2023/04/17 更新

写真a

サカイ トモヒサ
酒井 智久
SAKAI Tomohisa
所属
医学部附属病院 希少がんセンター 病院助教
職名
病院助教

学位 1

  1. 医学博士 ( 名古屋大学 ) 

 

論文 44

  1. Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression via BMP signaling.

    Mori N, Esaki N, Shimoyama Y, Shiraki Y, Asai N, Sakai T, Nishida Y, Takahashi M, Enomoto A, Mii S

    Pathology, research and practice   245 巻   頁: 154443   2023年4月

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    記述言語:英語  

    DOI: 10.1016/j.prp.2023.154443

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  2. Hyaluronan in articular cartilage: Analysis of hip osteoarthritis and osteonecrosis of femoral head

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

    JOURNAL OF ORTHOPAEDIC RESEARCH   41 巻 ( 2 ) 頁: 307 - 315   2023年2月

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    記述言語:英語   出版者・発行元:Journal of Orthopaedic Research  

    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.

    DOI: 10.1002/jor.25364

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  3. Case report: Novel NIPBL-BEND2 fusion gene identified in osteoblastoma-like phosphaturic mesenchymal tumor of the fibula

    Sakai Tomohisa, Okuno Yusuke, Murakami Norihiro, Shimoyama Yoshie, Imagama Shiro, Nishida Yoshihiro

    FRONTIERS IN ONCOLOGY   12 巻   頁: 956472   2023年1月

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    記述言語:英語   出版者・発行元:Frontiers in Oncology  

    Phosphaturic mesenchymal tumor (PMT) is a rare tumor that secretes fibroblast growth factor 23 (FGF23) and causes hypophosphatemia and tumor-induced osteomalacia (TIO). Fusion genes FN1-FGFR1 and FN1-FGF1 have been detected in some PMTs, but the pathogenesis of PMTs without these fusion genes remains unclear. Here, we report a 12-year-old boy with persistent muscle weakness and gait disturbance. Roentgenographic examination revealed a radiolucent lesion with endosteal scalloping in the left fibula, while his serum level of FGF23 was markedly increased. Combined with simple X-ray findings of other body parts, we suspected that TIO was caused by PMT, and resected the tumor. After resection, the serum level of FGF23 started to decrease immediately and normalized within 3 hours after resection, with this being earlier than normalization of the serum phosphorus level. In RNA sequencing, FN1-FGFR1 and FN1-FGF1 were not detected, but a novel NIPBL-BEND2 fusion gene was identified. When we forcedly expressed this fusion gene in HEK293T cells and MG63 cells, cell proliferation was enhanced in both cell lines. Furthermore, Gene set enrichment analysis of HEK293T cells showed significant upregulation of MYC-target genes. Our results suggest that this novel NIPBL-BEND2 fusion gene promotes cell proliferation possibly via the MYC pathway and might be one of the etiologies of PMTs other than FN1-FGFR1 or FN1-FGF1.

    DOI: 10.3389/fonc.2022.956472

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

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

    CANCER MEDICINE   12 巻 ( 5 ) 頁: 5245 - 5254   2022年10月

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    記述言語:英語   出版者・発行元:Cancer Medicine  

    Background: The treatment of choice for desmoid-type fibromatosis (DF) has been changed to active surveillance (AS). However, few studies have reported clinical outcomes of AS modality in Asian countries. This study aimed to clarify the significance of AS as a DF treatment modality. Methods: A total of 168 lesions from 162 patients with extra-abdominal DF were included. The mean age at diagnosis was 39 years (1–88 years), and the median maximum tumor diameter at the first visit was 64.1 mm (13.2–255.8 mm). The clinical outcomes of AS and the risk factors requiring active treatment (AT) (defined as an event) from AS modality were investigated. Results: Of the 168 lesions, 94 (56%) were able to continue AS, with a 5-year event-free survival of 54.8%. Of the 68 lesions with PD, 21 (30.9%) lesions were able to continue AS. Neck location (p = 0.043) and CTNNB1 S45F mutation (p = 0.003) were significantly associated with the transition to AT, and S45F mutation was a significant factor associated with the transition to AT by multivariate analysis (hazard ratio: 1.96, p = 0.048). AT outcomes after AS were evaluable in 65 lesions, and 49 (75%) lesions did not require a transition to a second AT. Conclusions: AS was revealed as an effective treatment modality. The transition to AT needs to be considered for neck location and CTNNB1 S45F mutation DF. Good results can be obtained by selecting a treatment method that considers the tumor location even in cases that require intervention.

    DOI: 10.1002/cam4.5329

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

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

    JOURNAL OF CLINICAL MEDICINE   11 巻 ( 19 )   2022年10月

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    記述言語:英語   出版者・発行元:Journal of Clinical Medicine  

    Background: Nodular plexiform neurofibromas in individuals with neurofibromatosis type 1 often cause significant symptoms and are treated with surgical excision despite the potential risk of complications. This study aimed to clarify the surgical outcomes of deep-seated nodular plexiform neurofibromas and identify the factors associated with postoperative complications. Methods: We retrospectively reviewed patients with neurofibromatosis type 1 who underwent surgical excision for deep-seated nodular plexiform neurofibromas in our hospital from 2015 to 2021. Enucleation while preserving the nerve fascicles was attempted first, and en bloc resection, ligating the nerve origin in cases in which the parent nerve was entrapped by the tumor, making the tumor difficult to dissect, was performed. Results: In 15 patients, 24 nodular plexiform neurofibromas received surgical excision. Sixteen tumors were enucleated, and eight were en bloc resected. The symptoms of all 10 patients with preoperative symptoms resolved after surgery. Four patients developed new neurological deficits immediately after surgery, two of whom had retained neurological symptoms at the last visit, but these symptoms were mild. Conclusions: The present study demonstrates that surgical treatment of nodular plexiform neurofibromas, even deep-seated neurofibromas, is safe with a low risk of severe complications and improvement in preoperative symptoms.

    DOI: 10.3390/jcm11195695

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  6. Efficacy of auranofin as an inhibitor of desmoid progression

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

    SCIENTIFIC REPORTS   12 巻 ( 1 ) 頁: 11918   2022年7月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    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.

