RA. FLSs pretreated with mithramycin were cultured with GLS. The mRNA expression levels of GLS and MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13 were determined using reverse transcription polymerase chain reactions. Protein levels were measured using enzyme immunoassay and gelatin zymography. Results: GLS upregulated the expression of GLS itself and of MMP-1, MMP-3, MMP-9, and MMP-13, an effect significantly reduced by treatment with mithramycin. GLS and mithramycin had no effect on MMP-2 expression. Conclusions: Mithramycin downregulated the increased expression of GLS and MMP-1, MMP-3, MMP-9, and MMP-13 in FLSs treated with GLS. Because GLS plays a pathological role in RA, blocking GLS stimulation using an agent such as mithramycin may be a novel approach to antirheumatic therapy.

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  70. 【運動器画像診療の最前線】部位別・疾患別画像診療の最前線 軟部腫瘍の画像診療

    生田 国大, 西田 佳弘

    関節外科   Vol. 37   page: 144-152   2018.4

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  71. Single metastasis of myxoid liposarcoma from the thigh to thyroid gland: A case report Reviewed

    Hiroshi Urakawa, Kenichi Nakanishi, Eisuke Arai, Kunihiro Ikuta, Shunsuke Hamada, Takehiro Ota, Naoki Ishiguro, Yoshihiro Nishida

    World Journal of Surgical Oncology   Vol. 16 ( 1 ) page: 71   2018.3

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    Background: Thyroid metastasis of soft tissue sarcoma is very rare, and the diagnosis is especially difficult when only a single lesion is present. Case presentation: A 50-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two and a half years after the surgery, a growing low-density area was incidentally observed in the right lobe of his thyroid gland on follow-up chest computed tomography. Fine needle aspiration biopsy was performed twice, and the thyroid mass was suspected of being a sarcoma metastasis. He was treated by hemithyroidectomy, and the lesion was pathologically confirmed as a metastasis of myxoid liposarcoma. Conclusion: We experienced single thyroid gland metastasis in patients with myxoid liposarcoma in whom a growing mass is observed in the thyroid gland after radical surgery of the primary site.

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  72. Pancreatoduodenectomy with portal vein resection for distal cholangiocarcinoma

    Maeta T., Ebata T., Hayashi E., Kawahara T., Mizuno S., Matsumoto N., Ohta S., Nagino M., Aoba T., Kaneoka Y., Arai T., Shimizu Y., Kiriyama M., Sakamoto E., Miyake H., Takara D., Shirai K., Ohira S., Morofuji N., Akutagawa A., Yamaguchi R., Takano M., Yamamoto H., Inoue M., Asaba Y., Watanabe T., Hashimoto M., Kawai S., Ikuta K., Matsubara H., Kato K., Kondo S.

    British Journal of Surgery   Vol. 104 ( 11 ) page: 1549 - 1557   2017.10

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    Background: Little is known about the value of portal vein (PV) resection in distal cholangiocarcinoma. The aim of this study was to evaluate the clinical significance of PV resection in distal cholangiocarcinoma. Methods: Patients who underwent pancreatoduodenectomy (PD) for distal cholangiocarcinoma between 2001 and 2010 at one of 31 hospitals in Japan were reviewed retrospectively with special attention to PV resection. Short- and long-term outcomes were evaluated. Results: In the study interval, 453 consecutive patients with distal cholangiocarcinoma underwent PD, of whom 31 (6·8 per cent) had combined PV resection. The duration of surgery (510 versus 427 min; P = 0·005) and incidence of blood transfusion (48 versus 30·7 per cent; P = 0·042) were greater in patients who had PV resection than in those who did not. Postoperative morbidity and mortality were no different in the two groups. Several indices of tumour progression, including high T classification, lymphatic invasion, perineural invasion, pancreatic invasion and lymph node metastasis, were more common in patients who had PV resection. Consequently, the incidence of R1/2 resection was higher in this group (32 versus 11·8 per cent; P = 0·004). Survival among the 31 patients with PV resection was worse than that for the 422 patients without PV resection (15 versus 42·4 per cent at 5 years; P < 0·001). Multivariable analyses revealed that age, blood loss, histological grade, perineural invasion, pancreatic invasion, lymph node metastasis and surgical margin were independent risk factors for overall survival. PV resection was not an independent risk factor. Conclusion: PV invasion in distal cholangiocarcinoma is associated with locally advanced disease and several negative prognostic factors. Survival for patients who have PV resection is poor even after curative resection.

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  73. Immunohistochemical staining with non-phospho beta-catenin as a diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with extra-peritoneal desmoid-type fibromatosis Reviewed

    Tomohisa Sakai, Yoshihiro Nishida, Shunsuke Hamada, Hiroshi Koike, Kunihiro Ikuta, Takehiro Ota, Naoki Ishiguro

    DIAGNOSTIC PATHOLOGY   Vol. 12 ( 1 ) page: 66   2017.8

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    Background: Immunohistochemical staining with conventional anti-beta-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatosis (DF). This study aimed to evaluate the diagnostic and prognostic value of immunohistochemical staining with anti-non-phospho beta-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-beta-catenin antibody.
    Methods: Between 2003 and 2015, 40 patients with extra-peritoneal sporadic DF were prospectively treated with meloxicam or celecoxib, a COX-2 inhibitor, therapy. The efficacy of this treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Immunohistochemical staining was performed on formalin-fixed material to evaluate the expression of beta-catenin and non-phospho beta-catenin, and the positivity was grouped as negative, weak, moderate, and strong. DNA was isolated from frozen tissue or formalin-fixed materials, and the CTNNB1 mutation status was determined by direct sequencing.
    Results: Of the 40 patients receiving COX-2 inhibitor treatment, there was one with complete remission, 12 with partial remission, 7 with stable disease, and 20 with progressive disease. The mutation sites in CTNNB1 were detected in 22 (55%) of the 40 cases: T41A (17 cases), S45F (3 cases), and T41I and S45P (1 each). The positive nuclear expression of non-phospho beta-catenin showed a significant correlation with positive CTNNB1 mutation status detected by Sanger method (p = 0.025), and poor outcome in COX-2 inhibitor therapy (p = 0.022). In contrast, nuclear expression of beta-catenin did not show a significant correlation with either CTNNB1 mutation status (p = 0.43) or outcome of COX-2 inhibitor therapy (p = 0.38).
    Conclusions: Nuclear expression of non-phospho beta-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho beta-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.

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  74. Conditional knockdown of hyaluronidase 2 in articular cartilage stimulates osteoarthritic progression in a mice model. Reviewed International journal

    Yoshitoshi Higuchi, Yoshihiro Nishida, Eiji Kozawa, Lisheng Zhuo, Eisuke Arai, Shunsuke Hamada, Daigo Morita, Kunihiro Ikuta, Koji Kimata, Takahiro Ushida, Naoki Ishiguro

    Scientific reports   Vol. 7 ( 1 ) page: 7028 - 7028   2017.8

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    The catabolism of hyaluronan in articular cartilage remains unclear. The aims of this study were to investigate the effects of hyaluronidase 2 (Hyal2) knockdown in articular cartilage on the development of osteoarthritis (OA) using genetic manipulated mice. Destabilization of the medial meniscus (DMM) model of Col2a promoter specific conditional Hyal2 knockout (Hyal -/- ) mice was established and examined. Age related and DMM induced alterations of articular cartilage of knee joint were evaluated with modified Mankin score and immunohistochemical staining of MMP-13, ADAMTS-5, KIAA11199, and biotinylated- hyaluronan binding protein staining in addition to histomorphometrical analyses. Effects of Hyal2 suppression were also analyzed using explant culture of an IL-1α induced articular cartilage degradation model. The amount and size of hyaluronan in articular cartilage were higher in Hyal2 -/- mice. Hyal2 -/- mice exhibited aggravated cartilage degradation in age-related and DMM induced mice. MMP-13 and ADAMTS-5 positive chondrocytes were significantly higher in Hyal2 -/- mice. Articular cartilage was more degraded in explant cultures obtained from Hyal2 -/- mice. Knockdown of Hyal2 in articular cartilage induced OA development and progression possibly mediated by an imbalance of HA metabolism. This suggests that Hyal2 knockdown exhibits mucopolysaccharidosis-like OA change in articular cartilage similar to Hyal1 knockdown.

