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Identification of exosomal surface marker derived from Ewing sarcoma cells

Aki Yoshida, Tomohiro Fujiwara, Koji Uotani, Yusuke Yoshioka, Koji Ueda, Takuya Morita, Ken Takeda, Toshiyuki Kunisada, Yutaka Nezu, Hiroyuki Kawashima, Takahiro Ochiya, Toshifumi Ozaki

CANCER RESEARCH 76 2016年7月

Tumor suppressor p53 reactivation by oncolytic adenovirus reverses chemoresistance in human osteosarcomas

Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016年7月

ROCK inhibition stimulates SOX9/Smad3-dependent COL2A1 expression in inner meniscus cells

Takayuki Furumatsu, Ami Maehara, Toshifumi Ozaki

JOURNAL OF ORTHOPAEDIC SCIENCE 21 ( 4 ) 524 - 529 2016年7月

記述言語：英語出版者・発行元：SPRINGER JAPAN KK

Background: Proper functioning of the meniscus depends on the composition and organization of its fibrocartilaginous extracellular matrix. We previously demonstrated that the avascular inner meniscus has a more chondrocytic phenotype compared with the outer meniscus. Inhibition of the Rho family GTPase ROCK, the major regulator of the actin cytoskeleton, stimulates the chondrogenic transcription factor Sry-type HMG box (SOX) 9-dependent alpha 1(II) collagen (COL2A1) expression in inner meniscus cells. However, the crosstalk between ROCK inhibition, SOX9, and other transcription modulators on COL2A1 upregulation remains unclear in meniscus cells. The aim of this study was to investigate the role of SOX9-related transcriptional complex on COL2A1 expression under the inhibition of ROCK in human meniscus cells.
Methods: Human inner and outer meniscus cells were prepared from macroscopically intact lateral menisci. Cells were cultured in the presence or absence of ROCK inhibitor (ROCKi, Y27632). Gene expression, collagen synthesis, and nuclear translocation of SOX9 and Smad2/3 were analyzed.
Results: Treatment of ROCKi increased the ratio of type I/II collagen double positive cells derived from the inner meniscus. In real-time PCR analyses, expression of SOX9 and COL2A1 genes was stimulated by ROCKi treatment in inner meniscus cells. ROCKi treatment also induced nuclear translocation of SOX9 and phosphorylated Smad2/3 in immunohistological analyses. Complex formation between SOX9 and Smad3 was increased by ROCKi treatment in inner meniscus cells. Chromatin immunoprecipitation analyses revealed that association between SOX9/Smad3 transcriptional complex with the COL2A1 enhancer region was increased by ROCKi treatment.
Conclusions: This study demonstrated that ROCK inhibition stimulated SOX9/Smad3-dependent COL2A1 expression through the immediate nuclear translocation of Smad3 in inner meniscus cells. Our results suggest that ROCK inhibition can stimulates type II collagen synthesis through the cooperative activation of Smad3 in inner meniscus cells. ROCKi treatment may be useful to promote the fibrochondrocytic healing of the injured inner meniscus. (C) 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jos.2016.02.013

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悪性軟部腫瘍に対するエリブリン投与例の検討(第2相試験)

荒木信人, 川井章, 内藤陽一, 尾崎敏文, 杉浦英志, 矢澤康男, 森岡秀夫, 松峯昭彦, 平岩昌英, 浅見俊, 井須和男

日本整形外科学会雑誌 90 ( 6 ) S1227 - S1227 2016年6月

Laminar closure rates in patients with cervical myelopathies treated with either open-door laminoplasty with reattachment of spinous processes and extensor musculature or Hirabayashi open-door laminoplasty: a case-control study

Kentaro Yamane, Yoshihisa Sugimoto, Masato Tanaka, Shinya Arataki, Tomoyuki Takigawa, Toshifumi Ozaki