    DOI: 10.1038/s41598-022-15756-9

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

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

    WORLD NEUROSURGERY   157 巻   頁: E207 - E214   2022年1月

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    記述言語:英語   出版者・発行元:World Neurosurgery  

    Objective: In patients with neurofibromatosis type 1 (NF1), it is important to accurately determine when plexiform neurofibroma (pNF) transforms to a malignant peripheral nerve sheath tumor (MPNST). The purpose of this study is to investigate the usefulness of diffusion-weighted imaging (DWI) in differentiating pNF and MPNST in NF1 patients. Methods: Among the NF1 patients who were referred to our hospital between 1985 and 2015, 10 cases of MPNST and 19 cases of pNF were included. We evaluated features of standard magnetic resonance imaging according to the differentiation criteria of malignancy from benignancy as previously reported, apparent diffusion coefficient (ADC) value based on the DWI and the correlation between ADC value and benignancy/malignancy. ROC analysis was performed to determine the appropriate cutoff value of ADC. Results: There were significant differences between MPNST and pNF in the size of the tumor (P = 0.009), peripheral enhancement pattern (P = 0.002), perilesional edema-like zone (P = 0.0008), and intratumoral cystic change (P = 0.02). The mean and minimum values of ADC were significantly lower in MPNST than those in pNF (P = 0.03 and P = 0.003, respectively). When we set a cutoff value of mean ADC as 1.85 × 10–3 mm2/s, the sensitivity and specificity were 80% and 74%, respectively. The area under the curve value improved by adding the Wasa score to the mean ADC evaluation. Conclusions: ADC values determined by DWI are useful in differentiating MPNST from pNF and adding ADC evaluation to standard MRI evaluation improved the diagnostic accuracy.

    DOI: 10.1016/j.wneu.2021.09.130

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  8. 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   100 巻 ( 49 ) 頁: e28138   2021年12月

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    記述言語:英語   出版者・発行元: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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  9. Reconstruction of the extensor mechanism augmented with reverse transferred iliotibial band after proximal tibia tumor resection and mega-prosthetic replacement

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

    KNEE   33 巻   頁: 102 - 109   2021年12月

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    記述言語:英語   出版者・発行元:Knee  

    Background: The optimal procedure for functional reconstruction of the extensor mechanism after proximal tibia mega-prosthetic replacement remains unclear. Methods: Since 2006, 14 consecutive patients with aggressive bone tumors in the proximal tibia who underwent mega-prosthetic replacement were prospectively treated with reconstruction of the extensor mechanism using an ipsilateral iliotibial band. The surgical procedure consisted of wrapping the reversed iliotibial band around the tibia component, firmly suturing it to the remaining patellar tendon and tibialis anterior fascia, and covering it with a muscle flap. At the last follow up, the function was assessed based on extensor lag, active flexion of the knee, and Musculoskeletal Tumor Society score. Patellar height was measured with the Insall–Salvati ratio (ISR) preoperatively, postoperatively, and at the last follow up. Results: At the last follow up, the extensor lag and active flexion in 14 patients averaged 2.5° and 86°, respectively. Musculoskeletal Tumor Society score could be obtained in nine surviving patients at the last follow up and was a mean of 20.7 points. The mean ISR preoperatively, postoperatively, and at the last follow up was 1.04, 0.75, and 0.89, respectively. The extensor lag was not associated with the ISR value at any points, while reduced active flexion significantly correlated with a low ISR at the last follow up (P = 0.015). Four patients underwent additional surgeries due to postoperative infection, but none required eventual revision or amputation. Conclusion: The extensor mechanism reconstruction with the reverse transferred iliotibial band for mega-prosthetic replacement after proximal tibia resection yielded reliable outcomes with functional benefit to stabilize active knee extension.

    DOI: 10.1016/j.knee.2021.09.006

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  10. Trends in diagnostic and therapeutic strategies for extra-abdominal desmoid-type fibromatosis: Japanese musculoskeletal oncology group questionnaire survey

    Murase Fuminori, Nishida Yoshihiro, Hamada Shunsuke, Sakai Tomohisa, Shimizu Koki, Ueda Takafumi

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   51 巻 ( 11 ) 頁: 1615 - 1621   2021年11月

  11. Diffusion-weighted magnetic resonance imaging improves the accuracy of differentiation of benign from malignant peripheral nerve sheath tumors. 査読有り

    Koike H, Nishida Y, Ito S, Shimoyama Y, Ikuta K, Urakawa H, Sakai T, Shimizu K, Ito K, Imagama S.

    World Neurosurg.   S1878-8750 巻 ( 21 ) 頁: 01483-2 - 01483-2   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  12. Reconstruction of the extensor mechanism augmented with reverse transferred iliotibial band after proximal tibia tumor resection and mega-prosthetic replacement. 査読有り

    Ikuta K, Nishida Y, Tsukushi S, Sakai T, Koike H, Imagama S.

    Knee.   33 巻   頁: 102 - 109   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  13. Less-invasive fascia-preserving surgery for abdominal wall desmoid. 査読有り

    Nishida Y, Hamada S, Sakai T, Ito K, Ikuta K, Urakawa H, Koike H, Imagama S.

    Sci Rep.   11 巻 ( 1 ) 頁: 19379 - 19379   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  14. Less-invasive fascia-preserving surgery for abdominal wall desmoid

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

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 19379   2021年9月

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    記述言語:英語   出版者・発行元:Scientific Reports  

    The mainstay of treatment for desmoid has been shifted to active surveillance (AS). However, surgery is still being performed on abdominal wall desmoid with a wide surgical margin. The purposes of this study are to clarify the treatment results of less-invasive, fascia preserving surgery for patients with abdominal wall desmoid, and to propose a new treatment modality. Since 2009, 34 patients with abdominal desmoid have been treated in our institution. Among them, as a final treatment modality, 15 (44%) were successful with AS, 15 were subjected to less-invasive surgery, and 4 methotrexate and vinblastine treatment. The clinical results of less-invasive surgery were clarified. In the surgical group, although the surgical margin was all microscopic positive (R1), only one patient (6.7%), who has the S45F mutation type of CTNNB1, showed recurrence, at a mean follow-up of 45 months. There were no patients with familial adenomatous polyposis (FAP)-related desmoid in this cohort. Only two patients (13%) required fascia lata patch reconstruction after removal of the tumor. In patients with non FAP-related abdominal wall desmoid, less-invasive, fascia preserving surgery is recommended as a favorable option as active treatment. Based on the results of this study, multi-institutional further research is warranted with an increased number of patients.

    DOI: 10.1038/s41598-021-98775-2

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  15. Trends in diagnostic and therapeutic strategies for extra-abdominal desmoid-type fibromatosis: Japanese musculoskeletal oncology group questionnaire survey. 査読有り

    Murase F, Nishida Y, Hamada S, Sakai T, Shimizu K, Ueda T.

    Jpn J Clin Oncol.     頁: hyab146. - hyab146.   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  16. Spontaneous Regression of Brown Tumor in a Patient Treated With Peritoneal Dialysis. 査読有り

    Ito K, Ikuta K, Nishida Y, Sakai T, Imagama S.

    Cureus.   13 巻 ( 8 ) 頁: el17078 - el17078   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

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

    CUREUS   13 巻 ( 8 ) 頁: e17078   2021年8月

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  18. Effect of Neoadjuvant Therapies on Soft Tissue Sarcomas with Tail-like Lesions: A Multicenter Retrospective Study. 査読有り

    Aiba H, Ikuta K, Asanuma K, Kawanami K, Tsukushi S, Matsumine A, Ishimura D, Nagano A, Shido Y, Kozawa E, Yamada K, Wasa J, Kimura H, Sakai T, Murakami H, Sakai T, Nakamura T, Nishida Y.

