研究者詳細 - 藤原　智洋

論文 - 藤原　智洋

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Empowering pediatric, adolescent, and young adult patients with cancer utilizing generative AI chatbots to reduce psychological burden and enhance treatment engagement: a pilot study

Joe Hasei, Mana Hanzawa, Akihito Nagano, Naoko Maeda, Shinichirou Yoshida, Makoto Endo, Nobuhiko Yokoyama, Motoharu Ochi, Hisashi Ishida, Hideki Katayama, Tomohiro Fujiwara, Eiji Nakata, Ryuichi Nakahara, Toshiyuki Kunisada, Hirokazu Tsukahara, Toshifumi Ozaki

Frontiers in Digital Health 7 2025年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers Media SA

Background

Pediatric and adolescent/young adult (AYA) cancer patients face profound psychological challenges, exacerbated by limited access to continuous mental health support. While conventional therapeutic interventions often follow structured protocols, the potential of generative artificial intelligence (AI) chatbots to provide continuous conversational support remains unexplored. This study evaluates the feasibility and impact of AI chatbots in alleviating psychological distress and enhancing treatment engagement in this vulnerable population.

Methods

Two age-appropriate AI chatbots, leveraging GPT-4, were developed to provide natural, empathetic conversations without structured therapeutic protocols. Five pediatric and AYA cancer patients participated in a two-week intervention, engaging with the chatbots via a messaging platform. Pre- and post-intervention anxiety and stress levels were self-reported, and usage patterns were analyzed to assess the chatbots’ effectiveness.

Results

Four out of five participants reported significant reductions in anxiety and stress levels post-intervention. Participants engaged with the chatbot every 2–3 days, with sessions lasting approximately 10 min. All participants noted improved treatment motivation, with 80% disclosing personal concerns to the chatbot they had not shared with healthcare providers. The 24/7 availability particularly benefited patients experiencing nighttime anxiety.

Conclusions

This pilot study demonstrates the potential of generative AI chatbots to complement traditional mental health services by addressing unmet psychological needs in pediatric and AYA cancer patients. The findings suggest these tools can serve as accessible, continuous support systems. Further large-scale studies are warranted to validate these promising results.

DOI： 10.3389/fdgth.2025.1543543

Radiographic and Clinical Assessment of Unidirectional Porous Beta-Tricalcium Phosphate to Treat Benign Bone Tumors. 国際誌

Toshiyuki Kunisada, Eiji Nakata, Tomohiro Fujiwara, Haruyoshi Katayama, Takuto Itano, Takanao Kurozumi, Teruhiko Ando, Toshifumi Ozaki

Biomimetics (Basel, Switzerland) 10 ( 2 ) 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

The purpose of this study was to evaluate radiographic changes, clinical outcomes, and complications following unidirectional porous beta-tricalcium phosphate (UDPTCP) implantation for the treatment of benign bone tumors. We retrospectively analyzed 46 patients who underwent intralesional resection. The patients were divided into two cohorts: Cohort 1 (n = 32), which included all bones except the phalanges and metacarpal/tarsal bones, and Cohort 2 (n = 14), which included the phalanges and metacarpal/tarsal bones. Radiographic changes were assessed at each reading based on resorption of the implanted UDPTCP and bone trabeculation through the defect. UDPTCP resorption and bone trabeculation were observed on radiographs within 3 months of surgery in all patients. Bone remodeling in the cavity progressed steadily for up to 3 years postoperatively. In Cohort 1, resorption and trabeculation progressed significantly in young patients, and trabeculation developed significantly in small lesions. The rates of resorption and trabeculation at 3 months postoperatively correlated statistically with their increased rates at one year. There was no statistical difference in resorption and trabeculation rates between Cohort 1 and Cohort 2. There were no cases of postoperative deep infections or allergic reactions related to the implant. UDPTCP is a useful bone-filling substitute for the treatment of benign bone tumors and has a low complication rate.