EUROPEAN SPINE JOURNAL 25 ( 6 ) 1869 - 1874 2016年6月

記述言語：英語出版者・発行元：SPRINGER

The presence of preoperative kyphosis has been identified as a risk factor for laminar closure (LC). We have been performing modified open-door laminoplasty with reattachment of the spinous processes and extensor musculature for patients with reduced cervical lordosis because this procedure can prevent progression of cervical kyphosis. This procedure may also prevent LC. The purpose of this study was to evaluate the rate of LC after the modified open-door laminoplasty.
A total of 104 patients who underwent open-door laminoplasty were retrospectively reviewed. Of these patients, 18 underwent modified open-door laminoplasty (group M), whereas the other 86 underwent Hirabayashi open-door laminoplasty (group H). Group H was divided into two classes according to the preoperative cervical lordosis angle (group H1 a parts per thousand currency sign 10A degrees vs. group H2 a parts per thousand yen 11A degrees). All 18 patients in group M had a preoperative lordosis angle a parts per thousand currency sign10A degrees. The outcomes were assessed using the rate of LC, the cross-sectional area (CSA) of the erector muscle on magnetic resonance imaging, and the Japanese Orthopaedic Association score (JOA score).
The rate of laminar closure was significantly lower in group M (39 %) than in group H1 (76 %) (P < 0.01). The CSAs tended to be larger in the muscle preservation side of group M than in the other groups. There was no significant difference in the JOA score among the three groups.
Although patients with decreased cervical lordosis have a higher risk of LC, the results suggested that modified open-door laminoplasty could reduce the rate of LC compared with Hirabayashi open-door laminoplasty.

DOI： 10.1007/s00586-016-4398-3

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Transuncovertebral joint screw placement: technical note

Tomoyuki Takigawa, Masato Tanaka, Takuya Morita, Yoshihisa Sugimoto, Ozaki Toshifumi

EUROPEAN SPINE JOURNAL 25 ( 6 ) 1655 - 1660 2016年6月

記述言語：英語出版者・発行元：SPRINGER

Although a C2 pedicle screw and a C1-2 transarticular screw are the most rigid anchors, these screws cannot be used in cases with bilateral high-riding vertebral arteries. The authors describe their recent experience using a novel method of C2-3 transuncovertebral joint screw placement for occipitocervical fixation.
A 67-year-old patient suffered myelopathy due to instability at C1-2. The patient had bilateral high-riding vertebral arteries that precluded the use of a C2 pedicle screw or a C1-2 transarticular screw.
A C2-3 transuncovertebral joint screw was applied bilaterally under 3D navigation guidance. The patient's postoperative course was uneventful, and his neurological status improved after the surgery. Bony fusion was achieved after the surgery.
This is the first report to describe the technique of transuncovertebral joint screw. Using a C2-3 transuncovertebral joint screw, a long screw could be used, and it provided an anchor at C3 and C2 from a posterior approach.

DOI： 10.1007/s00586-015-4343-x

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Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 6 2016年6月

記述言語：英語出版者・発行元：NATURE PUBLISHING GROUP

Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

DOI： 10.1038/srep28953

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局所放射線療法後パゾパニブ投与中に腸管穿孔を来した後腹膜軟部肉腫の1例

杉原進介, 中田英二, 尾崎敏文

日本整形外科学会雑誌 90 ( 6 ) S1379 - S1379 2016年6月

脊椎転移に対する保存的治療と外科的治療脊椎SREsの治療成績

中田英二, 杉原進介, 菅原敬文, 尾崎敏文

日本整形外科学会雑誌 90 ( 6 ) S1287 - S1287 2016年6月

前十字再建術に伴う外側半月板縫合術による外側半月板サイズは変化する

柏原尚子, 宮澤慎一, 堅山佳美, 千田益生, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine ( JARM2016 ) I48 - I48 2016年6月