    Cancers (Basel).   13 巻 ( 15 ) 頁: 3901 - 3901   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

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

    CANCERS   13 巻 ( 15 )   2021年8月

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    記述言語:英語   出版者・発行元:Cancers  

    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.

    DOI: 10.3390/cancers13153901

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  20. Overexpression of KIAA1199, a novel strong hyaluronidase, is a poor prognostic factor in patients with osteosarcoma. 査読有り

    Ito K, Nishida Y, Ikuta K, Urakawa H, Koike H, Sakai T, Zhang J, Shimoyama Y, Imagama S.

    J Orthop Surg Res.   16 巻 ( 1 ) 頁: 439 - 439   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

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

    JOURNAL OF ORTHOPAEDIC SURGERY AND RESEARCH   16 巻 ( 1 ) 頁: 439   2021年7月

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    記述言語:英語   出版者・発行元:Journal of Orthopaedic Surgery and Research  

    Background: Hyaluronan (HA) has been shown to play important roles in the growth, invasion, and metastasis of malignant tumors. KIAA1199, which has potent HA-degrading activity, has been reported to be expressed in various malignancies and associated with patient prognosis. However, there are no reports on the expression of KIAA1199 in osteosarcoma. The aim of this study was to investigate the impact of KIAA1199 and HA expression in osteosarcoma tissues on the prognosis and other clinical characteristics of osteosarcoma patients. Methods: From 2003 to 2013, we included 49 patients with osteosarcoma at our institution, whose FFPE (formalin fixed paraffin embedded) tissue was available at the time of biopsy. The expressions of KIAA1199 and HA in each sample were assessed by immunohistochemistry using the primary antibody for KIAA1199 and HA-binding protein (HABP), respectively. For evaluation of the positivity of KIAA1199 staining, we divided the samples into two groups: High group with more than 75% positive staining and Low group with less than 75% positive staining. In the HABP staining, those with more than and less than 60% were assigned to a High group, and Low group respectively. Various clinical features were correlated with staining positivity. Prognostic factors including positivity of the staining were analyzed. Levels of mRNA expression for enzymes related to HA metabolism were assessed in two osteosarcoma cell lines using real-time RT-PCR. Results: In KIAA1199 staining, high positivity was significantly correlated with occurrence of distant metastases (P = 0.002). The necrosis rate after preoperative chemotherapy was significantly lower in the High positivity group (59%), compared to that in the Low group (84.8%) (P = 0.003). HABP positivity was not correlated with any demographic variables, although the Low positivity group had a significantly better overall survival than the High group with KIAA1199 and HABP staining (P = 0.026 and P = 0.029, respectively). In multivariable analysis, KIAA1199 (P = 0.036) and HABP staining (P = 0.002), location (P = 0.001), and distant metastasis at initial diagnosis (P < 0.001) were identified as significant prognostic factors. KIAA1199 and hyaluronan synthase mRNA were expressed at different levels in the two osteosarcoma cell lines. Conclusions: Our results showed that high expression of KIAA1199 and HA are both poor prognostic factors in osteosarcoma. KIAA1199 may be a useful marker for distant metastasis and chemoresistance.

    DOI: 10.1186/s13018-021-02590-4

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  22. 【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 査読有り

    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   ( 79 ) 頁: 55 - 57   2021年4月

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    担当区分:筆頭著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

  23. Comprehensive molecular and clinicopathological profiling of desmoid tumours

    Kohsaka Shinji, Hirata Makoto, Ikegami Masachika, Ueno Toshihide, Kojima Shinya, Sakai Tomohisa, Ito Kan, Naka Norifumi, Ogura Koichi, Kawai Akira, Iwata Shintaro, Okuma Tomotake, Yonemoto Tsukasa, Kobayashi Hiroshi, Suehara Yoshiyuki, Hiraga Hiroaki, Kawamoto Teruya, Motoi Toru, Oda Yoshinao, Matsubara Daisuke, Matsuda Koichi, Nishida Yoshihiro, Mano Hiroyuki

    EUROPEAN JOURNAL OF CANCER   145 巻   頁: 109 - 120   2021年3月

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    記述言語:英語   出版者・発行元:European Journal of Cancer  

    Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56–94.2; p = 8.0 × 106). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.

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  24. Limitations and benefits of FDG-PET/CT in NF1 patients with nerve sheath tumors: A cross-sectional/longitudinal study. 査読有り

    Nishida Y, Ikuta K, Ito S, Urakawa H, Sakai T, Koike H, Ito K, Imagama S.

    Cancer Sci.   112 巻 ( 3 ) 頁: 1114 - 1122   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.14802.

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

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

    CANCER SCIENCE   112 巻 ( 3 ) 頁: 1114 - 1122   2021年3月

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    記述言語:英語   出版者・発行元:Cancer Science  

    The purposes of this study were to re-confirm the usefulness of PET/CT in the differentiation of benignity/malignancy of neurogenic tumors in NF1 patients, and to analyze the natural course of plexiform neurofibroma (pNF) and clarify whether PET/CT is also useful for detecting tumors other than neurogenic tumors. PET/CT was prospectively imaged in 36 NF1 patients. There were 14 malignant peripheral nerve sheath tumors (MPNSTs) in 14 patients, and 54 pNFs in 30 patients. Nine patients had both MPNST and pNF. Maximal standardized uptake value (SUVmax) was significantly higher in MPNST (median 7.6: range 4.1-10.4) (P <.001) compared with that of pNF (median 3.7: range 1.6-9.3). The cut-off value of 5.8 resulted in a sensitivity of 78.6% and specificity of 88.9%. Median age was 29 y, and median maximum tumor diameter was 82 mm in 14 MPNST patients. The 5-y overall survival rate was 46.8%. Three patients with low-grade MPNST were alive without disease at the time of this report. In 9 patients in which pNF and MPNST co-existed, 2 showed a higher SUVmax of pNF than that of MPNST. Natural history analysis of pNF (n = 43) revealed that no factors significantly correlated with increased tumor size. Nine lesions other than neurogenic tumors were detected by PET/CT including 5 thyroid lesions and 3 malignant neoplasms. This study revealed the usefulness and limitation of PET/CT for NF1 patients. In the future, it will be necessary to study how to detect over time the malignant transformation of pNF to MPNST, via an intermediate tumor.