DOI： 10.3390/biomimetics10020101

The Three-Class Annotation Method Improves the AI Detection of Early-Stage Osteosarcoma on Plain Radiographs: A Novel Approach for Rare Cancer Diagnosis. 国際誌

Joe Hasei, Ryuichi Nakahara, Yujiro Otsuka, Yusuke Nakamura, Kunihiro Ikuta, Shuhei Osaki, Tamiya Hironari, Shinji Miwa, Shusa Ohshika, Shunji Nishimura, Naoaki Kahara, Aki Yoshida, Tomohiro Fujiwara, Eiji Nakata, Toshiyuki Kunisada, Toshifumi Ozaki

Cancers 17 ( 1 ) 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background/Objectives: Developing high-performance artificial intelligence (AI) models for rare diseases is challenging owing to limited data availability. This study aimed to evaluate whether a novel three-class annotation method for preparing training data could enhance AI model performance in detecting osteosarcoma on plain radiographs compared to conventional single-class annotation. Methods: We developed two annotation methods for the same dataset of 468 osteosarcoma X-rays and 378 normal radiographs: a conventional single-class annotation (1C model) and a novel three-class annotation method (3C model) that separately labeled intramedullary, cortical, and extramedullary tumor components. Both models used identical U-Net-based architectures, differing only in their annotation approaches. Performance was evaluated using an independent validation dataset. Results: Although both models achieved high diagnostic accuracy (AUC: 0.99 vs. 0.98), the 3C model demonstrated superior operational characteristics. At a standardized cutoff value of 0.2, the 3C model maintained balanced performance (sensitivity: 93.28%, specificity: 92.21%), whereas the 1C model showed compromised specificity (83.58%) despite high sensitivity (98.88%). Notably, at the 25th percentile threshold, both models showed identical false-negative rates despite significantly different cutoff values (3C: 0.661 vs. 1C: 0.985), indicating the ability of the 3C model to maintain diagnostic accuracy at substantially lower thresholds. Conclusions: This study demonstrated that anatomically informed three-class annotation can enhance AI model performance for rare disease detection without requiring additional training data. The improved stability at lower thresholds suggests that thoughtful annotation strategies can optimize the AI model training, particularly in contexts where training data are limited.

DOI： 10.3390/cancers17010029

がん遺伝子パネルによるfusion gene同定の診断的意義

中田英二, 國定俊之, 板野拓人, 片山晴喜, 安藤輝彦, 藤原智洋, 尾崎敏文

中国・四国整形外科学会雑誌 36 ( 3 ) 361 - 361 2024年10月

AIとメタバースを用いた骨軟部腫瘍診療革命早期診断から患者支援まで

長谷井嬢, 藤原智洋, 中田英二, 国定俊之, 尾崎敏文

日本癌治療学会学術集会抄録集 62回 PSP14 - 4 2024年10月

Identification of ENO-1 positive extracellular vesicles as a circulating biomarker for monitoring of Ewing sarcoma. 国際誌

Koji Uotani, Tomohiro Fujiwara, Koji Ueda, Aki Yoshida, Shintaro Iwata, Takuya Morita, Masahiro Kiyono, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Yusuke Yoshioka, Takahiro Ochiya, Toshifumi Ozaki

Cancer science 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The lack of circulating biomarkers for tumor monitoring is a major problem in Ewing sarcoma management. The development of methods for accurate tumor monitoring is required, considering the high recurrence rate of drug-resistant Ewing sarcoma. Here, we describe a sensitive analytical technique for tumor monitoring of Ewing sarcoma by detecting circulating extracellular vesicles secreted from Ewing sarcoma cells. Proteomic analysis of Ewing sarcoma cell-derived extracellular vesicles identified 564 proteins prominently observed in extracellular vesicles from three Ewing sarcoma cell lines. Among these, CD99, SLC1A5, and ENO-1 were identified on extracellular vesicles purified from sera of patients with Ewing sarcoma before treatment but not on extracellular vesicles from those after treatment and healthy individuals. Notably, not only Ewing sarcoma-derived extracellular vesicles but also Ewing sarcoma cells demonstrated proteomic expression of CD99 and ENO-1 on their surface membranes. ENO-1+CD63+ extracellular vesicle detection was reduced after tumor resection while both CD99+CD63+ and ENO-1+CD63+ extracellular vesicles were detected in serum from Ewing sarcoma-bearing mice. Finally, the accuracy of liquid biopsy targeting these candidates was assessed using extracellular vesicles from the sera of patients with Ewing sarcoma. Elevated ENO-1+CD81+ extracellular vesicles in the serum of patients before treatments distinguished patients with Ewing sarcoma from healthy individuals with an area under the curve value of 0.92 (P < 0.001) and reflected the tumor burden in patients with Ewing sarcoma during multidisciplinary treatments. Collectively, circulating ENO-1+CD81+ extracellular vesicle detection could represent a novel tool for tumor monitoring of Ewing sarcoma.