Carbon-ion radiotherapy of spinal osteosarcoma with long-term follow

Wei Zhang, Masato Tanaka, Yoshihisa Sugimoto, Tomoyuki Takigawa, Toshifumi Ozaki

EUROPEAN SPINE JOURNAL 25 ( S1 ) S113 - S117 2016年5月

記述言語：英語出版者・発行元：SPRINGER

Purpose Primary spinal osteosarcoma is quite rare, and the 5-year survival rate is very low. Because of its rarity, successful treatment experience with spinal osteosarcoma is limited. The purpose of this study is to report the effect of therapy of primary osteosarcoma of spine by carbon-ion radiotherapy (CIRT) and long-term follow.
Methods A 70-year-old with primary spinal osteosarcoma who received CIRT underwent combined anterior artificial vertebral body replacement and posterior lumbar fusion (L1-L5) 3 years later.
Results According to the surgical resection of tumoral lesion, pathological results showed that the intertrabecular space previously filled with tumor cells on the initial biopsy sample now contained necrotic tissue without tumor cells. This means that primary osteosarcoma of the spine was completely eliminated and achieved local control with CIRT, with a 7-year follow-up after the initial treatment.
Conclusions Carbon ion beam treatment is an effective local treatment for patients with spinal osteosarcoma for whom surgical resection is not a feasible option, especially for elderly patients. However, more patients need to be evaluated over a longer term to assess the curative effect of CIRT.

DOI： 10.1007/s00586-015-4202-9

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Carbon Ion Radiation Therapy for Unresectable Sacral Chordoma: An Analysis of 188 Cases

Reiko Imai, Tadashi Kamada, Nobuhito Araki

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 95 ( 1 ) 322 - 327 2016年5月

記述言語：英語出版者・発行元：ELSEVIER SCIENCE INC

Purpose: To evaluate the results of carbon ion radiation therapy administered to 188 patients with unresectable primary sacral chordomas.
Patients and Methods: One hundred eighty-eight patients were treated with carbon ion radiation therapy at a single institute between 1996 and 2013 and retrospectively analyzed. The median age was 66 years. The highest proximal invasion reached past S2 level in 137 patients. The median clinical target volume was 345 cm(3). One hundred six patients received 67.2 gray equivalents (GyE)/16 fractions (fr), 74 patients received 70.4 GyE/16 fr, 7 patients received 73.6 GyE/16 fr, and 1 patient received 64.0 GyE/16 fr.
Results: The median follow-up period was 62 months (range, 6.8-147.5 months). Seventy percent of patients were followed for 5 years or until death. The 5-year local control, overall survival, and disease-free survival rates were 77.2%, 81.1%, and 50.3%, respectively. Forty-one patients had a local recurrence. Sex, tumor volume, level of proximal invasion, and irradiated dose were unrelated to local control. There was grade 3 toxicity of the peripheral nerves in 6 patients and grade 4 toxicity of the skin in 2 patients. Ambulation remained in 97% of patients.
Conclusions: Carbon ion radiation therapy was safe and effective for unresectable chordoma and provided good local control and survival while preserving ambulation. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ijrobp.2016.02.012

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麻痺を認めない脊椎SREsに対する保存的治療

中田英二, 杉原進介, 尾崎敏文

整形外科と災害外科 65 ( Suppl.1 ) 89 - 89 2016年5月

Minimally Invasive Spinopelvic Fixation for Unstable Bilateral Sacral Fractures

Koichiro Koshimune, Yasuo Ito, Yoshihisa Sugimoto, Takeshi Kikuchi, Takuya Morita, Shoichiro Mizuno, Toshifumi Ozaki

CLINICAL SPINE SURGERY 29 ( 3 ) 124 - 127 2016年4月

記述言語：英語出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Study Design: Retrospective case series.
Objective: We present a minimally invasive spinopelvic fixation technique for unstable bilateral sacral fractures and describe a technical report.
Summary of Background Data: Unstable sacral fractures are severe injuries with high mortality and morbidity due to pain and malunion. Galveston technique is useful for rigid fixation of an unstable sacral fracture. However, wound-related complications with this technique have been relatively common because of extensive contusion of the skin or poor blood supply after embolization.
Materials and Methods: There were 34 patients with unstable pelvic fractures between 2005 and 2012. We performed conventional open surgery between 2005 and 2009. Minimally invasive spinopelvic fixation was performed between 2009 and 2012. Minimally invasive technique needs 4 small, lateral incisions for percutaneous lumbar pedicle screw insertion. We pushed a pure titanium rod into the paravertebral muscle.
Results: The average surgical time was 345 minutes in the conventional fixation and 208 minutes with the minimally invasive fixation. The average intraoperative bleeding was 520 mL in the conventional fixation and 290 mL in minimally invasive fixation. When comparing deep wound infection, 3 of 8 (38%) patients who received conventional fixation had methicillin-resistant Staphylococcus aureus infections, whereas nobody who received the minimally invasive fixation acquired infection. Bony union was achieved in 15 of the 16 patients.
Conclusions: In this study, minimally invasive spinopelvic fixation required a shorter surgical time, incurred less bleeding, and had a lower infection rate than fixation with the conventional Galveston technique.