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

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

    CANCER SCIENCE   111 巻 ( 11 ) 頁: 4187 - 4194   2020年11月

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    記述言語:英語   出版者・発行元:Cancer Science  

    Low-dose methotrexate (MTX) plus vinblastine (VBL) chemotherapy is an effective treatment for desmoid-type fibromatosis (DF). However, previous reports have described a weekly regimen, with no reports available on a biweekly one. The aim of this study was to determine the clinical outcomes of a biweekly regimen in a cohort prospectively treated in our single institution. Since 2010, we have prospectively treated refractory DF patients with biweekly MTX (30 mg/m2) + VBL (6 mg/m2). Efficacy, progression-free survival (PFS), and correlating factors were analyzed. Adverse events (AEs) were recorded. In total, 38 patients received low-dose MTX + VBL therapy, and its efficacy was assessed in 37 of them. Nineteen (51%) patients showed partial response (PR). Clinical benefit rate was 95%. PFS at 5 y was 80.8%. In PR cases, median time to response was 10 mo. Longer duration of therapy was significantly associated with the response of PR (P =.007) by univariate analysis. There was no clear association between various clinicopathological factors, including tumor size, location, catenin beta-1 (CTNNB1) mutation status with effect. Only 3 AEs of grade 3/4 were observed. Tumor regrowth after MTX + VBL discontinuation was observed in 5 (20%) of 25 patients. Biweekly administration of MTX + VBL chemotherapy was well tolerated compared with weekly administration, and its efficacy was anticipated in DF patents, although the time needed to achieve a response may be relatively long. The treatment interval should be determined taking into account both the condition of the tumor and the patient's preference.

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  27. Is tumour location a prognostic factor for pharmacological treatment in patients with desmoid-type fibromatosis? a systematic review

    Koike Hiroshi, Hamada Shunsuke, Sakai Tomohisa, Shimizu Koki, Yoshida Masahiro, Nishida Yoshihiro

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 9 ) 頁: 1032 - 1036   2020年9月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Background: The mainstay of the treatment for desmoid-type fibromatoses has been shifting from surgery to drug treatment, making accurate prediction of the efficacy of drug treatment of extreme importance. On the other hand, desmoid-type fibromatoses arise everywhere in the body. The purpose of this systematic review was to address the clinical question of whether tumour location has an impact on the efficacy of drug treatment. Methods: A literature search from January 1990 to August 2017 was conducted. Four reviewers independently assessed and screened the literature for eligibility and determined the final articles. They rated each report according to the Grading of Recommendations Development and Evaluation approach. Based on the quality of 'Body of Evidence', our clinical guideline committee developed a recommendation for the clinical question. Results: In total, 128 articles were extracted. After the screenings, 5 were chosen for the final evaluation. The drugs used in these articles were one each of toremifene, sorafenib, and methotrexate and vinblastine and of meloxicam. There were no randomized controlled trials, and two prospective and three retrospective case series were included. Therapeutic effects were observed slightly more markedly in extremity using meloxicam or methotrexate and vinblastine. In contrast, the efficacy of toremifene was slightly higher in non-extremity. However, the evidence level of all of the reports was judged to be low. Conclusions: Considering the low evidence level, we concluded that the site-specific therapeutic effects of drugs could not be confirmed in desmoid-type fibromatoses.

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  28. Is mutation analysis of beta-catenin useful for the diagnosis of desmoid-type fibromatosis? A systematic review

    Sakai Tomohisa, Hamada Shunsuke, Koike Hiroshi, Shimizu Koki, Yoshida Masahiro, Nishida Yoshihiro

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 9 ) 頁: 1037 - 1042   2020年9月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Background: An accurate diagnosis is crucial to determine the treatment modality for desmoid-type fibromatosis, although the histopathological diagnosis is occasionally difficult to make. Many desmoid-type fibromatosis have been reported to have hotspot mutation of β-catenin gene (CTNNB1). In the present study, we performed a systematic review to verify the usefulness of CTNNB1 mutation analysis in the diagnosis of desmoid-type fibromatosis. Methods: A literature search from January 1990 to August 2017 was conducted. Three reviewers independently assessed and screened the literature for eligibility and determined the final articles to be evaluated. Data regarding the sensitivity, specificity, accuracy and usefulness of CTNNB1 mutation analysis in the diagnosis of desmoid-type fibromatosis were recorded. We rated each report according to the Grading of Recommendations Development and Evaluation approach. Results: The search yielded 90 studies, seven of which were included after the first and second screenings. The positive rate of CTNNB1 mutation in desmoid-type fibromatosis was 86.8%, but the cohort of six of the seven reports was already diagnosed histopathologically as desmoid-type fibromatosis. Therefore, the usefulness of CTNNB1 mutation analysis in a cohort that is difficult to diagnose histopathologically is not clear in this review. Nevertheless, CTNNB1 mutation showed very high specificity in desmoid-type fibromatosis, indicating the usefulness of CTNNB1 mutation analysis in its diagnosis in combination with histological examination. Conclusion: Because the lack of data precludes any useful comparison with histological diagnosis, the evidence level is low. However, considering its specificity, CTNNB1 mutation analysis may be useful in cases in which the histopathological diagnosis is difficult.

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  29. Cardiac metastases from primary myxoid liposarcoma of the thigh: a case report

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

    WORLD JOURNAL OF SURGICAL ONCOLOGY   18 巻 ( 1 ) 頁: 227   2020年8月

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    記述言語:英語   出版者・発行元:World Journal of Surgical Oncology  

    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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  30. Risk factors of local recurrence after surgery in extraabdominal desmoid-type fibromatosis: A multicenter study in Japan

    Nishida Yoshihiro, Hamada Shunsuke, Kawai Akira, Kunisada Toshiyuki, Ogose Akira, Matsumoto Yoshihiro, Ae Keisuke, Toguchida Junya, Ozaki Toshifumi, Hirakawa Akihiro, Motoi Toru, Sakai Tomohisa, Kobayashi Eisuke, Gokita Tabu, Okamoto Takeshi, Matsunobu Tomoya, Shimizu Koki, Koike Hiroshi

    CANCER SCIENCE   111 巻 ( 8 ) 頁: 2935 - 2942   2020年8月

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    記述言語:英語   出版者・発行元:Cancer Science  

    This study was undertaken to clarify the risk factors, including the mutation status of CTNNB1, for the local recurrence after surgery of the rare disease desmoid-type fibromatosis. It was designed as a multiinstitutional joint research project with 7 major centers in Japan participating. The committee members of 7 major medical centers specializing in bone and soft tissue tumors formed this study group to develop clinical care guidelines. Of 196 cases with specimens and medical records collected from the 7 institutions, 88 surgically treated ones were analyzed regarding clinicopathologic prognostic factors including CTNNB1 mutation status. Excluding R2 cases (n = 3), 5-year local recurrence-free survival (LRFS) was 52.9%. No case had received pre- or postoperative radiotherapy. Univariate analysis revealed that extremity location (P <.001) and larger size (8 cm or more, P =.036) were significant adverse risk factors for LRFS. Multivariate analysis indicated that extremity location (P <.001) was a significantly adverse factor in addition to recurrent tumor (P =.041), S45F mutation (P =.028), and R1 surgical margin (P =.039). Preoperative drug treatment, including nonsteroidal antiinflammatory drugs, did not reduce the incidence of local recurrence (P =.199). This is the first study to analyze the factors correlating with outcomes of surgical treatment, including CTNNB1 mutation status, in a relatively large number of cases from an Asian country. Tumor location was found to be the most influential prognostic factor for local recurrence, similar to the results from Europe and North America. The development of more sensitive method(s) for determination of CTNNB1 mutation is a priority for future study.