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  75. 大腿骨遠位骨肉腫に対する加温処理骨と血管柄付き腓骨再建後の移植腓骨の骨癒合とサイズの変化

    中村 優, 高成 啓介, 蛯沢 克己, 神戸 未来, 中村 亮太, 亀井 譲, 生田 国大, 西田 佳弘

    日本形成外科学会会誌   Vol. 37 ( 8 ) page: 473 - 473   2017.8

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  76. Heat-stimuli-enhanced osteogenesis using clinically available biomaterials Reviewed

    Takehiro Ota, Yoshihiro Nishida, Kunihiro Ikuta, Ryuji Kato, Eiji Kozawa, Shunsuke Hamada, Tomohisa Sakai, Naoki Ishiguro

    PLOS ONE   Vol. 12 ( 7 ) page: e0181404   2017.7

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    A recent study reported that heat stress stimulates osteogenesis in an in vivo rat model using alginate gel and magnetite cationic liposomes. However, for clinical use, the efficacy for promoting osteogenesis needs to be investigated using clinically approved materials, and preferably with animals larger than rats. The aim of this study was to evaluate multiple heat stimuli-triggered osteogenesis in rat tibial defect models using already clinically applicable materials (Resovist (R) and REGENOS (R)) and determine the efficacy also in the rabbit. Fifty-eight rats and 10 rabbits were divided into two groups, respectively, with or without hyperthermia treatment at 45 degrees C for 15 min. (hyperthermia; 20 rats once a week, 8 rats three times a week, 5 rabbits once a week, control; 30 rats and 5 rabbits). Micro-CT assessment at 4 weeks revealed that a significantly stimulated osteogenesis was observed in the once a week group of both rats and rabbits as compared to the control group (p = 0.018 and 0.036, respectively). In contrast, the three times a week group did not show enhanced osteogenesis. Histological examination and image analysis showed consistent results in which the area of mineralized bone formation in the once a week hyperthermia group was significantly increased compared with that in the control group at four weeks (rat; p = 0.026, rabbit; p = 0.031). Newly formed bone was observed in the grafted materials from the periphery toward the center, and more osteoclasts were found in the once a week group. Heat stress also induced enhanced alkaline phosphatase expression in cultured osteoblastic cells, MC3T3, in vitro (p = 0.03). On the other hand, heat stress had no obvious effects on chondrogenic differentiation using ATDC5 cells. Our study demonstrates that heat-stimuli with clinically applicable novel heating materials can promote significant osteogenesis, and may thus be a promising treatment option for diseases associated with bone defects.

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  77. Recurrence after resection with curative intent for distal cholangiocarcinoma

    Komaya K., Ebata T., Shirai K., Ohira S., Morofuji N., Akutagawa A., Yamaguchi R., Nagino M., Aoba T., Kaneoka Y., Arai T., Shimizu Y., Fukami Y., Sakamoto E., Miyake H., Takara D., Tojima Y., Kawahara T., Mizuno S., Matsumoto N., Ota S., Takano M., Yamamoto H., Inoue M., Asaba Y., Watanabe T., Hashimoto M., Kawai S., Ikuta K., Matsubara H., Kondo S.

    British Journal of Surgery   Vol. 104 ( 4 ) page: 426 - 433   2017.3

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    Background: Few studies have been conducted on patterns of recurrence after resection for distal cholangiocarcinoma (DCC). The aim of this study was to investigate the incidence and pattern of recurrence after resection of DCC, and to evaluate prognostic factors for time to recurrence and recurrence-free survival (RFS). Methods: Patients who underwent pancreatoduodenectomy with curative intent for DCC between 2001 and 2010 at one of 30 hospitals in Japan were reviewed retrospectively, with special attention to recurrence patterns. The Cox proportional hazards model was used for multivariable analysis. Results: In the study interval, 389 patients underwent pancreatoduodenectomy for DCC with R0/M0 status. Recurrence developed in 213 patients (54·8 per cent). The estimated cumulative probability of recurrence was 54·3 per cent at 5 years. An initial locoregional recurrence occurred in 55 patients (14·1 per cent) and initial distant recurrence in 168 (43·2 per cent), most commonly in the liver. Isolated initial locoregional recurrence occurred in 45 patients (11·6 per cent). Independent prognostic factors for time to recurrence and RFS were perineural invasion (P = 0·001 and P = 0·009 respectively), pancreatic invasion (both P < 0·001) and lymph node metastasis (both P < 0·001). RFS worsened as the number of risk factors increased: the 5-year RFS rate was 70·6 per cent for patients without any risk factors, 50·3 per cent for patients with one factor, 31·8 per cent for those with two factors, and 13·4 per cent when three factors were present. Conclusion: More than half of patients with DCC experienced recurrence after R0 resection, usually within 5 years. Perineural invasion, pancreatic invasion and positive nodal involvement are risk factors for recurrence.

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  78. Iron overload patients with unknown etiology from national survey in Japan

    Ikuta Katsuya, Hatayama Mayumi, Addo Lynda, Toki Yasumichi, Sasaki Katsunori, Tatsumi Yasuaki, Hattori Ai, Kato Ayako, Kato Koichi, Hayashi Hisao, Suzuki Takahiro, Kobune Masayoshi, Tsutsui Miyuki, Gotoh Akihiko, Aota Yasuo, Matsuura Motoo, Hamada Yuzuru, Tokuda Takahiro, Komatsu Norio, Kohgo Yutaka

    INTERNATIONAL JOURNAL OF HEMATOLOGY   Vol. 105 ( 3 ) page: 353 - 360   2017.3

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    Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5 ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000 ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

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  79. Antitumor effects of 4-methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor Reviewed

    Kunihiro Ikuta, Takehiro Ota, Lisheng Zhuo, Hiroshi Urakawa, Eiji Kozawa, Shunsuke Hamada, Koji Kimata, Naoki Ishiguro, Yoshihiro Nishida

    INTERNATIONAL JOURNAL OF CANCER   Vol. 140 ( 2 ) page: 469 - 479   2017.1

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    Hyaluronan (HA) has been shown to play important roles in the growth, invasion and metastasis of malignant tumors. Our previous study showing that high HA expression in malignant peripheral nerve sheath tumors (MPNST) is predictive of poor patient prognosis, prompted us to speculate that inhibition of HA synthesis in MPNST might suppress the tumorigenicity. The aim of our study was to investigate the antitumor effects of 4-methylumbelliferone (MU), an HA synthesis inhibitor, on human MPNST cells and tissues. The effects of MU on HA accumulation and tumorigenicity in MPNST cells were analyzed in the presence or absence of MU in an in vitro as well as in vivo xenograft model using human MPNST cell lines, sNF96.2 (primary recurrent) and sNF02.2 (metastatic). MU significantly inhibited cell proliferation, migration and invasion in both MPNST cell lines. HA binding protein (HABP) staining, particle exclusion assay and quantification of HA revealed that MU significantly decreased HA accumulation in the cytoplasms and pericellular matrices in both MPNST cell lines. The expression levels of HA synthase2 (HAS2) and HA synthase3 (HAS3) mRNA were downregulated after treatment with MU. MU induced apoptosis of sNF96.2 cells, but not sNF02.2 cells. MU administration significantly inhibited the tumor growth of sNF96.2 cells in the mouse xenograft model. To the best of our knowledge, our study demonstrates for the first time the antitumor effects of MU on human MPNST mediated by inhibition of HA synthesis. Our results suggest that MU may be a promising agent with novel antitumor mechanisms for MPNST.

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  80. Impact of disease free status on prognosis in metastatic non-small round cell soft tissue sarcomas Reviewed

    Hiroshi Urakawa, Eiji Kozawa, Kunihiro Ikuta, Shunsuke Hamada, Naoki Ishiguro, Yoshihiro Nishida

    CLINICAL & EXPERIMENTAL METASTASIS   Vol. 33 ( 8 ) page: 799 - 807   2016.12

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    The aim of this study is to examine the impact of disease free (DF) status on the prognosis in patients with metastatic non-small round cell soft tissue sarcoma (STS). We retrospectively reviewed 51 metastatic STS patients who were treated in Nagoya University Hospital from 2005 to 2015. The relation between various clinical factors and overall survival (OS) was analyzed. The log rank test and Cox's proportional hazards test were used to evaluate the differences between groups. p-values of &lt; 0.05 were considered to indicate significance. The median follow-up period after first metastasis was 23.5 (1.6-97.1) months. There were 30 males and 21 females with a median age of 62 (15-88) years at first metastasis. The histologic subtypes were 17 undifferentiated pleomorphic sarcoma, 10 liposarcoma, 8 malignant peripheral nerve sheath tumor, and 16 others. Thirty patients had more than 2 metastases, and 15 patients had primary or local recurrent tumors. The metastatic sites were 31 lung only, 8 bone only, and 12 others. Twenty-two patients achieved DF status after surgeries and in one case proton radiotherapy for bone metastasis. DF status was marginally or significantly associated with good prognosis in patients with both pulmonary (p = 0.055) and extrapulmonary metastasis (p = 0.029). On multivariate analysis, DF status (p = 0.010) was an independent good prognostic factors for OS. In metastatic non-small round cell STS, it is an important treatment concept to achieve DF status whenever possible. This concept can apply both to pulmonary and extrapulmonary metastasis.