DOI： 10.1111/cas.16343

p53-armed oncolytic virotherapy induces abscopal effect in osteosarcoma by promoting immunogenic cell death. 国際誌

Koji Demiya, Hiroshi Tazawa, Hiroya Kondo, Miho Kure, Yusuke Mochizuki, Tadashi Komatsubara, Aki Yoshida, Koji Uotani, Joe Hasei, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Molecular therapy. Oncology 32 ( 3 ) 200845 - 200845 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteosarcoma (OS), the most frequent primary malignant tumor of bone in children and adolescents, is refractory to immune checkpoint inhibitors due to its poor antitumor immune response. Chemotherapy and virotherapy induce immunogenic cell death (ICD) and antitumor immune responses, leading to the abscopal effect in untreated tumors. We previously demonstrated the antitumor activity of the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 in human OS cells. Here, we show the therapeutic potential of chemotherapeutic drugs (doxorubicin, cisplatin) and telomerase-specific oncolytic adenoviruses (OBP-301, p53-armed OBP-702) to induce ICD in human OS cells (U2OS, MNNG/HOS, SaOS-2) and murine OS cells (NHOS). OBP-702 induced more profound ICD via the secretion of adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1) compared with chemotherapy and OBP-301 in human OS cells. Murine NHOS cells were also more sensitive to OBP-702 than OBP-301. Subcutaneous NHOS tumor models demonstrated that intratumoral injection of OBP-702 significantly increased the tumor infiltration of cytotoxic CD8+ T cells and induced the abscopal effect against non-treated tumors compared with OBP-301. Our results suggest that OBP-702 is a promising antitumor reagent to induce ICD with secretion of ATP and HMGB1 and the abscopal effect against OS.

DOI： 10.1016/j.omton.2024.200845

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

Joe Hasei, Ryuichi Nakahara, Yujiro Otsuka, Yusuke Nakamura, Tamiya Hironari, Naoaki Kahara, Shinji Miwa, Shusa Ohshika, Shunji Nishimura, Kunihiro Ikuta, Shuhei Osaki, Aki Yoshida, Tomohiro Fujiwara, Eiji Nakata, Toshiyuki Kunisada, Toshifumi Ozaki

Cancer science 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1111/cas.16330

悪性末梢神経鞘腫瘍における悪性化を促進する新規メカニズム転写因子PRRX1とTOP2Aのタンパク質間相互作用の発見

たき平将太, 山田大祐, 大曽根達則, 高尾知佳, 板野拓人, 藤原智洋, 中田英二, 国定俊之, 尾崎敏文, 宝田剛志

日本整形外科学会雑誌 98 ( 8 ) S1957 - S1957 2024年9月

肉腫におけるゲノム医療の進歩 C-CATデータを用いた肉腫のゲノム解析

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 国定俊之, 藤原智洋, 二川摩周, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 8 ) S1727 - S1727 2024年9月

Efficacy and safety of denosumab de‑escalation in giant cell tumor of bone. 国際誌

Eiji Nakata, Toshiyuki Kunisada, Tomohiro Fujiwara, Haruyoshi Katayama, Takuto Itano, Toshifumi Ozaki

Oncology letters 28 ( 2 ) 387 - 387 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Giant cell tumor of bone (GCTB) is a locally aggressive intermediate bone tumor. Denosumab has shown effectiveness in GCTB treatment; however, the benefits of denosumab de-escalation for unresectable GCTB have not been well discussed. The present study investigated the efficacy and safety of denosumab de-escalation for GCTB. The medical records of 9 patients with unresectable GCTB or resectable GCTB not eligible for resection, who received de-escalated denosumab treatment at Okayama University Hospital (Okayama, Japan) between April 2014 and December 2021, were retrospectively reviewed. The denosumab treatment interval was gradually extended to every 8, 12 and 24 weeks. The radiographic changes and clinical symptoms during standard and de-escalated denosumab therapy were assessed. The denosumab interval was de-escalated after a median of 12 months of a standard 4-weekly treatment. Imaging showed that the re-ossification of osteolytic lesions obtained with the 4-weekly treatment were sustained with 8- and 12-weekly treatments. The extraskeletal masses reduced significantly with standard treatment, while tumor reduction was sustained during de-escalated treatment. During the 24-weekly treatment, 2 patients remained stable, while 2 patients developed local recurrence. The clinical symptoms improved significantly with standard treatment and remained improved during de-escalated treatment. There were severe adverse events including osteonecrosis of the jaw (2 patients), atypical femoral fracture (1 patient) and malignant transformation of GCTB (1 patient). In conclusion, 12-weekly de-escalated denosumab treatment showed clinical benefits as a maintenance treatment in patients with unresectable GCTB, in addition to sustained stable tumor control and improved clinical symptoms with standard treatment. A 24-weekly treatment can also be administered, with careful attention paid to detecting local recurrence.