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

    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   50 巻 ( 7 ) 頁: 772 - 778   2020年7月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Background: The present study aimed to determine functional outcomes in patients undergoing deltoid muscle resection for soft tissue sarcoma. Methods: Between 2002 and 2014, 18 patients with soft tissue sarcoma of the shoulder who underwent wide resection including the deltoid muscle, and were followed up for more than 12 months, were retrospectively included in the study. In all, 11 patients were male and 7 were female. The median age was 59 years, median follow-up duration was 37 months. The extent of resection of deltoid muscle, with or without rotator cuff damage, reconstruction methods, adjuvant therapy, oncological outcomes, and the International Society of Limb Salvage (ISOLS) score as functional outcomes were analyzed. Results: Six patients underwent total resection, and twelve underwent partial resections of deltoid muscle. The rotator cuff was resected in four patients. Soft tissue reconstruction was performed in 17 patients using a pedicled latissimus dorsi muscle flap. Two local recurrences and three distant metastases occurred during follow-up. Median overall survival was 72 months. The mean ISOLS score was 25.0 points (±4.6points). Univariate analysis revealed that there was no significant difference in ISOLS score regarding the extent of deltoid muscle resection. Multivariate analysis identified only combined resection of the rotator cuff as a significant prognostic factor for poor functional outcomes (P < 0.001). Conclusions: The extent of resection of the deltoid muscle might not affect the functional outcomes determined by ISOLS score. If the rotator cuff is resected concurrently, satisfactory functional outcomes might not be obtained.

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  32. 症例報告 上腕骨近位部の骨表面に発生したグロムス腫瘍の1例

    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   55 巻 ( 4 ) 頁: 385 - 388   2020年4月

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    出版者・発行元:株式会社医学書院  

    DOI: 10.11477/mf.1408201651

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  33. Efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with extra-abdominal desmoid-type fibromatosis: a systematic review

    Shimizu Koki, Hamada Shunsuke, Sakai Tomohisa, Koike Hiroshi, Yoshida Masahiro, Nishida Yoshihiro

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   50 巻 ( 4 ) 頁: 419 - 424   2020年4月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    Objective: The treatment modality for desmoid-type fibromatosis has shifted from surgery to conservative treatment. This systematic review aims to evaluate the efficacy of low-dose chemotherapy with methotrexate and vinblastine for patients with extra-abdominal desmoid-type fibromatosis. Methods: We searched the pertinent literature from January 1990 to August 2017. Two reviewers evaluated and screened the literature independently for eligibility and extracted data.We evaluated the quality of body of evidence and made a recommendation according to the Grading of Recommendations Development and Evaluation methodology. Results: The search yielded 40 studies, 9 of which were included after the first and second screenings. There were three prospective case series but no randomized controlled trials among the nine studies. There was no case-control report (vs. no treatment). According to Response Evaluation Criteria in Solid Tumors criteria, the mean response rate (complete remission or partial response) was 36% (11-57%). Including stable disease, namely, clinical benefit was consistently as high as 85% (69-100%). Mean adverse event rate of G3 or G4 according to CTCAE was 31%. One study reported improvement of pain (87.5%) because of this chemotherapy. Conclusion: The efficacy of this chemotherapy was convincing. However, the overall evidence was weak, and this chemotherapy is not covered by insurance in Japan; we only weakly recommend low-dose chemotherapy with methotrexate and vinblastine in patients with extra-abdominal desmoid-type fibromatosis.

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  34. 上腕骨近位部の骨表面に発生したグロムス腫瘍の1例 査読有り

    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   55 巻 ( 4 ) 頁: 385 - 388   2020年4月

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  35. Targetable driver mutations in multicentric reticulohistiocytosis

    Murakami Norihiro, Sakai Tomohisa, Arai Eisuke, Muramatsu Hideki, Ichikawa Daisuke, Asai Shuji, Shimoyama Yoshie, Ishiguro Naoki, Takahashi Yoshiyuki, Okuno Yusuke, Nishida Yoshihiro

    HAEMATOLOGICA   105 巻 ( 2 ) 頁: E61 - E64   2020年1月

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    出版者・発行元:Haematologica  

    DOI: 10.3324/haematol.2019.218735

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  36. Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations

    Tsuda Yusuke, Hirata Makoto, Katayama Kotoe, Motoi Toru, Matsubara Daisuke, Oda Yoshinao, Fujita Masashi, Kobayashi Hiroshi, Kawano Hirotaka, Nishida Yoshihiro, Sakai Tomohisa, Okuma Tomotake, Goto Takahiro, Ogura Koichi, Kawai Akira, Ae Keisuke, Anazawa Ukei, Suehara Yoshiyuki, Iwata Shintaro, Miyano Satoru, Imoto Seiya, Shibata Tatsuhiro, Nakagawa Hidewaki, Yamaguchi Rui, Tanaka Sakae, Matsuda Koichi

    INTERNATIONAL JOURNAL OF CANCER   145 巻 ( 12 ) 頁: 3276 - 3284   2019年12月

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    出版者・発行元:International Journal of Cancer  

    Tenosynovial giant cell tumor (TSGCT) is a rare neoplasm. Although surgical resection is the widely accepted primary treatment for TSGCT, recurrences are frequent, and patients’ joint function may be severely compromised. Previous studies reported that CSF1-COL6A3 fusion genes were identified in approximately 30% of TSGCTs. The aim of our study was to comprehensively clarify the genomic abnormalities in TSGCTs. We performed whole exome sequencing in combination with target sequence validation on 34 TSGCT samples. RNA sequencing was also performed on 18 samples. RNA sequencing revealed fusion transcripts involving CSF1, including novel CSF1-VCAM1, CSF1-FN1 and CSF1-CDH1 fusions, in 13/18 (72%) cases. These fusion genes were validated by chromogenic in situ hybridization. All CSF1 fusions resulted in the deletion of CSF1 exon 9, which was previously shown to be an important negative regulator of CSF1 expression. We also found that 12 (35%) of the 34 TSGCT samples harbored CBL missense mutations. All mutations were detected in exons 8 or 9, which encode the linker and RING finger domain. Among these mutations, C404Y, L380P and R420Q were recurrent. CBL-mutated cases showed higher JAK2 expression than wild-type CBL cases (p = 0.013). CSF1 fusion genes and CBL mutations were not mutually exclusive, and both alterations were detected in six of the 18 (33%) tumors. The frequent deletion of CSF1 exon 9 in the fusion transcripts suggested the importance of this event in the etiology of TSGCT. Our results may contribute to the development of new targeted therapies using JAK2 inhibitors for CBL-mutated TSGCT.