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  81. Short-range ultraviolet irradiation with LED device effectively increases serum levels of 25(OH)D Reviewed

    Daigo Morita, Yoshihiro Nishida, Yoshitoshi Higuchi, Taisuke Seki, Kunihiro Ikuta, Hideki Asano, Naoki Ishiguro

    JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY   Vol. 164   page: 256 - 263   2016.11

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    Impairment of the activities of daily living (ADL) by osteoporosis is an important concern in developed countries with a super-aging population. Vitamin D, which is a crucial molecule in bone metabolism and mainly produced endogenously with ultraviolet (UV) light exposure, is known to be insufficient in the elderly population. We used an UV Light-Emitting Diode (UV-LED) instrument generating a narrow-range wavelength to analyze the efficacy of endogenous vitamin D production. The primary purpose of this study was to examine the effects of UV irradiation at various narrow-range wavelengths using UV-LED on vitamin D supplementation. The second one was to clarify the short-term effects of UV irradiation on bone morphology in mice. Vitamin D-starved C57BL/6 female mice (n = 7 per group) were UV-irradiated (268 nm, 282 nm, 290 nm, 305 nm, and 316 nm) with 1 kJ/m(2) twice a week for 4 weeks. UV irradiation using UV-LED had significant effects on increasing serum 25(OH)D levels in all wavelength groups (P &lt; 0.001, all groups) as compared to a control group. Among irradiated groups, wavelength of 316 nm had a less marked effect on 25(OH)D production-compared with other wavelengths at 1 week of UV irradiation (P &lt; 0.05). Levels of 1,25(OH)(2)D were significantly increased after 4 weeks irradiation with UV-B or UV-C irradiation (P &lt; 0.05). mRNA levels of vitamin D 25-hydroxylase were increased with UV-B or UV-C irradiation (268 nm-305 nm), significantly. Micro-CT examination revealed that short-term (4 weeks) UV-irradiation did not induce morphological change of mice in any group. This study provides essential information that narrow-range UV irradiation with LED can increase the endogenous production of vitamin D, and mRNA levels of the responsible enzyme. Although bone morphology was not altered by short-term UV irradiation in this study, an increase of serum vitamin D might improve bone morphology with long-term irradiation. (C) 2016 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.jphotobiol.2016.09.036

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  82. Simple resection of truncal desmoid tumors: A case series Reviewed

    Yoshihiro Nishida, Satoshi Tsukushi, Hiroshi Urakawa, Shunsuke Hamada, Eiji Kozawa, Kunihiro Ikuta, Naoki Ishiguro

    ONCOLOGY LETTERS   Vol. 12 ( 2 ) page: 1564 - 1568   2016.8

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    Desmoid tumors of the extra-abdominal and abdominal wall have been associated with morbidity due to the aggressive nature of cause functional impairment is desired for patients with desmoid tumors. In the present study, among patients with desmoid tumors who were prospectively and consecutively treated with identical conservative treatment with meloxicam, a selected patients of patients were treated with less invasive surgery than wide-resection. Out of 60 patients pathologically diagnosed with desmoid tumors, 9 patients with tumors refractory to conservative treatment and 4 patients who refused to receive this type of treatment were treated with planned simple resection. Subsequently, the clinical outcome of the patients and the mutational status of the catenin beta-1 (CTNNB1) gene in the tumors were analyzed. The mean age of the 13 patients that underwent planned simple resection was 39 years, and the tumors were located in the abdominal wall in 6 cases, the chest wall in 4 cases and the neck in 3 cases. All excised specimens were evaluated and positive microscopic margins were identified; however, during the mean follow-up period of 30 months, 12/13 cases, 7 of which had T41A mutations and 5 of which had no mutations (wild-type), did not develop recurrence. Only 1 initial case with an S45F mutation in the CTNNB1 gene developed recurrence. The results of the present prospectively treated with simple resection and retrospectively analyzed study suggest that planned simple resection could serve as a therapeutic modality for extraperitoneal desmoid tumors, particularly truncal ones with a wild-type or T41A mutational status.

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  83. Characteristics of cultured desmoid cells with different CTNNB1 mutation status Reviewed

    Shunsuke Hamada, Hiroshi Urakawa, Eiji Kozawa, Eisuke Arai, Kunihiro Ikuta, Tomohisa Sakai, Naoki Ishiguro, Yoshihiro Nishida

    CANCER MEDICINE   Vol. 5 ( 2 ) page: 352 - 360   2016.2

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    Desmoid tumors are benign mesenchymal neoplasms with a locally aggressive nature. The mutational status of -catenin gene (CTNNB1) is presumed to affect the tumorous activity of the cells. In this study, we isolated three kinds of desmoid cell with different CTNNB1 status, and compared their characteristics. Cells were isolated from three patients with abdominal wall desmoid during surgery, all of which were resistant to meloxicam treatment. The mutational status of the CTNNB1 exon 3 was determined for both parental tumor tissues and isolated cultured cells. -catenin expression was determined with immunohistochemistry. Responsiveness to meloxicam was investigated with MTS assay together with COX-2 immunostaining. mRNA expressions of downstream molecules of Wnt/-catenin pathway were determined with real-time RT-PCR. Three kinds of cell isolated from desmoid tumors harboring different CTNNB1 mutation status (wild type, T41A, and S45F), all exhibited a spindle shape. These isolated cells could be cultured until the 20th passage with unchanged proliferative activity. Nuclear accumulation of -catenin was observed in all cultured cells, particularly in those with S45F. Proliferating activity was significantly suppressed by meloxicam (25mol/L, P&lt;0.007) in all three cell cultures, of which parental desmoid was resistant to meloxicam clinically. The mRNA expressions of Axin2, c-Myc, and Cyclin D1 differently increased in the three cultured cell types as compared with those in human skin fibroblast cells (HDF). Inhibitors of Wnt/-catenin pathway downregulated Axin2, c-Myc, and Cyclin D1 significantly. Isolated and cultured desmoid tumor cells harboring any one of the CTNNB1 mutation status had unique characteristics, and could be useful to investigate desmoid tumors with different mutation status of CTNNB1.

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  84. Low-dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors: relationship to CTNNB1 mutation status

    Nishida Yoshihiro, Tsukushi Satoshi, Urakawa Hiroshi, Hamada Shunsuke, Kozawa Eiji, Ikuta Kunihiro, Ando Yuichi, Ishiguro Naoki

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   Vol. 20 ( 6 ) page: 1211 - 1217   2015.12

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    Background: This study was conducted to determine the efficacy and safety of low-dose chemotherapy with methotrexate (MTX) and vinblastine (VBL) for patients with desmoid tumors refractory to meloxicam treatment, focusing in particular on the relationship between the efficacy of this chemotherapy and catenin β-1 (CTNNB1) mutation status. Patients and methods: Since March 2003, patients pathologically diagnosed with extraperitoneal desmoid tumors have been prospectively treated with meloxicam, a COX-2 inhibitor, at our institution. Patients with inoperable tumors who were resistant to meloxicam treatment underwent MTX and VBL therapy every other week. The responses of all patients were evaluated, and factors that were correlated with efficacy were analyzed, including CTNNB1 mutation status. Results: Sixty-eight patients were prospectively treated with meloxicam. MTX + VBL therapy was administered in 15 patients. Six patients showed a partial response. Only one patient presented disease progression. A few patients showed grade 3–4 treatment-related toxicity with the administration of MTX and VBL every other week. Intriguingly, CTNNB1 status did not affect the efficacy of this treatment. Conclusion: MTX and VBL treatment every other week is well tolerated and achieved a favorable response in patients resistant to meloxicam treatment, regardless of CTNNB1 mutation status.

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  85. Expression of colony-stimulating factor 1 is associated with occurrence of osteochondral change in pigmented villonodular synovitis

    Ota Takehiro, Urakawa Hiroshi, Kozawa Eiji, Ikuta Kunihiro, Hamada Shunsuke, Tsukushi Satoshi, Shimoyama Yoshie, Ishiguro Naoki, Nishida Yoshihiro

    TUMOR BIOLOGY   Vol. 36 ( 7 ) page: 5361 - 5367   2015.7

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    Pigmented villonodular synovitis (PVNS) is a benign, translocation-derived neoplasm. Because of its high local recurrence rate after surgery and occurrence of osteochondral destruction, a novel therapeutic target is required. The present study aimed to evaluate the significance of protein expression possibly associated with the pathogenesis during the clinical course of PVNS. In 40 cases of PVNS, positivity of colony-stimulated factor 1 (CSF1), its receptor (CSF1R), and receptor activator of nuclear factor kappa-B ligand (RANKL) were immunohistochemically determined. The relationship between the positivity and clinical outcomes was investigated. High positivity of CSF1 staining intensity was associated with an increased incidence of osteochondral lesions (bone erosion and osteoarthritis) (p = 0.009), but not with the rate of local recurrence. Positivity of CSF1R and RANKL staining was not associated with any clinical variables. The number of giant cells was not correlated with positivity of any of the three proteins, or with the clinical outcome. Focusing on knee cases, CSF1 positivity was also associated with the incidence of osteochondal change (p = 0.02). CSF1R positivity was high in cases which had local recurrence, but not significantly so (p = 0.129). Determination of CSF1 and CSF1R expression may be useful as a prognosticator of the clinical course and/or outcomes of PVNS.

