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| 1.
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Igarashi, Kentaro ; Kawaguchi, Kei ; Kiyuna, Tasuku ; Miyake, Kentaro ; Miyake, Masuyo ; Li, Yunfeng ; Nelson, Scott D. ; Dry, Sarah M. ; Singh, Arun S. ; Elliott, Irmina A. ; Russell, Tara A. ; Eckardt, Mark A. ; Yamamoto, Norio ; Hayashi, Katsuhiro ; Kimura, Hiroaki ; Miwa, Shinji ; Tsuchiya, Hiroyuki ; Eilber, Fritz C. ; Hoffman, Robert M. ; 五十嵐, 健太郎 ; 山本, 憲男 ; 林, 克洋 ; 三輪, 真嗣 ; 土屋, 弘行
概要:
金沢大学医薬保健研究域医学系<br />Relapsed osteosarcoma is a recalcitrant tumor. A patient's cisplatinum (CDDP)- resistant relapsed os
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teosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once); temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093; GEM+DOC: p = 0.0002, TEM+IRN: p < 0.0001. TEM combined with IRN was significantly more effective than either CDDP (p = 0.0001) or GEM combined with DOC (p = 0.0003) and significantly regressed the tumor volume compared to day 0 (p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX. © Igarashi et al.
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Shinmura, Kazuya ; Murakami, Hideki ; Demura, Satoru ; Kato, Satoshi ; Yoshioka, Katsuhito ; Hayashi, Hiroyuki ; Inoue, Kei ; Ota, Takashi ; Yokogawa, Noriaki ; Ishii, Takayoshi ; Igarashi, Takashi ; Tsuchiya, Hiroyuki ; 新村, 和也 ; 村上, 英樹 ; 出村, 諭 ; 加藤, 仁志 ; 土屋, 弘行
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金沢大学医薬保健研究域医学系<br />Our aim was to compare the process of bone formation after reconstruction of the vertebral body usin
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g a titanium cage with either a liquid nitrogen-treated (frozen) bone autograft or non-treated fresh bone autograft. Twelve canine beagles underwent anterior reconstruction of the 5th lumbar vertebrae using a titanium cage and bone autograft. Bone formation was compared across four experimental groups: fresh bone autograft groups, with animals sacrificed at either 8 or 16 weeks post-reconstruction, and liquid nitrogen-treated (frozen) bone autograft groups, with animals again sacrificed at either 8 or 16 weeks post-reconstruction. Bone formation was evaluated histologically by calculating the proportion of 'reaction' and 'mature bone' regions at the ends of the cage, its center, and ventral/dorsal sides. The reaction region contained osteocytes with a nucleus and osteoblasts accumulated on the surface of an osteoid, while a laminar structure was visible for mature bone regions. For fresh bone autografts, the reaction and mature bone regions significantly increased from 8 to 16 weeks post-reconstruction. By comparison, for frozen autografts, the reaction bone region did not significantly increase from 8 to 16 weeks post-reconstruction, while the mature bone region did increase over this time period. The proportion of reaction bone was higher at the ends and dorsal side of the cage at 8 weeks, for both graft types, with greater bone formation at the center of the cage at 16 weeks only for the fresh bone autograft. Therefore, bone formation in the anterior spinal reconstruction site tended to be delayed when using a frozen bone autograft compared to a fresh bone autograft. The bone formation process, however, was similar for both groups, beginning at the ends and dorsal side of the cage adjacent to the surrounding vertebral bone. © 2018 Shinmura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Miwa, Shinji ; Nishida, Hideji ; Tsuchiya, Hiroyuki ; 三輪, 真嗣 ; 西田, 英司 ; 土屋, 弘行
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金沢大学医薬保健研究域医学系<br />Although the development of anticancer drugs has improved the outcomes of bone and soft tissue sarco
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mas, the clinical outcome of patients with relapsed sarcomas remains unsatisfactory due to therapeutic toxicities and resistance to anticancer drugs. Therefore, novel therapeutic modalities are needed to improve the outcome of patients with bone and soft tissue sarcomas. Dendritic cells present tumor antigens and stimulate immune responses, and immune cells, such as cytotoxic T lymphocytes, kill tumor cells by recognizing tumor antigens. However, immune-suppressive conditions by immune regulator PD-1, CTLA-4 and regulatory T cells help tumor growth and progression. In this report, current immunotherapies including cellular immunotherapy and checkpoint inhibitors are introduced, and the advantages and disadvantages of the treatments are discussed. © 2017 2017 Future Medicine Ltd.<br />Embargo Period 12 months