    DOI: 10.1002/ijc.32421

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

    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   63 巻 ( 6 ) 頁: 751 - 757   2019年12月

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    記述言語:英語   出版者・発行元:Journal of Medical Imaging and Radiation Oncology  

    Introduction: This study aimed to determine the clinical significance of MRI characteristics as a possible predictor of responsiveness to meloxicam treatment in patients with desmoid-type fibromatosis (DF). Additionally, it analysed the correlation between CTNNB1 mutation status and signal intensity of MRI. Methods: Forty-six patients consecutively treated with meloxicam composed this study. The low-intensity area (LIA) on T2-weighted MRI was determined. We divided patients into two groups based on the efficacy of meloxicam: a clinical benefit group (CB group, including CR: complete response; PR: partial response; and SD: stable disease) and non-clinical benefit group (NB group, including PD: progressive disease). Correlations of the efficacy with LIA and CTNNB1 mutation status with LIA were investigated. Results: In total, 11, 17 and 18 patients showed PR, SD and PD, respectively. The mean LIA ratio before treatment was significantly higher (P < 0.001) in the CB group than in the NB group. For predicting the efficacy, sensitivity was 68%, and specificity was 89% when setting the cut-off value as 20% for LIA. Mean changes in the LIA ratio before and after treatment were significantly higher (P = 0.01) in the CB group than in the NB group. Mean LIA ratio before treatment was significantly lower (P < 0.001) in the S45F mutation group than in the other mutation group. In multivariate analysis, the LIA ratio before treatment was a significant predictor of responsiveness (P = 0.02). Conclusions: MRI characteristics were a useful predictor of the efficacy of meloxicam in DF patients. It may be possible to predict the clinical outcome more accurately when combined with other factors, such as CTNNB1 mutantion status.

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  38. Pazopanib for progressive desmoid tumours: children, persistant effects, and cost.

    Nishida Y, Sakai T, Koike H, Ito K

    The Lancet. Oncology   20 巻 ( 10 ) 頁: e555   2019年10月

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    出版者・発行元:The Lancet Oncology  

    DOI: 10.1016/S1470-2045(19)30543-1

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  39. Pazopanib for progressive desmoid tumours: children, persistant effects, and cost

    Nishida Yoshihiro, Sakai Tomohisa, Koike Hiroshi, Ito Kan

    LANCET ONCOLOGY   20 巻 ( 10 ) 頁: E555 - E555   2019年10月

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  40. 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

    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   54 巻 ( 7 ) 頁: 665 - 670   2019年7月

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    出版者・発行元:株式会社医学書院  

    DOI: 10.11477/mf.1408201410

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

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

    JOURNAL OF CLINICAL ONCOLOGY   37 巻 ( 15 )   2019年5月

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  42. Is immunohistochemical staining for beta-catenin the definitive pathological diagnostic tool for desmoid-type fibromatosis? A multi-institutional study

    Koike Hiroshi, Nishida Yoshihiro, Kohno Kei, Shimoyama Yoshie, Motoi Toru, Hamada Shunsuke, Kawai Akira, Ogose Akira, Ozaki Toshifumi, Kunisada Toshiyuki, Matsumoto Yoshihiro, Matsunobu Tomoya, Ae Keisuke, Gokita Tabu, Sakai Tomohisa, Shimizu Koki, Ishiguro Naoki

    HUMAN PATHOLOGY   84 巻   頁: 155 - 163   2019年2月

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    記述言語:英語   出版者・発行元:Human Pathology  

    Immunohistochemical staining with anti–β-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatoses (DFs). In recent years, specific gene mutation (CTNNB1) analysis has also been reported to be useful for diagnosis of DF; however, the association between CTNNB1 mutation status and immunohistochemical staining pattern of β-catenin is rarely reported. The purposes of this study are to clarify the relationship of the staining pattern of β-catenin with the CTNNB1 mutation status and various clinical variables, and to investigate the significance of immunohistochemical staining of β-catenin in cases diagnosed as DF. Between 1997 and 2017, 104 cases diagnosed as DF from 6 institutions in Japan were enrolled in this study: Nagoya University, National Cancer Center Hospital, Niigata University, Okayama University, Kyushu University, and Cancer Institute Hospital. For all cases, immunohistochemical staining of β-catenin and gene mutation analysis of CTNNB1 were performed. Of 104 cases, 87 (84%) showed nuclear staining of β-catenin, and 95 (91%) showed positive staining in the cytoplasm. The proportion of cases showing strong nuclear staining of β-catenin was significantly higher in the cases with S45F than in those with T41A or wild type. The proportion of cases stained strongly in the cytoplasm rather than in the nucleus was significantly higher in the group of T41A than that of S45F or wild type. Among 17 cases in which nuclear immunostaining was absent, CTNNB1 mutation was observed in 5 cases (29.4%). There were unignorable cases of DF with negative β-catenin immunostaining despite a definitive clinical and pathological diagnosis of DF and/or positive CTNNB1 mutation.

    DOI: 10.1016/j.humpath.2018.09.018

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  43. 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

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

    DIAGNOSTIC PATHOLOGY   12 巻 ( 1 ) 頁: 66   2017年8月

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    記述言語:英語   出版者・発行元:Diagnostic Pathology  

    Background: Immunohistochemical staining with conventional anti-β-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 β-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-β-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 β-catenin and non-phospho β-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 β-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 β-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 β-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho β-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.

    DOI: 10.1186/s13000-017-0654-z

    Web of Science

    Scopus

    PubMed

  44. Heat-stimuli-enhanced osteogenesis using clinically available biomaterials

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

    PLOS ONE   12 巻 ( 7 ) 頁: e0181404   2017年7月

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    記述言語:英語   出版者・発行元:PLoS ONE  

    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® and REGENOS®) 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 45C 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.

    DOI: 10.1371/journal.pone.0181404

    Web of Science

    Scopus

    PubMed

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MISC 1

  1. 多中心性細網組織球症における遺伝子解析と治療可能性 査読有り

    奥野 友介, 酒井 智久, 浅井 秀司, 村松 秀城, 村上 典寛, 西田 佳弘  

    リウマチ科65 巻 ( 2 ) 頁: 243 - 246   2021年2月

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    記述言語:日本語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

講演・口頭発表等 6

  1. 左大腿軟部腫瘍の1例

    酒井 智久, 西田 佳弘, 生田 国大, 小池 宏, 伊藤 鑑, 榊原 綾子, 下山 芳恵, 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年7月16日  日整会

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    開催年月日: 2021年7月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:広島   国名:日本国  

  2. 病的骨折は大腿骨転移性骨腫瘍患者の予後に影響するか -傾向スコアマッチングを用いた解析―

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

    第94回日本整形外科学会学術総会  日整会

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    開催年月日: 2021年5月

    記述言語:日本語   会議種別:口頭発表(一般)  

    国名:日本国  

  3. 大腿骨近位部転移性骨腫瘍患者の短期予後予測 -改訂版片桐スコアとMEP scoreの有用性の検討―

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

    第94回日本整形外科学会学術総会  日整会

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    開催年月日: 2021年5月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:オンライン   国名:日本国  