DOI： 10.3892/ol.2024.14520

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

Joe Hasei, Hisashi Ishida, Hideki Katayama, Naoko Maeda, Akihito Nagano, Motoharu Ochi, Masako Okamura, Shintaro Iwata, Kunihiro Ikuta, Shinichirou Yoshida, Tomohiro Fujiwara, Eiji Nakata, Ryuichi Nakahara, Toshiyuki Kunisada, Toshifumi Ozaki

Cancers 16 ( 15 ) 2617 - 2617 2024年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

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

DOI： 10.3390/cancers16152617

A Characteristic Magnetic Resonance Imaging Finding to Identify Morton Neuroma: The Slug Sign

Masahiro Horita, Kenta Saiga, Tomohiro Fujiwara, Eiji Nakata, Toshifumi Ozaki

Foot & Ankle Orthopaedics 9 ( 3 ) 2024年7月

掲載種別：研究論文（学術雑誌）出版者・発行元：SAGE Publications

Background:

Morton neuroma is a common cause of forefoot pain and sensory disturbances, but it is difficult to identify on magnetic resonance imaging (MRI). The aim of this study was to verify the usefulness of a characteristic MRI finding (slug sign) for identifying Morton neuroma and to clarify the relationship between excised neuroma characteristics and preoperative MRI findings.

Methods:

Twenty-two web spaces were retrospectively assessed from the second and third intermetatarsal spaces of 11 feet of 10 patients (7 women and 3 men, aged average 59.5 years) who underwent surgical excision of Morton neuroma between 2017 and 2022. Asymptomatic web spaces were used as control. Neuromas with 2 branches of the plantar digital nerves on axial T1-weighted MRI (MRI-T1WI) were considered the slug sign. We investigated the preoperative presence of the slug sign in Morton neuroma and asymptomatic control web spaces. We also investigated the relationship between the maximum transverse diameter of the excised specimen and that estimated on coronal MRI-T1WI.

Results:

A total of 15 Morton neuromas were excised and assessed. The slug signs were present in 10 intermetatarsal spaces in 15 web spaces with Morton neuroma whereas the sign was found in 1 intermetatarsal space in 7 asymptomatic web spaces. The sensitivity and specificity for the slug sign to diagnose Morton neuroma was 66.7% and 85.7%, respectively. The positive and negative predictive values were 90.9% and 54.5%, respectively. The mean maximum transverse diameter of excised neuromas was 4.7 mm. The mean maximum transverse diameter of neuromas on coronal MRI-T1WI was 3.4 mm. A significant positive correlation was found between the maximum transverse diameters of excised specimens and diameters estimated on coronal MRI-T1WI ( r = 0.799, P < .001).

Conclusion:

The slug sign may be a useful indicator of Morton neuroma on MRI to confirm nerve involvement after bifurcation.

Level of Evidence:

Level IV, retrospective series.

DOI： 10.1177/24730114241268285

その他リンク： https://journals.sagepub.com/doi/full-xml/10.1177/24730114241268285

悪性末梢神経鞘腫瘍におけるPRRX1とTOP2Aの相互作用による悪性化メカニズムの新規解明

たき平将太, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 大曽根達則, 山田大祐, 高尾知佳, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1529 - S1529 2024年6月

神経線維腫症1型を中心とした遺伝性骨・軟部腫瘍に対する専門外来の有用性

中田英二, 二川摩周, 平沢晃, 山本英喜, 国定俊之, 板野拓人, 藤原智洋, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1614 - S1614 2024年6月

加速する骨・軟部腫瘍に対するゲノム医療: 現状と課題肉腫におけるゲノム医療の現状と課題

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 藤原智洋, 国定俊之, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1457 - S1457 2024年6月

多職種から見た骨・軟部腫瘍治療の現状と課題肉腫発生ハイリスク患者に対する遺伝性骨・軟部腫瘍外来の取り組み

二川摩周, 中田英二, 山本英喜, 深野智華, 加藤芙美乃, 大住理沙, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1579 - S1579 2024年6月

Clinical Application of Unidirectional Porous Hydroxyapatite to Bone Tumor Surgery and Other Orthopedic Surgery. 国際誌

Toshiyuki Kunisada, Eiji Nakata, Tomohiro Fujiwara, Toshiaki Hata, Kohei Sato, Haruyoshi Katayama, Ayana Kondo, Toshifumi Ozaki