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Higuchi, Takashi ; Takeuchi, Akihiko ; Munesue, Seiichi ; Yamamoto, Norio ; Hayashi, Katsuhiro ; Kimura, Hiroaki ; Miwa, Shinji ; Inaki, Hiroyuki ; Shimozaki, Shingo ; Kato, Takashi ; Aoki, Yu ; Abe, Kensaku ; Taniguchi, Yuta ; Aiba, Hisaki ; Murakami, Hideki ; Harashima, Ai ; Yamamoto, Yasuhiko ; Tsuchiya, Hiroyuki ; 武内 , 章彦 ; 棟居, 聖一 ; 山本, 憲男 ; 林 , 克洋 ; 三輪, 真嗣 ; 谷口, 裕太 ; 原島, 愛 ; 山本, 靖彦 ; 土屋, 弘行
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金沢大学医薬保健研究域医学系<br />Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemoth
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erapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti-inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti-tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ-responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase-2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.<br />29573200
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El‑Far, Ali Hafez Ali MohammedTsuchiya Hiroshi Yamamoto Hazem M.E. Shaheen Yasser S. El‑Sayed Shuhei Kawano Sei‑Ichi Tanuma Yasuhiko Yamamoto ; Munesue, Seiichi ; Harashima, Ai ; Satoh, Akira ; Shindo, Mika ; Nakajima, Shingo ; Inada, Mana ; Tanaka, Mariko ; Takeuchi, Akihiko ; Tsuchiya, Hiroyuki ; Yamamoto, Hiroshi ; Shaheen, Hazem M.E. ; El‑Sayed, Yasser S. ; Kawano, Shuhei ; Tanuma, Sei‑Ichi ; Yamamoto, Yasuhiko ; 棟居, 聖一 ; 原島, 愛 ; 武内 , 章彦 ; 土屋, 弘行 ; 山本, 靖彦
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金沢大学医薬保健研究域医学系<br />Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in
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the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized‑peptide strategy drug design system. Papaverine significantly inhibited RAGE‑dependent nuclear factor κ‑B activation driven by high mobility group box‑1, a RAGE ligand. Using RAGE‑ or dominant‑negative RAGE‑expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE‑dependent cell proliferation and migration dose‑dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.<br />Embargo Period 6 months
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| 6.
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Higuchi, Takashi ; Yamamoto, Norio ; Nishida, Hideji ; Hayashi, Katsuhiro ; Takeuchi, Akihiko ; Kimura, Hiroaki ; Miwa, Shinji ; Inatani, Hiroyuki ; Shimozaki, Shingo ; Kato, Takashi ; Aoki, Yu ; Abe, Kensaku ; Taniguchi, Yuta ; Tsuchiya, Hiroyuki
概要:
Purpose: To preserve the joint structure in order to maintain good limb function in patients with osteosarcoma, we perfo
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rm epiphyseal or metaphyseal osteotomy and reconstruction using frozen autografts that contain a tumour treated with liquid nitrogen. There are two methods of using liquid nitrogen-treated autografts: the free-freezing method and the pedicle-freezing method. The purpose of this study was to evaluate the results of intentional joint-preserving reconstruction using the free-freezing method and the pedicle-freezing method in patients with osteosarcoma. Methods: Between 2006 and 2014, we performed joint-preserving surgery (12 with the free-freezing method and six with the pedicle freezing method) to treat 18 cases of osteosarcoma (12 distal femurs and six proximal tibias) in patients who had achieved a good response to neoadjuvant chemotherapy. Results: Among the 18 patients (nine boys and nine girls) who had a mean age of 11.6 years, 13 remained continuously disease-free, three showed no evidence of disease, one was alive with the disease, and one died from the disease. Functional outcomes were assessed as excellent in 15 patients and poor in three, with a mean follow-up period of 46.1 months. The mean Musculoskeletal Tumour Society (MSTS) score was 90.2%. Except for one patient who underwent amputation, all patients could bend their knee through >90° flexion, and nine achieved full ROM. All but two patients could walk without aid, and 11 were able to run normally throughout the follow-up period. No intraoperative complications were observed, such as surrounding soft-tissue damage, neurovascular injury, or recurrence from frozen bone. Conclusions: Joint-preserving reconstruction using frozen autografts yielded excellent function in patients with osteosarcoma. © 2017 The Author(s)<br />in Press / Embargo Period 12 months