  4. 超希少な骨・軟部腫瘍に対する全エクソーム解析の有用性と今後の展望

    酒井 智久, 西田 佳弘, 奥野 友介, 村上 典寛, 生田 国大, 小池 宏, 伊藤 鑑, 石黒 直樹

    第35回日本整形外科学会基礎学術集会  日整会

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    開催年月日: 2020年10月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:オンライン   国名:日本国  

  5. Surgical dislocation of hip(Granz approach)を用いて切除を行った股関節滑膜性骨軟骨腫症の2例

    酒井 智久, 西田 佳弘, 浦川 浩, 生田 国大, 小池 宏

    第53回日本整形外科学会骨・軟部腫瘍学術総会  日整会

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    開催年月日: 2020年9月

    記述言語:日本語   会議種別:ポスター発表  

    開催地:オンライン   国名:日本国  

  6. Phosphaturic mesenchymal tumorにおける新規融合遺伝子NIPBL-BEND2の同定

    酒井 智久, 西田 佳弘, 奥野 友介, 村上 典寛, 浦川 浩, 新井 英介, 生田 国大, 小池 宏, 伊藤 鑑, 石黒 直樹

    第93回日本整形外科学会学術総会  日整会

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    開催年月日: 2020年6月 - 2020年8月

    記述言語:日本語   会議種別:ポスター発表  

    開催地:オンライン   国名:日本国  

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科研費 6

  1. 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

    研究課題/研究課題番号:21K09321  2021年4月 - 2024年3月

    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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    担当区分:研究分担者 

    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。

  2. 発生母地あるいはその周辺組織の硬度がデスモイド型線維腫症の病態に与える影響の検証

    研究課題/研究課題番号:20K16328  2020年4月 - 2023年3月

    科学研究費助成事業  若手研究

    酒井 智久

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    担当区分:研究代表者 

    配分額:2470000円 ( 直接経費:1900000円 、 間接経費:570000円 )

    デスモイドは特異的な挙動を示す疾患であり、予後予測因子及び有用な薬物療法はまだ確立されていない。力学的要素が発症・進展に関与することが示唆されており、本研究の目的は基質硬度がデスモイドの腫瘍進展に与える影響の検証である。デスモイド由来の培養細胞を異なる硬度の基質上で培養し、その分子生物学的意義を明らかにし、新規の予後予測因子及び治療ターゲットを探索することを目的とする。
    機械的刺激伝達シグナルおよび組織硬度がデスモイド型線維腫症の病態において果たす役割について検証することを目的としている。デスモイド型線維腫症培養細胞を用いて、基質硬度の上昇に伴い細胞の増殖・筋線維芽細胞に強く発現するα-SMAタンパク・デスモイド型線維腫症で発現と核内集積が既知であるβ-cateninタンパク発現が上昇することを確認した。また、過去に間葉系細胞での発現が報告されている機械的シグナル受容体Transient Receptor Potential Vanilloid 4(Trpv4)のデスモイド型線維腫症培養細胞における発現を免疫蛍光細胞染色で確認した。実験に用いる初代培養細胞が枯渇したため新規に3例から腫瘍組織を採取し初代培養細胞を培養した。
    臨床側からのデスモイド型線維腫症に対する病態の理解を深めるアプローチとして、保存的治療における臨床成績および画像上の増大・治療介入に至るリスクの検討を行った。当院において半年以上の経過観察が可能であった168病変を対象として検討を行い、168病変中44%に当たる74病変で治療介入が行われていた。機械的刺激や基質硬度に関連すると考え発生部位による増大や治療介入リスクの差異を検討し、頸部発生例では画像上の増大とは有意な関連を示さなかったが、他の部位と比較し有意に治療介入に至るリスクが高かった。他の治療介入リスクとしてはCTNNB1 S45F変異を持つ例が単変量・多変量解析ともに治療介入リスクであった。
    昨年度の課題であった初代培養細胞は使用可能となったが、基質硬度別の6-well plateが生産中止となっており別のデバイスや自作を検討したが再現が困難であったため研究の推進が困難であった。過日別のメーカーから同商品が再販されたため再び入手可能となった。
    Trpv4以外のメカノレセプターであるIntegrin family (VLA-1, 3, 5, 6, αvβ1など)の発現確認を行う。基質硬度の変化がデスモイド線維腫症細胞内のTrpv4を介したCaイオン流入に対する影響についてCa蛍光プローブを用いて調べる。またIntegrinを介したFAK/MAPKシグナルに与える影響について免疫細胞染色、western blotによるタンパク発現解析, realtime-PCRによるmRNA発現解析等により調べる。また、基礎研究で有意な成果が得られない場合を考慮し、関連研究としてデスモイド線維腫症に関与する臨床因子を調査、統計解析を行い予後予測因子の同定を試みる。

  3. 深紫外線LEDによる横断的加齢性疾患治療の基盤構築

    研究課題/研究課題番号:17K19903  2017年6月 - 2020年3月

    挑戦的研究(萌芽)

    西田 佳弘

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    担当区分:研究分担者 

    深紫外線の波長を限局して照射できるLED機器により、副作用の少ない波長(315nm)で、血中25(OH)D値を有意に上昇させることを明らかにした。血中25(OH)D値を有意に上昇させる最小照度・照射量の条件(週2回、1回照射照度0.16mW/cm2、照射量1 kJ/m2)を決定し、加齢モデルマウス(SAM-P6マウス)を用いて、Trabecular bone mineral densityの上昇を確認し、破骨細胞誘導が抑制されることが確認された。また筋量も有意に上昇することを確認した。波長限定LED照射により、骨粗鬆症、サルコペニアの新規治療法となる非臨床POCを得ることができた。
    骨粗鬆症に対しては有効な薬物治療は各種開発されているがコストが高く、大きな副作用が報告されている。患者の薬物に対するアドヒアランスも問題となる。またサルコペニアに対する有効な治療法はまだ確立されていない。本研究により、LED機器を使用した深紫外線照射は、ビタミンD産生上昇を介して副作用少なく骨粗鬆症とサルコペニアの新規治療法となる可能性が示された。超高齢化社会を迎える日本、世界に対して低コストで汎用性のある治療法となることが期待される。また治療機器は携帯化が可能であるため、多様な医療現場、家庭で使用できることも利点である。

  4. デスモイド型線維腫症の病態に基づく診断、新規治療開発への学際的・国際的共同研究

    研究課題/研究課題番号:17H01585  2017年4月 - 2021年3月

    科学研究費助成事業  基盤研究(A)