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  86. Low-dose chemotherapy with methotrexate and vinblastine for Japanese patients with desmoid tumors: Relationship to CTNNB1 mutational status. Reviewed

    Yoshihiro Nishida, Satoshi Tsukushi, Hiroshi Urakawa, Shunsuke Hamada, Eiji Kozawa, Kunihiro Ikuta, Yuichi Ando, Naoki Ishiguro

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 33 ( 15 )   2015.5

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  87. Avian Influenza Virus Infection of Immortalized Human Respiratory Epithelial Cells Depends upon a Delicate Balance between Hemagglutinin Acid Stability and Endosomal pH

    Daidoji Tomo, Watanabe Yohei, Ibrahim Madiha S., Yasugi Mayo, Maruyama Hisataka, Masuda Taisuke, Arai Fumihito, Ohba Tomoyuki, Honda Ayae, Ikuta Kazuyoshi, Nakaya Takaaki

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 290 ( 17 ) page: 10627 - 10642   2015.4

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    The highly pathogenic avian influenza (AI) virus, H5N1, is a serious threat to public health worldwide. Both the currently circulating H5N1 and previously circulating AI viruses recognize avian-type receptors; however, only the H5N1 is highly infectious and virulent in humans. The mechanism(s) underlying this difference in infectivity remains unclear. The aim of this study was to clarify the mechanisms responsible for the difference in infectivity between the current and previously circulating strains. Primary human small airway epithelial cells (SAECs) were transformed with the SV40 large T-antigen to establish a series of clones (SAEC-Ts). These clones were then used to test the infectivity of AI strains. Human SAEC-Ts could be broadly categorized into two different types based on their susceptibility (high or low) to the viruses. SAEC-T clones were poorly susceptible to previously circulating AI but were completely susceptible to the currently circulating H5N1. The hemagglutinin (HA) of the current H5N1 virus showed greater membrane fusion activity at higher pH levels than that of previous AI viruses, resulting in broader cell tropism. Moreover, the endosomal pH was lower in high susceptibility SAEC-T clones than that in low susceptibility SAEC-T clones. Taken together, the results of this study suggest that the infectivity of AI viruses, including H5N1, depends upon a delicate balance between the acid sensitivity of the viral HA and the pH within the endosomes of the target cell. Thus, one of the mechanisms underlying H5N1 pathogenesis in humans relies on its ability to fuse efficiently with the endosomes in human airway epithelial cells.

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  88. レックリングハウゼン病の連携診療 名大病院における神経線維腫症I型診療ネットワークの構築

    西田 佳弘, 夏目 敦至, 城所 博之, 大瀬戸 久美子, 生田 国大, 石黒 直樹, 若林 俊彦, 尾崎 紀夫

    日本レックリングハウゼン病学会雑誌   Vol. 6 ( 1 ) page: 35 - 35   2015.4

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  89. Postoperative brain metastases in soft tissue sarcomas

    Urakawa Hiroshi, Tsukushi Satoshi, Kozawa Eiji, Ikuta Kunihiro, Hamada Shunsuke, Ishiguro Naoki, Nishida Yoshihiro

    CLINICAL & EXPERIMENTAL METASTASIS   Vol. 32 ( 4 ) page: 345 - 351   2015.4

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    Brain metastases (BMs) from soft tissue sarcoma (STS) are rare but lethal. We reviewed 187 consecutive patients with STS treated with definitive surgery in Nagoya University Hospital from 2004 to 2014. There were 10 patients with neurofibromatosis-1 (NF-1). We investigated estimated brain metastasis free survival (BMFS) after surgery and overall survival (OS) after BMs in STS. The factors that affected BMFS were also investigated. Eight of 187 patients (4.3 %) developed BM with a median period of 18.2 (range 8.8–42.6) months after surgery. Seven of 8 BM patients had metastases at other sites. Estimated 5 year BMFS rate after surgery was 95.2 %, and 3 month OS rate after BM was 25.0 %. NF-1 (p < 0.0001), histological subtype of MPNST (p = 0.008), and primary tumor size ≥5 cm (p = 0.021) were significantly associated with increasing incidence of BM. In this study, postoperative BMs were common in patients with NF-1, MPNST, and large tumors. Considering the impact of NF-1 on BMFS, careful follow up for BM is necessary for NF-1 patients with metastases at other sites.

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  90. Prognostic impact of lymph node metastasis in distal cholangiocarcinoma

    Kiriyama M., Ebata T., Aoba T., Kaneoka Y., Arai T., Shimizu Y., Nagino M., Fukami Y., Miyake H., Sakamoto E., Takara D., Shirai K., Ohira S., Tojima Y., Hashimoto M., Akutagawa A., Yamaguchi R., Morofuji N., Kawahara T., Asaba Y., Mizuno S., Kawai S., Yamamoto H., Ikuta K., Matsubara H., Watanabe T.

    British Journal of Surgery   Vol. 102 ( 4 )   2015.3

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    Background: The aim of the study was to investigate the prognostic impact of lymph node metastasis in cholangiocarcinoma using three different classifications. Methods: Patients who underwent pancreaticoduodenectomy for distal cholangiocarcinoma in 24 hospitals in Japan between 2001 and 2010 were included. Survival was calculated by means of the Kaplan-Meier method and differences between subgroups were assessed with the log rank test. The Cox proportional hazards model was used to identify independent predictors of survival. χ2 scores were calculated to determine the cut-off value of the number of involved nodes, lymph node ratio (LNR) and total lymph node count (TLNC) for discriminating survival. Results: Some 370 patients were included. The median (range) TLNC was 19 (3-59). Nodal metastasis occurred in 157 patients (42.4 per cent); the median (range) number of involved nodes and LNR were 2 (1-19) and 0-11 (0.02-0.80) respectively. Four or more involved nodes was associated with a significantly shorter median survival (1.3 versus 2.2years; P = 0.001), as was a LNR of at least 0.17 (1.4 versus 2.3years; P = 0.002). Involvement of nodes along the common hepatic artery, present in 21 patients (13.4 per cent), was also associated with a shorter survival (median 1.3 versus 2.1years; P = 0.046). Multivariable analysis among 157 node-positive patients identified the number of involved nodes as an independent prognostic factor (risk ratio 1.87; P = 0.002). Conclusion: The number of involved nodes was a strong predictor of survival in patients with distal cholangiocarcinoma.

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  91. In vivo heat-stimulus-triggered osteogenesis. International journal

    Ikuta K, Urakawa H, Kozawa E, Hamada S, Ota T, Kato R, Honda H, Kobayashi T, Ishiguro N, Nishida Y

    Int J Hyperthermia.   Vol. 31 ( 1 ) page: 58 - 66   2015.2

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    Several studies have reported that heat stress stimulates the activity of osteoblastic cells in vitro. However, few have addressed the effects of heat stress on osteogenesis in vivo, nor have the optimal temperatures for bone formation been determined. The aim of the present study was to investigate the effects of hyperthermia treatment on osteogenesis in a rat tibial defect model. Forty-four Sprague Dawley rats were divided into two groups with or without hyperthermia treatment. A 3-mm circular defect in the proximal tibia filled with magnetite cationic liposomes embedded in alginate beads was subjected to hyperthermia treatment (43-46 °C). Radiological assessment at 2 weeks after the treatment showed that significantly stimulated osteogenesis was observed in the hyperthermia group as compared to the control group (p = 0.003). Histomorphometrical analysis at 2 weeks revealed a significant increase of newly formed bone in the hyperthermia group, compared with the control group (p < 0.001). Area of newly formed bone in each hyperthermia group was significantly increased as compared with the control group (43 °C; p = 0.005, 44 °C; p = 0.019, 45 °C; p = 0.003, and 46 °C; p = 0.003, respectively). Alkaline phosphatase was overexpressed at the surfaces of newly formed bone adjacent to magnetite cationic liposome implantation. Our results demonstrate for the first time that heat stimulus accelerates osteogenesis in vivo, and may thus be of interest as a novel and promising tool to induce osteogenesis clinically as well.