Biomimetics (Basel, Switzerland) 9 ( 5 ) 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Unidirectional porous hydroxyapatite (UDPHAp) was developed as a remarkable scaffold characterized by a distinct structure with unidirectional pores oriented in the horizontal direction and connected through interposes. We evaluated the radiographic changes, clinical outcomes, and complications following UDPHAp implantation for the treatment of bone tumors. Excellent bone formation within and around the implant was observed in all patients treated with intralesional resection and UDPHAp implantation for benign bone tumors. The absorption of UDPHAp and remodeling of the bone marrow space was observed in 45% of the patients at a mean of 17 months postoperatively and was significantly more common in younger patients. Preoperative cortical thinning was completely regenerated in 84% of patients at a mean of 10 months postoperatively. No complications related to the implanted UDPHAp were observed. In a pediatric patient with bone sarcoma, when the defect after fibular resection was filled with UDPHAp implants, radiography showed complete resorption of the implant and clear formation of cortex and marrow in the resected part of the fibula. The patient could walk well without crutches and participate in sports activities. UDPHAp is a useful bone graft substitute for the treatment of benign bone tumors, and the use of this material has a low complication rate. We also review and discuss the potential of UDPHAp as a bone graft substitute in the clinical setting of orthopedic surgery.

DOI： 10.3390/biomimetics9050294

p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression.

Tadashi Komatsubara, Hiroshi Tazawa, Joe Hasei, Toshinori Omori, Kazuhisa Sugiu, Yusuke Mochizuki, Koji Demiya, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Acta medica Okayama 78 ( 2 ) 151 - 161 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

DOI： 10.18926/AMO/66924

PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumours. 国際誌

Shota Takihira, Daisuke Yamada, Tatsunori Osone, Tomoka Takao, Masakiyo Sakaguchi, Michiyuki Hakozaki, Takuto Itano, Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Takeshi Takarada

British journal of cancer 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. METHODS: PRRX1 expression in human Malignant peripheral nerve sheath tumours (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA-seq and structural prediction were used to identify proteins interacting with PRRX1. RESULTS: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2 A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumour malignancy-related gene sets including mTORC1, KRAS and SRC signalling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. CONCLUSION: Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

DOI： 10.1038/s41416-024-02632-8

Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors. 国際誌

Haruyoshi Katayama, Atsushi Fujimura, Rongsheng Huang, Yusuke Otani, Takuto Itano, Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Toshifumi Ozaki

Cancer science 115 ( 3 ) 871 - 882 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through β2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

DOI： 10.1111/cas.16077

悪性末梢神経鞘腫瘍において転写因子PRRX1はTOP2Aと相互作用し悪性化を促進させる

たき平将太, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 大曽根達則, 山田大祐, 高尾知佳, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 98 ( 2 ) S76 - S76 2024年3月

肉腫におけるがん遺伝子パネルによるfusion gene同定の意義

中田英二, 藤原智洋, 板野拓人, 片山晴喜, 二川摩周, 山元英崇, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 98 ( 3 ) S1246 - S1246 2024年3月

AIとDXを用いた骨・軟部腫瘍診療への新たな挑戦

長谷井嬢, 中原龍一, 藤原智洋, 中田英二, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 98 ( 3 ) S1371 - S1371 2024年3月

術前がん患者の各ロコモ度テストにおける関連因子

堅山佳美, 中田英二, 近藤彩奈, 濱田全紀, 藤原智洋, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 98 ( 3 ) S1321 - S1321 2024年3月

悪性末梢神経鞘腫瘍において転写因子PRRX1はTOP2Aと相互作用し悪性化を促進させる

たき平将太, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 大曽根達則, 山田大祐, 高尾知佳, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 98 ( 2 ) S76 - S76 2024年3月

遺伝性骨・軟部腫瘍外来における肉腫発生at-risk者への取り組み

二川摩周, 中田英二, 山本英喜, 深野智華, 加藤芙美乃, 大住理沙, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本レックリングハウゼン病学会学術大会プログラム・抄録集 15回 25 - 25 2024年2月

Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes. 国際誌

Yoshifumi Hotta, Keiichiro Nishida, Aki Yoshida, Yoshihisa Nasu, Ryuichi Nakahara, Shuichi Naniwa, Noriyuki Shimizu, Chinatsu Ichikawa, Deting Lin, Tomohiro Fujiwara, Toshifumi Ozaki