    西田 佳弘, 莚田 泰誠, 酒井 智久, 青木 正博, 松田 浩一, 新井 英介, 濱田 俊介

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    担当区分:研究分担者 

    (i) Apc1638N変異マウスにおいてデスモイド様腫瘍組織が発生することを確認した。次にdrug repositioning法で特定した薬剤Xを本マウスに投与して、デスモイド様組織の発症を抑制していることを明らかにした。Meflin特異的CTNNB1exon3欠損マウスを作成し、皮下にデスモイド様組織が発生することを見いだした。(ii)Pdgf-CreとCTNNB1exon3欠損マウスをかけあわせると皮下に線維芽細胞様腫瘍が発生することを見いだした。(iii)64例のデスモイドに対してwhole exome sequencingとRNA sequencingを実施し、従来から報告されているCTNNB1変異に加えてchr6コピー数の喪失が、デスモイド腫瘍形成の原因変異である可能性を示した。また、デスモイドに対する術後成績に関して、3つの遺伝子セット(IFI6、LGMN、およびCKLF)の発現が強力な予後マーカーとなることを見いだした。(iv)ゲノムワイド関連解析については24例を追加して合計98例の解析を実施した。有望な遺伝子Yについてはカットオフ以下となった。(v)drug repositioningによって特定された薬剤Xについてはモデルマウスによってデスモイド発症抑制を確認した。この結果に基づき、PMDAの事前相談、対面助言を実施した。(vi)NIHで作成されたデスモイド患者報告型のQOL評価の和訳版を完成させた。(vii)腹腔外発生デスモイド型線維腫症の診療ガイドラインを完成させて発刊した(2019年9月)。市民公開講座を2019年7月に開催して、ガイドラインや海外での臨床試験の情報を患者・家族に対して発信した。国際的デスモイド研究組織であるDTRFに参加して情報共有を行った。
    腹腔外発生デスモイドの診療ガイドラインを完成させ、発刊することができた。デスモイド患者のQOLを評価するNIHの作成したシステムを和訳することができ、今後国際的共通スケールによって評価、比較することが可能となった。デスモイドの発症原因であるCTNNB1のエクソン3の変異遺伝子をmeflinやpdgf特異的に発現させることでデスモイド様腫瘍が発生することを見いだした。多施設共同研究により集積された64例のデスモイに対してwhole exome sequencingとRNA sequencing解析を実施することで、CTNNB1変異以外には明らかな病因遺伝子がないこと、手術成績に関連する3種の有意な遺伝子セットを明らかにした。 Drug repositioning法により特定された薬剤Xのデスモイド発症抑制効果が明らかとなり、今後医師主導治験を開始する基盤データとなった。以上より本研究はおおむね順調に進んでいる。
    腹腔外発生デスモイドに対する診療ガイドラインについては、策定しても遵守されるかは不明であるため、今後診療専門施設に対して、診断治療のアンケート調査を実施し、ガイドラインに準じた診療を実施しているかについて調査する。またガイドライン作成過程で各クリニカルクエスチョンに対して実施したシステマティックレビューを各々英語論文化する予定である。Drug repositioning法によって同定された薬剤Xについては、デスモイドを抑制するメカニズムを解析することを予定している。また、薬剤Xの臨床試験に向けてのPMDAとの対面助言の結果に基づいて、医師主導治験用のプロトコール作成を行うとともに臨床試験実施の向けての研究助成金の取得をめざす。whole exome sequencingとRNA sequencing解析を実施することで、CTNNB1変異以外には明らかな病因遺伝子がないこと、手術成績に関連する3種の有意な遺伝子セットを明らかにした成果を論文発表する。ゲノムワイド関連解析について合計98例の解析結果について、臨床情報つけて有望な遺伝子Yについて再解析を実施する。NIHの作成したデスモイド患者のQOL評価和訳版を使用して、日本のデスモイド患者に対する各種治療に関するQOL評価を実施する予定である。Pdgf-CreとCTNNB1exon3欠損マウスをかけあわせたマウスに対してkrasやp53欠損を掛け合わせた場合の発生腫瘍について解析予定としている。Meflin特異的CTNNB1exon3欠損マウスの皮下に発生するデスモイド様組織の再現性の評価および炎症下での発生について追加して評価を行う。

  5. 進行期骨軟部肉腫に対する細胞外マトリックス制御による新規腫瘍免疫療法の開発

    研究課題/研究課題番号:17K10963  2017年4月 - 2020年3月

    浦川 浩

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    担当区分:研究分担者 

    骨軟部肉腫におけるヒアルロン酸を中心とした細胞外マトリックス・細胞膜上受容体・細胞内シグナル伝達のネットワークと腫瘍免疫との関係を明らかにし、これらをターゲットとした新規免疫治療の確立を目的として免疫チェックポイント分子とヒアルロン酸ネットワークの関係を評価した。骨軟部肉腫細胞においては豊富な細胞外マトリックスを認め免疫チェックポイント分子の発現との関係において一定の関係がみられ、骨軟部肉腫腫瘍組織においては豊富なヒアルロン酸発現を認め、一部の組織型において免疫細胞浸潤と免疫チェックポイント分子発現を認めた。
    腫瘍内では腫瘍免疫により抗がん剤など既存治療への抵抗性が獲得されており、骨軟部肉腫においてヒアルロン酸を中心とした細胞外マトリックス・細胞膜上受容体・細胞内シグナル伝達のネットワークが腫瘍免疫にかかわっている可能性が示唆された。細胞外マトリックスの産生・蓄積の制御、あるいはマトリックス-細胞膜上受容体の相互作用を制御することにより、骨軟部腫瘍において抗腫瘍免疫応答を引き起こすことが可能となり、新規腫瘍免疫療法の開発が期待される。

  6. プロテオーム解析を用いたデスモイド腫瘍の病態と新規バイオマーカーの探索的研究

    研究課題/研究課題番号:16K20047  2016年4月 - 2019年3月

    濱田 俊介

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    担当区分:その他 

    デスモイド型線維腫症の治療予測マーカーとなり得るCTNNB1遺伝子変異型毎の分子生物学的相違とその意義について研究を行った。変異型毎に核内β-catenin蓄積や下流遺伝子の発現状態に相違が見られ、全体的な傾向としてS45F変異型細胞が全体にWNT/β-catenin系シグナルの亢進がより著しい傾向が示唆され、各学会での報告および核内β-catenin核内蓄積の違いについて論文として報告を行った。また蛋白発現の評価としてprotein microarrayを行い、TGF-βやEGFRの蛋白発現亢進が遺伝子変異型によってみられることが示唆された。
    デスモイド型線維腫症のCTNNB1遺伝子変異型は臨床的に術後再発率や薬物治療効果に影響を与えることが報告されており実際に本邦における治療アルゴリズムでも取り入れられている。本研究結果より変異型の相違が何らかの形で主にWNT/β-catenin系シグナル発現亢進を通し下流の蛋白発現に相違を及ぼしていることが示唆され、最終的に再発や薬物治療抵抗性といった臨床的予後の相違に関与していると考えられた。今後より厳密な治療マーカーとしての確立化や新たな治療標的薬の開発につながることが期待される。

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担当経験のある科目 (本学) 1

  1. 整形外科学

    2020

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    骨・軟部腫瘍について