    DOI: 10.3109/02656736.2014.988662

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MISC 25

  1. 骨形成促進と腫瘍抑制効果を有する骨転移新規治療法開発に向けた臨床研究-Bench to bedside approach-

    西田佳弘, 西田佳弘, 西田佳弘, 小池宏, 木村浩明, 生田国大, 相羽久輝, 浦川浩, 浦川浩, 酒井智久, 酒井智久, 伊藤鑑, 村上英樹, 今釜史郎

    日本整形外科学会雑誌   Vol. 97 ( 3 )   2023

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  2. 薬物療法の適応と限界1・2 デスモイドに対する薬物治療 Reviewed

    西田佳弘、酒井智久、生田国大、小池 宏、伊藤 鑑、今釜史郎

    日本整形外科学会雑誌   Vol. 96 ( 7 ) page: 488 - 493   2022.7

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  3. 【整形外科画像診断・評価の進歩】MRI 骨肉腫の術前化学療法評価における拡散強調画像の有用性 Reviewed

    西田佳弘、小池 宏、生田国大、酒井智久、伊藤 鑑、今釜史郎

    整形外科   Vol. 73 ( 6 ) page: 601 - 604   2022.5

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  4. 【軟部肉腫の治療update】後腹膜発生軟部肉腫に対する治療戦略 Reviewed

    生田国大、西田佳弘、横山幸弘、酒井智久、小池 宏、今釜史郎

    整形・災害外科   Vol. 65 ( 3 ) page: 289 - 294   2022.3

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  5. デュアルコンセプトの骨転移治療法開発:抗腫瘍と骨形成促進効果

    西田佳弘, 大田剛広, 生田国大, 鈴木喜貴, 小池宏, 相羽久輝, 木村浩明, 酒井智久, 伊藤鑑, 村上英樹, 今釜史郎

    日本整形外科学会雑誌   Vol. 96 ( 6 )   2022

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  6. Tail-like lesionを有する悪性軟部腫瘍に対する術前療法の効果に関する検討-東海骨軟部腫瘍コンソーシアム多施設共同研究-

    相羽久輝, 生田国大, 淺沼邦洋, 河南勝久, 筑紫聡, 松峯昭彦, 石村大輔, 永野昭仁, 紫藤洋二, 小澤英史, 山田健志, 和佐潤志, 木村浩明, 酒井貴央, 村上英樹, 酒井智久, 中村知樹, 西田佳弘

    日本整形外科学会雑誌   Vol. 96 ( 6 )   2022

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  7. 骨・軟部腫瘍のマネジメント(その1) I. 総論 1. 診療体制 癌の遺伝的素因を有する患者に対する診療体制-神経線維腫症1型 Reviewed

    西田佳弘、生田国大、夏目敦至、城所博之、野々部典枝、森川真紀、尾崎紀夫

    別冊整形外科   Vol. 79   page: 13 - 17   2021.4

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  8. 肉腫の外科的治療 骨の再建 自家処理骨-パスツール処理骨- Reviewed

    杉浦英志、生田国大、中島浩敦、西田佳弘

    日本臨床   Vol. 7 ( 増刊5 ) page: 333 - 338   2020.10

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  9. LEDライトによるショートレンジ紫外線照射のvitamin D供給に有効な最小照度の検討 骨粗鬆症治療機器開発に向けての基礎研究

    牧田 和也, 西田 佳弘, 森田 大悟, 樋口 善俊, 関 泰輔, 落合 聡史, 生田 国大, 石黒 直樹

    日本整形外科学会雑誌   Vol. 92 ( 8 ) page: S1669 - S1669   2018.8

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  10. 骨形成促進のための整形外科バイオマテリアル β-TCP配向連通多孔体を用いた骨腫瘍切除後欠損部再建の臨床成績 多施設共同前向き研究

    生田 国大, 大田 剛広, 山田 芳久, 筑紫 聡, 中島 浩敦, 山田 健志, 浦川 浩, 新井 英介, 濱田 俊介, 石黒 直樹, 西田 佳弘

    日本整形外科学会雑誌   Vol. 92 ( 8 ) page: S1932 - S1932   2018.8

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  11. デスモイド型線維腫症におけるMRIの信号強度とCTNNB1遺伝子によるメロキシカム治療反応性の予後予測解析

    清水 光樹, 濱田 俊介, 酒井 智久, 浦川 浩, 新井 英介, 生田 国大, 大田 剛広, 小池 宏, 石黒 直樹, 西田 佳弘

    日本整形外科学会雑誌   Vol. 92 ( 8 ) page: S1737 - S1737   2018.8

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  12. AYA世代高悪性度骨肉腫患者における受診の遅れと予後の検討

    浦川 浩, 新井 英介, 生田 国大, 濱田 俊介, 大田 剛広, 石黒 直樹, 西田 佳弘

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1484 - S1484   2018.6

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  13. 骨転移治療に対する院内コンセンサス形成 当院における骨転移カンファレンスの実際

    浦川 浩, 新井 英介, 満間 綾子, 前田 修, 杉下 美保子, 生田 国大, 濱田 俊介, 大田 剛広, 安藤 雄一, 石黒 直樹, 西田 佳弘

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1509 - S1509   2018.6

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  14. 軟骨芽細胞腫17例の治療成績

    清水 光樹, 西田 佳弘, 浦川 浩, 新井 英介, 生田 国大, 濱田 俊介, 大田 剛広, 酒井 智久, 小池 宏, 石黒 直樹

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1580 - S1580   2018.6

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  15. 色素性絨毛結節性滑膜炎における骨軟骨破壊の発生、進行に関与する因子の検討

    大田 剛広, 西田 佳弘, 杉浦 英志, 山田 健志, 山田 芳久, 浦川 浩, 新井 英介, 生田 国大, 濱田 俊介, 石黒 直樹

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1563 - S1563   2018.6

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  16. 伸長型人工膝関節と健側大腿骨骨端線抑制を併用した大腿骨遠位骨肉腫の1例

    小池 宏, 西田 佳弘, 新井 英介, 浦川 浩, 生田 国大, 濱田 俊介, 大田 剛広, 石黒 直樹

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1493 - S1493   2018.6

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  17. デスモイド型線維腫症の診断におけるCTNNB1変異解析の有用性

    酒井 智久, 西田 佳弘, 濱田 俊介, 清水 光樹, 浦川 浩, 新井 英介, 生田 国大, 大田 剛広, 小池 宏, 石黒 直樹

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1562 - S1562   2018.6

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  18. デスモイド型線維腫症に対する薬物治療における治療予測マーカーとしてのCTNNB1変異解析の役割

    濱田 俊介, 西田 佳弘, 酒井 智久, 浦川 浩, 新井 英介, 生田 国大, 大田 剛広, 石黒 直樹

    日本整形外科学会雑誌   Vol. 92 ( 6 ) page: S1563 - S1563   2018.6

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  19. Clinical outcome of surgical treatment in patients with malignant peripheral nerve sheath tumors

      Vol. 7 ( 1 ) page: 60-63 - 63   2016.4

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    Language:Japanese   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

    Other Link: http://search.jamas.or.jp/link/ui/2016271263

  20. Low-dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors: relationship to CTNNB1 mutation status. Reviewed

    Nishida Y, Tsukushi S, Urakawa H, Hamada S, Kozawa E, Ikuta K, Ando Y, Ishiguro N

    Int J Clin Oncol.   Vol. 20 ( 6 ) page: 1211-7   2015.12

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

    DOI: 10.1007/s10147-015-0829-0.

  21. Expression of colony-stimulating factor 1 is associated with occurrence of osteochondral change in pigmented villonodular synovitis. Reviewed

    Ota T, Urakawa H, Kozawa E, Ikuta K, Hamada S, Tsukushi S, Shimoyama Y, Ishiguro N, Nishida Y

    Tumour Biol.   Vol. 36 ( 7 ) page: 5361-7.   2015.7

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    DOI: 10.1007/s13277-015-3197-5.

  22. Low-dose chemotherapy with methotrexate and vinblastine for Japanese patients with desmoid tumors: Relationship to CTNNB1 mutational status.

    Yoshihiro Nishida, Satoshi Tsukushi, Hiroshi Urakawa, Shunsuke Hamada, Eiji Kozawa, Kunihiro Ikuta, Yuichi Ando, Naoki Ishiguro

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 33 ( 15 )   2015.5

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    Web of Science

  23. Malignant peripheral nerve sheath tumors arising in juveniles

      Vol. 6 ( 1 ) page: 68-71 - 71   2015.4

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    Other Link: http://search.jamas.or.jp/link/ui/2015264855

  24. Postoperative brain metastases in soft tissue sarcomas. Reviewed

    Urakawa H, Tsukushi S, Kozawa E, Ikuta K, Hamada S, Ishiguro N, Nishida Y

    Clin Exp Metastasis.   Vol. 32 ( 4 ) page: 345-51.   2015.4

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    DOI: 10.1007/s10585-015-9713-6.