DOI： 10.1097/BSD.0000000000000090

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Biomechanical Comparison of Posterior Fixation Using Spinal Instrumentation and Conventional Posterior Plate Fixation in Unstable Vertical Sacral Fracture

Kensuke Shinohara, Tomoyuki Takigawa, Masato Tanaka, Yoshihisa Sugimoto, Shinya Arataki, Yasuo Ito, Toshifumi Ozaki

ACTA MEDICA OKAYAMA 70 ( 2 ) 97 - 102 2016年4月

記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

Vertical sacral fracture is one of the most difficult fractures to treat. Posterior fixation using spinal dual rods is a novel method for treating this fracture, but its biomechanical strength has not yet been reported. The aim of this study was to evaluate the biomechanical strength produced by posterior fixation using spinal instrumentation. Sacral fractures were created in eight pelvic bone models and classified into a posterior plate fixation group [P group, n=4] and a spinal instrumentation group [R group, n=4]. The biomechanical strength was tested by pushing down on the S1 vertebra from the top. The mean maximum loads were 1,057.4 N and 1,489.4 N in the P and R groups, respectively (p= 0.014). The loads applied to the construct at displacements of 5 mm and 7.5 mm from the start of the universal testing machine loading were also significantly higher in the R group. The mean stiffness levels in the P and R groups were 88.3N/mm and 119.6N/mm, respectively (p=0.014). Posterior fixation using spinal instrumentation is biomechanically stronger than conventional posterior plate fixation. This procedure may be the optimal method for treating unstable sacral fracture fixation.

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新しい統合指針の導入により倫理審査体制はどう変化したか倫理審査を兼任する整形外科医が読み取る倫理申請の現状とこれから

藤原智洋, 吉原久美子, 大野彩, 三橋利晴, 丸山貴之, 桑木健志, 加藤有加, 伊東孝, 難波志穂子, 樋之津史郎, 尾崎敏文

日本整形外科学会雑誌 90 ( 3 ) S657 - S657 2016年3月

A randomized, double-blind, placebo-controlled, Phase III study of pazopanib in patients with soft tissue sarcoma: results from the Japanese subgroup

Akira Kawai, Nobuhito Araki, Hiroaki Hiraga, Hideshi Sugiura, Akihiko Matsumine, Toshifumi Ozaki, Takafumi Ueda, Takeshi Ishii, Taito Esaki, Michiko Machida, Nobuaki Fukasawa

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 3 ) 248 - 253 2016年3月

記述言語：英語出版者・発行元：OXFORD UNIV PRESS

This analysis of the Japanese subpopulation of the PALETTE Phase III, randomized, placebo-controlled study investigated efficacy and safety of pazopanib in patients with metastatic soft tissue sarcoma after failure of standard chemotherapy.
Patients were randomly assigned in a 2:1 ratio to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Primary endpoint was progression-free survival. Secondary endpoints included overall survival and overall response rate. Efficacy analysis was by intent-to-treat. Safety was also investigated.
Forty-seven patients received either pazopanib (n = 31) or placebo (n = 16). Median progression-free survival was 7.0 weeks (95% confidence interval: 4.0-11.7) for placebo and 24.7 weeks (95% confidence interval: 8.6-28.1) for pazopanib (hazard ratio = 0.41 [95% confidence interval: 0.19-0.90]; P = 0.002). Median overall survival was 14.9 months (95% confidence interval: 6.8-not calculable) for placebo and 15.4 months (95% confidence interval: 7.9-28.8) for pazopanib (hazard ratio = 0.87 [95% confidence interval: 0.41-1.83]; P = 0.687). More patients receiving pazopanib experienced best response of stable disease versus placebo. Adverse events were similar to the global population; those leading to dose reduction were more common and mean daily dose was lower in the Japanese population versus the global population (45 vs. 32% and 624.4 vs. 700.4 mg, respectively).
The efficacy and safety of pazopanib observed in the Japanese subpopulation of PALETTE were similar to those in the global population. Pazopanib is a new treatment option for Japanese patients with metastatic non-adipocytic soft tissue sarcoma after chemotherapy.
NCT00753688; GSK study ID: VEG110727;.