International journal of molecular sciences 25 ( 3 ) 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and β-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1β in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1β, as well as the nuclear translocation of NF-κB and β-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of β-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

DOI： 10.3390/ijms25031443

Fluorescence-guided assessment of bone and soft-tissue sarcomas for predicting the efficacy of telomerase-specific oncolytic adenovirus. 国際誌

Koji Uotani, Hiroshi Tazawa, Joe Hasei, Tomohiro Fujiwara, Aki Yoshida, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Hiroya Kondo, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Toshiaki Hata, Toshiyuki Kunisada, Ken Takeda, Yasuo Urata, Toshiyoshi Fujiwara, Toshifumi Ozaki

PloS one 19 ( 2 ) e0298292 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

DOI： 10.1371/journal.pone.0298292

Does primary tumor resection improve survival for patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at diagnosis ? 国際誌

Xianglin Hu, Tomohiro Fujiwara, Yangbai Sun, Wending Huang, Wangjun Yan

European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 32 ( 12 ) 4362 - 4376 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Recent studies demonstrated that primary tumor resection (PTR) improves survival of patients with metastatic bone sarcomas. However, it remains quite unclear regarding the role of PTR in the treatment of sarcomas of pelvic bones with synchronous metastasis at diagnosis. METHODS: Using the Surveillance, Epidemiology, and End Results Program, we enrolled a total of 385 patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at initial diagnosis, including 139 patients with osteosarcoma, 176 with Ewing sarcoma, and 70 with chondrosarcoma. Association between PTR and disease-specific survival (DSS) were investigated using the univariable and multivariable Cox regression models. Hazard ratio (HR) and 95% confidence interval (CI) were reported. Representative institutional PTR strategies and clinical outcomes for patients with metastatic pelvic sarcomas from our cancer center were displayed. RESULTS: The usage rate of PTR was 28.1% (39/139) in osteosarcoma, 13.6% (24/176) in Ewing sarcoma, and 41.4% (29/70) in chondrosarcoma with synchronous metastatic lesions. PTR was not associated with an improved DSS for metastatic pelvic osteosarcoma (HR = 0.686, 95% CI = 0.430 ~ 1.094, P = 0.113) and Ewing sarcoma (HR = 0.580, 95% CI = 0.291 ~ 1.154, P = 0.121). The use of PTR was associated with an improved DSS for metastatic pelvic chondrosarcoma (HR = 0.464, 95% CI = 0.225 ~ 0.954, P = 0.037). CONCLUSION: Primary lesion resection may provide a survival benefit for metastatic chondrosarcoma, but not for osteosarcoma and Ewing sarcoma of pelvic bones, sacrum, and coccyx. This population-based study recommends an active surgical intervention for metastatic chondrosarcoma while non-surgical treatment for metastatic osteosarcoma and Ewing sarcoma of the pelvis in terms of survival improvement.

DOI： 10.1007/s00586-023-07985-x

【がん時代の整形外科必携! 骨転移診療アップデート】骨転移治療総論骨転移におけるロコモティブシンドローム

中田英二, 堅山佳美, 明崎禎輝, 濱田全紀, 藤原智洋, 国定俊之, 尾崎敏文

臨床整形外科 58 ( 12 ) 1431 - 1438 2023年12月

記述言語：日本語出版者・発行元：(株)医学書院

＜文献概要＞がんは高齢者に多いため,ロコモティブシンドロームが発生しやすい.がんの切除を行う患者の約9割は,ロコモを合併している.したがって,がん患者では,適切ながんロコモのスクリーニングが重要である.また,最近,がん治療は外来に移行しつつあり,がん患者が日常生活動作を維持することが求められ,がんロコモ予防に対する社会のニーズが増えている.したがって,各施設において,診療科横断的にがんロコモ予防に取り組む体制を構築することが重要である.

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01554&link_issn=&doc_id=20231129020009&doc_link_id=10.11477%2Fmf.1408202843&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1408202843&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

ヒトiPS細胞由来肢芽間葉系細胞から作製した軟骨組織体を用いた骨再生

中田英二, 佐藤浩平, 高尾知佳, 藤澤祐樹, 山田大祐, 上原健敬, 藤原智洋, 尾崎敏文, 宝田剛志

移植 58 ( 3 ) 293 - 293 2023年12月

Factors associated with survival in patients with clear cell sarcoma. 国際誌

Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Toshiharu Mitsuhashi, Toshifumi Ozaki, Akira Kawai