  25. In vivo heat-stimulus-triggered osteogenesis. Reviewed

    Ikuta K, Urakawa H, Kozawa E, Hamada S, Ota T, Kato R, Honda H, Kobayashi T, Ishiguro N, Nishida Y

    Int J Hyperthermia.   Vol. 31 ( 1 ) page: 58-66.   2015.2

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Presentations 20

  1. Useful reconstruction of the extensor mechanism supplemental with an iliotibial tendon after mega-prosthetic replacement of the proximal tibia (Poster) International conference

    Kunihiro Ikuta1, Yoshihiro Nishida2, Satoshi Tsukushi3, Tomohisa Sakai1, Hiroshi Koike1, Kan Ito1, Shiro Imagama1

    ISOLS 2022 21st general meeting of the International Society of Limb Salvage  2022.9  International Society of Limb Salvage

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    Event date: 2022.9

    Language:English   Presentation type:Poster presentation  

    Venue:Los Angeles   Country:United States  

  2. Clinical outcomes in elderly patients over 80 years with soft tissue sarcomas International conference

    Kunihiro Ikuta1, Yoshihiro Nishida1, Satoshi Tsukushi2, Eiji Kozawa3, Tomohisa Sakai1, Hiroshi Koike1, Kan Ito1, Shiro Imagama1

    ISOLS 2022 21st general meeting of the International Society of Limb Salvage  2022.9.7  International Society of Limb Salvage

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    Event date: 2022.9

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Los Angeles   Country:United States  

  3. 80歳以上の高齢者軟部肉腫の治療成績

    生田 国大, 西田 佳弘, 筑紫 聡, 小澤 英史, 酒井 智久, 小池 宏, 伊藤 鑑, 今釜 史郎

    第55回日本整形外科学会骨・軟部腫瘍学術集会  2022.7  日整会

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    Event date: 2022.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京、WEB  

  4. 専攻医に向けた骨・軟部腫瘍医のキャリアパス

    生田 国大, 西田 佳弘, 酒井 智久, 小池 宏, 伊藤 鑑, 今釜 史郎

    第55回日本整形外科学会骨・軟部腫瘍学術集会  2022.7  日整会

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    Event date: 2022.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京、WEB  

  5. 本邦における悪性末梢神経鞘腫瘍の治療成績 JMOG多施設共同研究による中間報告

    生田 国大, 西田 佳弘, 横尾 賢, 萩 智仁, 鬼頭 宗久, 王谷 英達, 森井 健司, 江森 誠人, 永野 昭仁, 土岐 俊一, 河野 博隆

    第95回日本整形外科学会学術総会  2022.5.21  日整会

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    Event date: 2022.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:神戸  

  6. 主題:治療に難渋する良性骨腫瘍について 腸脛靱帯を用いた脛骨近位腫瘍用人工膝関節置換術後の膝伸展機構再建

    生田 国大, 西田 佳弘, 酒井 智久,小池 宏, 筑紫 聡, 今釜 史郎

    第138回中部日本整形外科災害外科学・学術集会  2022.4.8  中部整形外科災害外科学会

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    Event date: 2022.4

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋  

  7. 神経線線維腫症1型患者における深部発生の結節性神経線維腫の手術成績

    生田 国大, 酒井 智久, 小池 宏, 伊藤 鑑, 今釜 史郎, 西田 佳弘

    第13回日本レックリングハウゼン病学会学術集会  2022.2.20  日本レックリングハウゼン病学会

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    Event date: 2022.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン  

  8. 進行性軟部肉腫に対するパゾパニブによる一次治療の成績

    生田 国大, 西田 佳弘, 酒井 智久, 小池 宏, 今釜 史郎

    第54回日本整形外科学会骨軟部腫瘍学術集会  2021.7.16  日整会

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    Event date: 2021.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:広島   Country:Japan  

  9. シンポジウム 処理骨移植の現状と課題 悪性骨・軟部腫瘍切除後の骨性再建における自家加温処理骨の長期成績

    生田 国大、西田 佳弘、筑紫 聡、山田 健志、小澤 英史、杉浦 英志、今釜 史郎

    第54回日本整形外科学会骨・軟部腫瘍学術総会  2021.7.16  日整会

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    Event date: 2021.7

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:広島  

  10. 下肢原発性悪性骨腫瘍における血管柄付き腓骨移植を併用した加温処理骨再建の中長期成績

    生田 国大, 筑紫 聡, 山田 健志, 小澤 英史, 杉浦 英志, 今釜 史郎, 西田 佳弘

    第94回日本整形外科学会学術総会  2021.5  日整会

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    Event date: 2021.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン   Country:Japan  

  11. 骨腫瘍切除後欠損部に対するβ-TCP配向連通多孔体移植後の臨床成績 多施設前向き共同研究(ポスター)

    生田 国大, 大田 剛広, 筑紫 聡, 小澤 英史, 中島 浩敦, 山田 健志, 今釜 史郎, 西田 佳弘

    第94回日本整形外科学会学術総会  2021.5  日整会

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    Event date: 2021.5

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン   Country:Japan  

  12. 動脈瘤様骨嚢腫変化を伴った線維性骨異形成に対するデノスマブ治療の経験

    生田 国大, 西田 佳弘, 酒井 智久, 小池 宏, 今釜 史郎

    第136回中部日本整形外科災害外科学会学術集会  2021.4  中部日本整形外科災害外科学会

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    Event date: 2021.4

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン  

  13. 神経線維腫による過成長のため四肢長差をきたした小児神経線維腫症1型の治療経験

    生田 国大, 西田 佳弘, 酒井 智久, 小池 宏, 杉浦 喬也, 今釜 史郎

    第12回日本レックリングハウゼン病学会学術大会  2021.2.21  日本レックリングハウゼン病学会

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    Event date: 2021.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン  

  14. β-TCP配向連通多孔体を用いた骨腫瘍切除後欠損部再建:多施設前向き共同研究の中間成績

    生田 国大, 大田 剛広, 筑紫 聡, 小澤 英史, 山田 健志, 中島 浩敦, 濱田 俊介, 細野 幸三, 西田 佳弘

    第35回日本整形外科学会基礎学術集会  2020.10  日整会

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    Event date: 2020.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン   Country:Japan  

  15. 四肢体幹発生の脱分化型脂肪肉腫の臨床学的特徴と治療成績

    生田 国大, 西田 佳弘, 筑紫 聡, 小澤 英史, 浦川 浩, 酒井 智久, 小池 宏, 石黒 直樹

    第53回日本整形外科学会骨・軟部腫瘍学術総会  2020.9  日整会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン   Country:Japan  

  16. 初発時切除不能であった局所進行性悪性末梢神経鞘腫瘍の治療検討

    生田 国大, 筑紫 聡, 西田 佳弘

    第11回日本レックリングハウゼン病学会学術大会  2020.2.9  日本レックリングハウゼン病学会

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    Event date: 2020.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京   Country:Japan  

  17. Surgical Outcomes In Elderly Patients Over 80 Years of age with soft tissue sarcomas International conference

    Kunihiro Ikuta, MD1; Yoshihiro Nishida2; Eiji Kozawa3; Satoshi Tsukushi4; Hiroshi Urakawa1; Eisuke Arai1;Tomohisa Sakai1; Hiroshi Koike1; Naoki Ishiguro1

    The CTOS 2019 Annual Meeting   2019.11  CTOS

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    Event date: 2019.11

    Language:English   Presentation type:Poster presentation  

    Venue:Tokyo   Country:Japan  

  18. 骨腫瘍切除後欠損部におけるβ-TCP配向連通多孔体の適用範囲

    生田 国大, 大田 剛広, 筑紫 聡, 小澤 英史, 中島 浩敦, 山田 健志, 浦川 浩, 新井 英介, 酒井 智久, 石黒 直樹, 西田 佳弘

    第34回⽇本整形外科学会基礎学術集会   2019.10.18  日整会

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    Event date: 2019.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:横浜   Country:Japan  

  19. 神経線維腫症1型診療ネットワークにおける整形外科腫瘍診療

    生田 国大, 西田 佳弘, 夏目 敦至, 城所 博之, 森川 真紀, 野々部 典枝, 尾崎 紀夫

    第52回⽇本整形外科学会⾻・軟部腫瘍学術集会  2019.7.12  日整会

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    Event date: 2019.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:川越   Country:Japan  

  20. 80歳以上の高齢者における軟部肉腫の手術治療成績

    生田 国大, 西田 佳弘, 小澤 英史, 筑紫 聡, 浦川 浩, 新井 英介, 大田 剛広, 酒井 智久, 石黒 直樹

    第92回日本整形外科学会学術総会  2019.5.9  日整会

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    Event date: 2019.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:横浜   Country:Japan  

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Research Project for Joint Research, Competitive Funding, etc. 2

  1. ABC輸送体阻害による抗がん剤増感作用を介した軟部肉腫の新規治療開発

    2022.11 - 2024.3

    公募式研究助成  整形外科学

    生田国大

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    Authorship:Principal investigator 

    Grant amount:\1780000

  2. 骨軟部腫瘍領域における細胞外マトリックスを主体とした細胞外微小環境の制御による新規治療開発の研究

    2021.10 - 2022.3

    第一三共奨学寄付プログラム  がん領域

    生田国大

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    Authorship:Principal investigator  Grant type:Other

    Grant amount:\300000

KAKENHI (Grants-in-Aid for Scientific Research) 13

  1. Fundamental research for the application of effective combination therapy of sarcomatoid kidney cancer to bone and soft tissue sarcoma

    Grant number:23K08696  2023.4 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Authorship:Coinvestigator(s) 

  2. 患者由来組織を用いた神経線維腫に対する新規治療開発:神経線維腫症1型の進行予防

    Grant number:21K09321  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    生田 国大, 西田 佳弘, 酒井 智久, 小池 宏, 伊藤 鑑

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    Authorship:Principal investigator 

    Grant amount:\3770000 ( Direct Cost: \2900000 、 Indirect Cost:\870000 )