DOI： 10.1093/jjco/hyv184

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Implant Failure of Titanium Versus Cobalt-Chromium Growing Rods in Early-onset Scoliosis

Kensuke Shinohara, Tomoyuki Takigawa, Masato Tanaka, Yoshihisa Sugimoto, Shinya Arataki, Kentaro Yamane, Noriyuki Watanabe, Toshifumi Ozaki, Takaaki Sarai

SPINE 41 ( 6 ) 502 - 507 2016年3月

記述言語：英語出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Study Design.Retrospective case series of one institute database.Objective.To investigate the differences in the metallic strength of rods used for implant failure in the dual growing rod technique and evaluate clinical outcomes.Summary of Background Data.The dual growing rod technique in which implanted rods extend with the growth of the spine is a useful treatment for early onset scoliosis. However, many complications, particularly those associated with rods, exist. Especially, the implant failure of growing rod focused on metallic strength is unknown.Methods.Thirteen patients (42 lengthening surgeries) who underwent surgery by this technique at our hospital from 2007 were divided into a titanium rod plus titanium connector group (T group, n=4, 26 lengthening surgeries) and cobalt-chromium rod plus titanium connection group (C group, n=9, 16 lengthening surgeries). The incidence of implant failure and the site of fracture were retrospectively investigated.Results.Implant failure occurred in three patients in the T group, because of rod fracture in two patients and connector fracture in one. In the C group, implant failure occurred in six patients, because of rod fracture in one patient and connector fracture in seven. Fracture occurred twice in two patients. The rod fracture rate decreased with the use of cobalt-chromium rods but the rate of connector fracture increased.We performed a stress distribution analysis using the finite element method to clarify the mechanisms underlying implant failure in both groups. Regardless of the rod type, the greater load was placed on the distal rod. However, differences in the metallic strength caused the rod to fracture when titanium rods were used and connectors (weak metallic strength) to fracture when cobalt-chromium rods were used.Conclusion.Rod fractures occurred more commonly with titanium rods and connector fractures with cobalt-chromium rods.Level of Evidence: 4

DOI： 10.1097/BRS.0000000000001267

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The anterior cruciate ligament-lateral meniscus complex: A histological study

Takayuki Furumatsu, Yuya Kodama, Ami Maehara, Shinichi Miyazawa, Masataka Fujii, Takaaki Tanaka, Hiroto Inoue, Toshifumi Ozaki

CONNECTIVE TISSUE RESEARCH 57 ( 2 ) 91 - 98 2016年3月

記述言語：英語出版者・発行元：TAYLOR & FRANCIS INC

The anterior root of the lateral meniscus (LM) dives underneath the tibial attachment of the anterior cruciate ligament (ACL). Although the distinct role of meniscal attachments has been investigated, the relationship between the LM anterior insertion (LMAI) and ACL tibial insertion (ACLTI) remains unclear. This study histologically analyzed the LMAI and ACLTI. Samples were divided into four regions in an anterior-to-posterior direction. Histological measurements of these insertion sites were performed using safranin O-stained coronal sections. Distribution and signal densities of type I and II collagen were quantified. The ACLTI and LMAI formed the ACL-LM complex via fiber connections. The anterior part of the ACLTI had a widespread attachment composed of dense fibers. Attachment fibers of the LMAI became dense and wide gradually at the middle-to-posterior region. The ACL-LM transition zone (ALTZ) was observed between the LMAI and the lateral border of the ACLTI at the middle part of the ACL tibial footprint. Type II collagen density of the LMAI was higher than that of the ACLTI and ALTZ. Our results can help create an accurate tibial bone tunnel within the dense ACL attachment during ACL reconstruction surgery.

DOI： 10.3109/03008207.2015.1081899

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四肢転移性骨腫瘍に対する治療戦略四肢転移性骨腫瘍患者の予後予測について

杉原進介, 中田英二, 尾崎敏文

日本整形外科学会雑誌 90 ( 3 ) S614 - S614 2016年3月

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