The bone & joint journal 105-B ( 11 ) 1216 - 1225 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Clear cell sarcoma (CCS) of soft-tissue is a rare melanocytic subtype of mesenchymal malignancy. The aim of this study was to investigate the clinical and therapeutic factors associated with increased survival, stratified by clinical stage, in order to determine the optimal treatment. METHODS: The study was a retrospective analysis involving 117 patients with histologically confirmed CCS, between July 2016 and November 2017, who were enrolled in the Bone and Soft Tissue Tumour Registry in Japan. RESULTS: The five- and ten-year survival rates were 41% (95% confidence interval (CI) 29 to 52) and 37% (95% CI 25 to 49), respectively. On multivariable analysis, the size of the tumour of > 10 cm (p = 0.006), lymph node metastasis at the time of diagnosis (p < 0.001), distant metastases at the time of diagnosis (p < 0.001), and no surgery for the primary tumour (p = 0.019) were independently associated with a poor survival. For N0M0 CCS (n = 68), the development of distant metastases was an independent prognostic factor for survival (early (< 12 months), hazard ratio (HR) 116.78 (95% CI 11.69 to 1,166.50); p < 0.001; late (> 12 months), HR 14.79 (95% CI 1.66 to 131.63); p = 0.016); neoadjuvant/adjuvant chemotherapy (p = 0.895) and/or radiotherapy (p = 0.216) were not significantly associated with survival. The five-year cumulative incidence of local recurrence was 19% (95% CI 8 to 35) and the size of the tumour was significantly associated with an increased rate of local recurrence (p = 0.012). For N1M0 CCS (n = 18), the risk of mortality was significantly lower in patients who underwent surgery for both the primary tumour and lymph node metastases (HR 0.03 (95% CI 0.00 to 0.56); p = 0.020). For M1 CCS (n = 31), excision of the primary tumour was independently associated with better survival (HR 0.26 (95% CI 0.09 to 0.76); p = 0.013). There was no significant difference in survival between the different types of systemic treatment (p = 0.523). CONCLUSION: Complete excision of the primary tumour and lymph nodes is associated with a better survival in patients with CCS. Systemic treatment appears to provide limited benefits, demonstrating a pressing need for novel systemic agents.

DOI： 10.1302/0301-620X.105B11.BJJ-2022-0743.R3

著明な疼痛を伴う椎間板発生の仙骨脊索腫の一例

藤原智洋, 魚谷弘二, 国定俊之, 中田英二, 小田孔明, 三澤治夫, 尾崎敏文

中国・四国整形外科学会雑誌 35 ( 3 ) 423 - 423 2023年11月

Advances in treatment of alveolar soft part sarcoma: an updated review. 国際誌

Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Kenji Nishida, Hiroyuki Yanai, Tomoki Nakamura, Kazuhiro Tanaka, Toshifumi Ozaki

Japanese journal of clinical oncology 53 ( 11 ) 1009 - 1018 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.

DOI： 10.1093/jjco/hyad102

テロメラーゼ依存性腫瘍融解アデノウイルスの骨・軟部腫瘍への応用を目指した蛍光タンパクによるウイルスの治療効果予測

魚谷弘二, 藤原智洋, 田澤大, 植田昌敬, 志渡澤央和, 小田孔明, 鉄永倫子, 三澤治夫, 中田英二, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1714 - S1714 2023年8月

翻訳制御機構を標的とした横紋筋肉腫の新規治療法の開発

板野拓人, 中田英二, 藤村篤史, 黄栄生, 片山晴喜, 藤原智洋, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1884 - S1884 2023年8月

ヒトiPS細胞由来肢芽間葉系細胞を用いた骨再建法の開発

佐藤浩平, 高尾知佳, 中田英二, 藤澤佑樹, 山田大祐, 上原健敬, 藤原智洋, 依光正則, 国定俊之, 尾崎敏文, 宝田剛志

日本整形外科学会雑誌 97 ( 8 ) S1868 - S1868 2023年8月

悪性末梢神経鞘腫瘍におけるPRRX1の悪性化因子としての役割

たき平将太, 中田英二, 板野拓人, 片山晴喜, 藤原智洋, 国定俊之, 山田大祐, 高尾知佳, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1890 - S1890 2023年8月

テロメラーゼ依存性腫瘍融解アデノウイルスの骨・軟部腫瘍への応用を目指した蛍光タンパクによるウイルスの治療効果予測

魚谷弘二, 藤原智洋, 田澤大, 植田昌敬, 志渡澤央和, 小田孔明, 鉄永倫子, 三澤治夫, 中田英二, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1714 - S1714 2023年8月