    NF1は多発する神経線維腫を特徴とする遺伝性腫瘍症候群である。神経線維腫は疼痛、機能障害、醜状をきたし患者QOLの低下につながるが、保険診療による薬物治療は現状ない。本邦の患者数は4万人であり、神経線維腫に対する薬物治療、予防治療の開発へのニーズは高い。本研究では、NF1患者の神経線維腫に対する実現可能な新規治療法の基盤データの構築を目指す。経年的に増大、増加する全身の神経線維腫に対して、drug repositioning法により既存薬剤から腫瘍抑制効果を有する候補薬剤を同定し、神経線維腫培養細胞における薬効メカニズムの確認とpreclinical modelにおける抗腫瘍効果の評価・検討をおこなう。
    神経線維腫症1型は疼痛、醜状、機能障害をきたしうる神経線維腫が多発性に生じることを特徴とする遺伝性腫瘍症候群である。神経線維腫は全身のあらゆる部位に発生し、その数・大きさが経年的に増加する。これらは患者Quality of life の低下につながるが、悪性腫瘍ではないために研究開発の対象となりにくく、現在まで保険診療による薬物治療はない。一方、本邦の患者数は4万人であり、手術切除以外に治療選択のない神経線維腫に対する薬物治療・予防治療の開発へのニーズは非常に高い。本研究では、神経線維腫症1型患者に発生する神経線維腫に対する実現可能な新規治療法の基盤データの構築を目指す。研究実績として、令和3年度は主にPDXマウスモデル作製に注力した。令和3年度に神経線維腫の切除術を受けた神経線維腫症1型患者から採取した腫瘍組織を断片化して重症免疫不全マウスに異種移植した。一般に軟部肉腫のPDXモデルは生着達成の判断までに数ヶ月かかることも稀ではなく、良性腫瘍である神経線維腫は増殖速度も遅く生着率もよくないことがわかった。そのため、現状はPDXモデル確立に難渋しており、生着が向上するための工夫を試みている。Drug repositioning法をはじめ、in vitro実験は神経線維腫の培養細胞の継代が安定することが必須である。現状では神経線維腫細胞は継代早期に形態変化をきたし実験すべきタイミングと細胞量が見合わないため、in vitro実験を開始できていない。
    神経線維腫は良性であるため、継代による培養細胞の老化、膨化が著しい。研究対象とできる継代が限られており、冷凍保管後の発育も不良であるため実験効率が悪い。培養液や保管条件(保管mediumの変更や温度条件設定)について見直す必要がある。研究立案時は3系統の培養細胞の確立を目指していたが、より多くの対象患者を要する見込みである。同様の理由でPDXモデルの生着にも難渋している。これらの理由により、令和3年度の研究進捗は遅れている。
    培養細胞の安定した継代の条件を確立して、体系的なin vitro実験を実施できるよう務める。PDXモデルについては、重症免疫マウスよりも生着率が見込める系統のマウスへの移植を試す。移植の際の基材としてのゲルが課題となると考えている。令和4年度における進行具合では、市販で入手できる細胞株を購入してin vitro実験を選考していくことも検討するが、臨床情報が揃う自施設での培養細胞継代の安定化をしばらくは優先していく。

  3. 細胞外マトリックス制御による悪性末梢神経鞘腫瘍に対する新規治療

    Grant number:19K16769  2019.4 - 2023.3

    科学研究費助成事業  若手研究

    生田 国大

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    Authorship:Principal investigator 

    Grant amount:\2860000 ( Direct Cost: \2200000 、 Indirect Cost:\660000 )

    本研究の目的は、MPNSTにおいて4-MUによる抗がん薬の抗腫瘍効果の増強作用について明らかにすることである。さらに、既存の抗がん薬の中から最も有望な薬剤を抽出して臨床使用に向けてのデータを蓄積することである。4-MUは利胆剤として臨床使用されており、本研究により有用なデータが得られれば早期に実現可能な治療法であると考えられる。実現可能な治療戦略の開発として本研究を行うことにより、MPNST患者の治療成績向上につなげられる。また、正常組織である細胞微小環境を制御する新規治療法の開発は、MPNSTだけでなく他のがん治療への応用も期待できる。
    悪性末梢神経鞘腫瘍(MPNST)は化学療法や通常の放射線の治療効果が不十分であり、その標準治療は手術治療のみである。多くの新規抗がん剤や標的治療が開発されている現在でも、MPNSTに対して有効な新規薬剤の情報はない。本研究の目的は、MPNSTにおいてヒアルロン酸合成阻害剤である4-methylumbelliferone(4-MU)による既存抗がん薬の抗腫瘍効果の増強作用を評価することで、実現可能な治療戦略を開発することである。研究実績として、令和元年度は主にin vitro実験を中心に進めた。ヒトMPNST細胞株(sNF96.2、sNF02.2)を用いて、4-MU 投与下における腫瘍細胞周囲および細胞内ヒアルロン酸の評価について、particle exclusion assay にて細胞周囲マトリクスの可視化、ELISA にて細胞内/細胞周囲/培養液中のヒアルロン酸濃度測定をおこなった。ヒアルロン酸合成酵素(HAS1-3)とヒアルロン酸受容体CD44 発現についてペルオキシダーゼ標識した抗体による細胞免疫染色とmRNA 解析にて評価した。さらに、HAS1-3 とCD44 のsiRNA によるknockdown 条件下において、腫瘍原性がどう変化するか観察するためにMTS assay、invasion assay、migration assay により評価した。また、臨床検体でのvalidityを評価するために、MPNST患者の腫瘍組織を採取して培養、継代をおこない細胞株を樹立した。令和2年度は、樹立した細胞株について同様に、上記アッセイ、解析をおこなった。令和3年度は、ヒトMPNST細胞株による皮下移植マウスモデルの作製と生存解析、および移植腫瘍を用いたex vivo実験を実施した。患者から採取した腫瘍検体によるPDXマウスモデルの作製も試みた。
    4-MUの抗腫瘍効果について、ヒトMPNST細胞株を用いた皮下移植マウスモデル作製(in vivo)は難渋したが達成できている。In vitroにおける抗がん薬の選定が済んでいないため、当面はヒトMPNST細胞株における各種抗がん薬のアッセイが優先される。MTTアッセイやアポトーシス活性をはじめとするin vitro実験では、ヒトMPNST細胞に対するダメージが臨床血中濃度を用いた場合に強く出てしまい、各種抗がん薬間の有意差を抽出できなかった。まずは細胞株に対する抗がん薬の至適濃度を同定することが急がれる。COVID19のパンデミックによる動物や試薬の納入が遅れたことで実験の進捗に影響がでた時期もあった。令和2年以降は研究代表者がCOVID診療応援の増加により、通常診療に加えて臨床業務に従事する時間が大幅に増えた。そのため、特定の研究日がなくなり現在も基礎研究に費やすエフォートは減少している。
    有望な候補薬を抽出後に、薬剤輸送体に対する4-MU の作用の解析をin vitroでおこなう。MPNST 細胞株において、膜蛋白に存在する薬剤輸送体MDR1、MRP1、BCRPのmRNA と蛋白発現を評価する。各輸送体の抗体を用いて細胞免疫染色をおこない、抗がん薬および4-MU 投与による発現変化について評価する。抗がん薬および4-MU 投与による各輸送体のmRNAと蛋白量の変化について、リアルタイムPCR、ウェスタンブロッティングにより解析する。MPNST異種移植マウスモデルにおける腫瘍原性の評価 (in vivo)について、抗がん薬と4-MU 併用群、4-MU 投与群、抗がん薬投与群、コントロール群(vehicle)を作製し、各群における抗腫瘍効果、遠隔転移抑制、生存率曲線による生命予後を解析する。抗腫瘍効果については腫瘍重量および肺転移数の解析により局所および遠隔転移に対する効果を評価する。Ex vivo実験として、各群の異種移植腫瘍におけるヒアルロン酸、ヒアルロン酸合成酵素(HAS1-3)、薬剤輸送体蛋白発現を組織染色およびELISA(ヒアルロン酸)、mRNA(HAS1-3、薬剤輸送体蛋白)、ウェスタンブロッティング(薬剤輸送体蛋白)を評価、比較する。

  4. Fundamental research for treatment of age-associated diseases using deep-ultraviolet light emitting diode

    Grant number:17K19903  2017.6 - 2020.3

    Grant-in-Aid for Challenging Research (Exploratory)

    Nishida Yoshihiro

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    Authorship:Coinvestigator(s) 

    It was revealed that an LED device capable of irradiating a specific wavelength of deep ultraviolet light significantly increases blood 25 (OH) D value at a wavelength (315 nm) without side effects. The minimum illuminance / irradiation dose conditions that significantly increase blood 25 (OH) D levels (twice a week, 0.16 mW / cm2 irradiation irradiance, 1 kJ / m2 irradiation dose) were determined, and aged model mice ( Using SAM-P6 mice), we confirmed an increase in Trabecular bone mineral density and confirmed that osteoclast induction was suppressed. By using wavelength-limited LED irradiation, we were able to obtain a non-clinical POC, which is a new treatment for osteoporosis and sarcopenia.