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Hayashi, Katsuhiro ; Niu, Xiaohui ; Tang, Xiaodong ; Singh, Vivek Ajit ; Asavamongkolkul, Apichat ; Kawai, Akira ; Yamamoto, Norio ; Shirai, Toshiharu ; Takeuchi, Akihiko ; Kimura, Hiroaki ; Miwa, Shinji ; Tsuchiya, Hiroyuki ; 林, 克洋 ; 山本, 憲男 ; 白井, 寿治 ; 武内, 章彦 ; 木村, 浩彰 ; 三輪, 真嗣 ; 土屋, 弘行
概要:
Total scapulectomy and reconstruction has been performed for scapular tumor, however, most of the reconstruction methods
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have resulted in poor functional outcomes and there is still room for improvement. Most of the reports of reconstruction after scapulectomy are from a single institution. In the present study, we investigated functional outcomes after total scapulectomy in a multicenter study in The Eastern Asian Musculoskeletal Oncology Group (EAMOG). Thirty-three patients who underwent total scapulectomy were registered at EAMOG affiliated hospitals. The patients were separated into no reconstruction group (n=8), humeral suspension group (n=15) and prosthesis group (n=10). Functional outcome was assessed by the Enneking score. One-way ANOVA was used to compare parameters between the patient groups. Complications included five local recurrences, one superficial infection, one dislocation and one clavicle protrusion. The average follow-up period was 43.5. months. The average active flexion range was 45.8° (0-120°), and 37.1° in abduction (0-120°). The mean total functional score was 22.9 out of 30 (15-29), which is a satisfactory score following resection of the shoulder girdle. There were significant differences in reconstruction methods for active range of motion. Bony reconstruction provided better range of motion in this study. There was a variety of reconstruction methods after scapulectomy in the eastern Asian countries. Although better functional score was obtained using scapular prosthesis or recycled bone and prosthesis composite grafting, postoperative function is still lower than preoperative function. Modified designed prosthesis with or without combination of recycle bone or allograft would restore the lost shoulder function in the future. © 2016 The Authors.<br />Embargo Period 12 months
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Miwa, Shinji ; Shirai, Toshiharu ; Yamamoto, Norio ; Hayashi, Katsuhiro ; Takeuchi, Akihiko ; Tada, Kaoru ; Kajino, Yoshitomo ; Inatani, Hiroyuki ; Higuchi, Takashi ; Abe, Kensaku ; Taniguchi, Yuta ; Tsuchiya, Hiroyuki ; 三輪, 真嗣 ; 白井, 寿治 ; 山本, 憲男 ; 林, 克洋 ; 武内, 章彦 ; 多田, 薫 ; 樋口, 貴史 ; 阿部, 健作 ; 土屋, 弘行
概要:
金沢大学医薬保健研究域医学系<br />Background: Postoperative deep infection after bone tumor surgery remains a serious complication. Al
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though there are numerous reports about risk factors for postoperative deep infection in general surgery, there is only a small number of reports about those for bone tumor surgery. This retrospective study aimed to identify risk factors for postoperative deep infection after bone tumor resection. Methods: We reviewed data of 681 patients (844 bone tumors) who underwent surgery. Associations between variables, including age, recurrent tumor, pathological fracture, surgical site (pelvis/other), chemotherapy, biological reconstruction, augmentation of artificial bone or bone cement, the use of an implant, intraoperative blood loss, operative time, additional surgery for complications, and postoperative deep infection were evaluated. Results: The rate of postoperative deep infection was 3.2% (27/844 tumors). A pelvic tumor (odds ratio [OR]: 3.4, 95% confidence interval [CI]: 1.0–11.3) and use of an implant (OR: 9.3, 95% CI: 1.9–45.5) were associated with an increased risk of deep infection. Conclusions: This retrospective study showed that pelvic tumor and use of an implant were independent risk factors for deep infection. This information will help surgeons prepare an adequate surgical plan for patients with bone tumors. © 2017 Miwa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Matsubara, Hidenori ; Tsuchiya, Hiroyuki ; Watanabe, Koji ; Takeuchi, Akihiko ; Tomita, Katsuro