  5. Study of novel tumor immunotherapy by modulating extracellular matrix of advanced bone and soft tissue sarcoma

    Grant number:17K10963  2017.4 - 2020.3

    URAKAWA HIROSHI

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    Authorship:Coinvestigator(s) 

    To clarify the relationship between tumor immunity and extracellular matrix / receptor / intracellular signal network mediated by hyaluronan and to establish new immunotherapy targeting in bone and soft tissue sarcoma, we evaluated the relationship between immune checkpoint molecules and hyaluronan network in bone and soft tissue sarcoma. Abundant extracellular matrix was observed in bone and soft tissue sarcoma cells, and a certain relationship between extracellular matrix/ receptor / intracellular signal network and immune checkpoint molecules was observed. Abundant expression of hyaluronan was observed in bone and soft tissue sarcoma tumor tissue, and the immune cell infiltration and immune checkpoint molecule expression were observed in certain type of sarcomas.

  6. The role of cathepsin K in the bone and lung metastases

    Grant number:15K10438  2015.4 - 2018.3

    KOZAWA EIJI

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    Authorship:Coinvestigator(s) 

    CatK synthesized by osteoclasts and/or tumor cells, tumor microenvironmental macrophage/fibroblasts to be an obvious candidate for a key enzyme involved in the destruction of bone matrix. To establish a murine bone metastasis model, a needle with syringe was used to inject MDA-MB-231 cells and Lewis lung cancer cells into the tibia of mice. Osteolytic lesions progressed markedly at tibia of mice. Scion image analysis revealed that the size of the osteolytic increased from 2 to 4 weeks. The expansion of bone lytic areas of tibia with Lewis lung cancer progressed rapidly for 2 weeks. Histological stain for bone tumor was performed.
    The sample included 50 patients with lung tumors and 19 patients with musculoskeletal tumors. The overall 5-year survival rate of the patients was 57.7%. Pre-operative MRI evaluation is helpful to determine whether tumors should be resected with adjacent bone or not.

  7. Antitumor effects of 4-Methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor

    Grant number:15K19992  2015.4 - 2018.3

    Ikuta Kunihiro

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    Authorship:Principal investigator 

    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    Hyaluronan (HA) has been shown to play important roles in the growth, invasion, and metastasis of malignant tumors. Our previous study showing that high HA expression in malignant peripheral nerve sheath tumors (MPNST) is predictive of poor patient prognosis. The aim of this study was to investigate the antitumor effects of 4-Methylumbelliferone (MU), an HA synthesis inhibitor, on human MPNST cells and tissues.MU significantly inhibited cell proliferation, migration, and invasion in both MPNST cell lines. HABP staining, particle exclusion assay, and quantification of HA revealed that MU significantly decreased HA accumulation in the cytoplasms and pericellular matrices in both MPNST cell lines.MU administration significantly inhibited the tumor growth in the mouse xenograft model. Our results suggest that MU may be a promising agent with novel antitumor mechanisms for MPNST.

  8. Establishment of bone metastasis treatment by regulating hyaluronan network and osteoclast

    Grant number:26462261  2014.4 - 2018.3

    Urakawa Hiroshi

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    Authorship:Coinvestigator(s) 

    Bone metastases impair the quality of patients with malignancies. We focused on the co-effect of regulation of hyaluronan (HA) and bone modifying agents. We investigated the effects of 4-methylumbelliferone (MU) and/or bone modifying agents on HA expression in breast and lung cancer cell lines in addition to their tumorigenicity in vitro and in vivo. MU or zoledronic acid treatment individually suppressed proliferation, migration and invasion of breast and lung cancer cell lines, and combination treatment of MU and zoledronic acid showed synergistic effects. Combination therapy showed additive inhibitory effects on metastatic bone lesions in vivo, which paralleled the inhibition of HA accumulation by MU, and inhibition of osteoclastogenesis. These data suggest that inhibition of HA synthesis is a promising novel therapeutic candidate for bone metastasis in addition to bone modifying agents.

  9. Image-guided cryoablation for palliative therapy of skeletal metastases.

    Grant number:26462260  2014.4 - 2018.3

    Tsukushi Satoshi

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    Authorship:Coinvestigator(s) 

    The aim of this study was to investigate local control of in non-small round cell soft tissue sarcomas.The overall survival rates at 5 years were 85.7%.The local recurrence-free survival rates at 5 years were 89.8% (positive margin: 72.5%, margin of 2 mm or less: 60.6%). In the univariate analysis size, depth, histological grade and positive margin were significant unfavorable prognostic factors for local recurrence free survival. In multivariate analyses, we showed that positive margin and histological grade were significant independent predictors of local recurrence free survival.Positive margin and histological grade were important prognostic factors for local recurrence. Close margin (2 mm or less) in the longitudinal direction was associated with a high risk of local recurrence.The reach of the local treatment should be decided based on these factors.

  10. Establishment of a novel method for heat-stimulus induced osteogenesis using magnetite nanoparticles

    Grant number:26670659  2014.4 - 2017.3

    Yoshihiro Nishida

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    Authorship:Coinvestigator(s) 

    New bone formation was significantly increased by hyperthermia using magnetite cationic liposome embedded in alginate beads with an alternating magnetic field (AMF) in a rat tibial defect model. Heating materials were changed to Resovist containing ferucarbotoran and hydroxyapatite scaffold, which have been already approved in clinical use in Japan. Combination materials were grafted in tibial defect of rat and rabbit and subjected to the multiple hyperthermia in AMF. Results demonstrated that newly formed bone was observed in the grafted materials from the periphery toward the center, and more osteoclasts were found in the once a week hyperthermia group compared with non-hyperthermia group.
    Experiments of hyperthermia were performed in vitro using ATDC-5 and MC3T3 cells. Heat stress also induced enhanced alkaline phosphatase expression in cultured osteoblastic cells, MC3T3. On the other hand, heat stress had no obvious effects on chondrogenic differentiation using ATDC5 cells.

  11. Mutaion analysis for desmoid type fibromatosis and research for the establishment of a novel treatment algorithm

    Grant number:26293334  2014.4 - 2017.3

    Nishida Yoshihiro

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    Authorship:Coinvestigator(s) 

    CTNNB1 analyses were achieved in over 70 cases with pathologically diagnosed as desmoid-type fibromatosis (DF). Mutational status was 41A, 45F and 45P in order of descending prevalence. Relationship between CTNNB1 mutation analysis and clinical outcome of meloxicam or simple resection was determined. Based on the results of these studies, three English papers were accepted. According to the evidence of these study, treatment algorithm was established and approved by Japanese Orthopaedic Association. This algorithm is used for establishment of clinical care guideline for DF. Genome wide association study revealed that gene X is related to the clinical outcome of low dose chemotherapy for DF. APC deficient mice is obtained and subjected to the experiment for DF-development model.

  12. The role of Cathepsin K in bone metastasis and tumor progression

    Grant number:25861304  2013.4 - 2016.3

    KOZAWA Eiji

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    Authorship:Other 

    CatK synthesized by osteoclasts and/or tumor cells, tumor microenvironmental macrophage/ fibroblasts to be an obvious candidate for a key enzyme involved in the destruction of bone matrix.
    To establish a murine bone metastasis model, a needle with syringe was used to inject MDA-MB-231 cells and Lewis lung cancer cells into the tibia of mice. Osteolytic lesions progressed markedly at tibia of mice. Scion image analysis revealed that the size of the osteolytic increased from 2 to 4 weeks. The expansion of bone lytic areas of tibia with Lewis lung cancer progressed rapidly for 2 weeks. Histological stain for bone tumor was performed.
    To investigate the expression of Cathepsins, histological stain was performed on human cartilage and synovium. Increased expression of CatK in human OA cartilages/chondrocytes an synovial cells, compared with control cartilages/chondrocytes and synovial cells. Moreover, enzymatically activated CatK was also upregulated in OA chondrocytes.

  13. Research for a sensitizer of molecular targeted therapy by a regulation of extra-cellular matrix in bone and soft tissue sarcomas

    Grant number:24791533  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    URAKAWA Hiroshi, NISHIDA Yoshihiro, KOZAWA Eiji, IKUTA Kunihiro, HAMADA Shunsuke

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    Hyaluronan (HA) is known to have pivotal roles in the growth, migration and invasion of malignant tumors. We initially investigated the prognostic value of HA in patients with malignant peripheral nerve sheath tumors (MPNST). In multivariate analysis, large tumor size was an independent prognostic factor for overall survival, and HA expression and tumor size were independent prognostic factors for disease-free survival. We also investigated the effects of 4-Methylumbelliferone (MU) on bone and soft tissue sarcoma cell lines. MU treatment inhibited extra-cellular matrix, HA accumulation, cell growth, cell motility, and cell invasiveness. In vivo, administration of MU inhibited the tumor growth in isograft models of Rat chondrosarcoma cells. These data suggest that MU might be a therapeutic candidate for sarcomas via suppression of HA synthesis and accumulation. HA-targeting therapy may have potential as a sensitizer of molecular targeted therapy.

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