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金沢大学医薬保健研究域医学系<br />Hepatocyte growth factor (HGF) was initially identified in cultured hepatocytes and subsequently rep
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orted to induce angiogenic, morphogenic, and antiapoptotic activity in various tissues. These properties suggest a potential influence of HGF on bone healing. We asked if gene transfer of human HGF (hHGF) into an osteotomy gap with a hemagglutinating virus of Japan-envelope (HVJ-E) vector promotes bone healing in rabbits. HVJ-E that contained either hHGF or control plasmid was percutaneously injected into the osteotomy gap of rabbit tibias on Day 14. The osteotomy gap was evaluated by radiography, pQCT, mechanical tests, and histology at Week 8. The expression of hHGF was evaluated by reverse transcriptase-polymerase chain reaction and immunohistochemistry at Week 3. Radiography, pQCT, and histology suggested the hHGF group had faster fracture healing. Mechanical tests demonstrated the hHGF group had greater mechanical strength. The injected tissues at 3 weeks expressed hHGF mRNA by reverse transcriptase-polymerase chain reaction. hHGF-positive immunohistochemical staining was observed in various cells at the osteotomy gap at Week 3. The data suggest delivery of hHGF plasmid into the osteotomy gap promotes fracture repair, and HGF could become a novel agent for fracture treatment.全文公開200912
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Yokogawa, Noriaki ; Murakami, Hideki ; Demura, Satoru ; Kato, Satoshi ; Yoshioka, Katsuhito ; Yamamoto, Miyuki ; Iseki, Shoichi ; Tsuchiya, Hiroyuki
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Purpose Spinal surgery in a previously irradiated field carries increased risk of perioperative complications, such as d
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elayed wound healing or wound infection. In addition, adhesion around the dura mater is often observed clinically. Therefore, similar to radiation-induced fibrosis- a major late-stage radiation injury in other tissue-epidural fibrosis is anticipated to occur after spinal radiation. In this study, we performed histopathologic assessment of postirradiation changes in the spinal dura mater and peridural tissue in mice. Materials and Methods The thoracolumbar transition of ddY mice was irradiated with a single dose of 10 or 20 Gy. After resection of the irradiated spine, occurrence of epidural fibrosis and expression of transforming growth factor beta 1 in the spinal dura mater were evaluated. In addition, microstructures in the spinal dura mater and peridural tissue were assessed using an electron microscope. Results In the 20-Gy irradiated mice, epidural fibrosis first occurred around 12 weeks postirradiation, and was observed in all cases from 16 weeks postirradiation. In contrast, epidural fibrosis was not observed in the nonirradiated mice. Compared with the nonirradiated mice, the 10- and 20-Gy irradiated mice had significantly more overexpression of transforming growth factor beta 1 at 1 week postirradiation and in the late stages after irradiation. In microstructural assessment, the arachnoid barrier cell layer was thinned at 12 and 24 weeks postirradiation compared with that in the nonirradiated mice. Conclusion In mice, spinal epidural fibrosis develops in the late stages after high-dose irradiation, and overexpression of transforming growth factor beta 1 occurs in a manner similar to that seen in radiation-induced fibrosis in other tissue. Additionally, thinning of the arachnoid barrier cell layer was observed in the late stages after irradiation. Thus, consideration should be given to the possibility that these phenomena can occur as radiation-induced injuries of the spine. Copyright © 2015 Yokogawa et al.
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