Computer assisted orthopaedic surgeryがもたらす整形外科の次世代診療希少疾患に対するAI開発戦略

長谷井嬢, 中原龍一, 藤原智洋, 中田英二, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1783 - S1783 2023年8月

悪性末梢神経鞘腫瘍における治療標的PRRX1の同定と新規創薬開発の可能性

たき平将太, 山田大祐, 岡本真幸, 高尾知佳, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 尾崎敏文, 宝田剛志

日本整形外科学会雑誌 97 ( 6 ) S1428 - S1428 2023年6月

肉腫診療におけるゲノム医療

板野拓人, 中田英二, 藤原智洋, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 97 ( 6 ) S1449 - S1449 2023年6月

小児悪性骨腫瘍切除後の延長型腫瘍用人工関節の長期成績 JMOG多施設共同研究

津田祐輔, 西田佳弘, 坂本昭夫, 藤原智洋, 河本旭哉, 永野昭仁, 橋本和彦, 山本憲男, 河野博隆, 小林寛

日本整形外科学会雑誌 97 ( 6 ) S1442 - S1442 2023年6月

悪性末梢神経鞘腫瘍における治療標的PRRX1の同定と新規創薬開発の可能性

たき平将太, 山田大祐, 岡本真幸, 高尾知佳, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 尾崎敏文, 宝田剛志

日本整形外科学会雑誌 97 ( 6 ) S1428 - S1428 2023年6月

骨盤悪性骨腫瘍に対する股関節包内切除術と包外切除術の腫瘍学的予後および機能的予後の比較検討

藤原智洋, Stevenson Jonathan, Parry Michael, Grimer Robert, 津田祐輔, 長谷井嬢, 中田英二, 国定俊之, 尾崎敏文, Jeys Lee

日本整形外科学会雑誌 97 ( 6 ) S1443 - S1443 2023年6月

Like a shot-through manubrium: A rare presentation of skeletal tuberculosis. 国際誌

Tomohiro Fujiwara, Hiroyuki Yanai, Hideharu Hagiya

Clinical case reports 11 ( 5 ) e7119 2023年5月

記述言語：英語

A 22-year-old Vietnamese woman presented with anterior chest swelling. Computed tomography revealed an osteolytic lesion in the manubrium, whereas MRI showed an extra-osseous expansion. A needle biopsy showed granuloma formation, whereas a 3-week mycobacterial culture indicated Mycobacterium tuberculosis infection. Manubrium/sternum involvement in tuberculosis is extremely rare but should be considered.

DOI： 10.1002/ccr3.7119

軟部肉腫に対する広範切除後の機能回復は成人患者と高齢患者でどのように異なるか? 下肢発生肉腫の検討

藤原智洋, 中田英二, 近藤彩奈, 堅山佳美, 濱田全紀, 国定俊之, 尾崎敏文, 千田益生

The Japanese Journal of Rehabilitation Medicine 60 ( 特別号 ) 3 - 3 2023年5月

ヒト多能性幹細胞から誘導した肢芽間葉系細胞と、その拡大培養法の開発

中田英二, 山田大祐, 高尾知佳, たき平将太, 藤原智洋, 尾崎敏文, 宝田剛志

移植 57 ( 4 ) 363 - 363 2023年4月

Cathepsin protease expression in infiltrative soft tissue sarcomas: cathepsin-K correlates with infiltrative tumor growth and clinical outcomes. 国際誌

Tomohiro Fujiwara, Lingxin Zhang, Andrew Chandler, Shijun Sung, Mohamed Yakoub, Irina Linkov, Meera Hameed, John H Healey

Human pathology 134 30 - 44 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cathepsin proteases, activated in the lysosomes, are upregulated in many cancers. Intraoperative detection systems of microscopic residual tumor using cathepsin-mediated release of fluorescent nanoparticles may guide surgical excisions to improve local control. We sought to define the genetic and proteomic expression of cathepsins and their clinicopathological correlates in myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS)-soft tissue sarcomas with high rates of positive resection margins and local recurrence-and to establish a cellular justification for cathepsin-dependent systems to identify residual cancer in the resection bed. Real-time quantitative polymerase chain reaction analysis of 58 fresh-frozen tumor specimens revealed that 56 (97%) had elevated mRNA expression of ≥1 cathepsin, including cathepsin-B (79%), cathepsin-K (59%), cathepsin-L (71%), and -S (71%). Immunohistochemical analysis of these fresh-frozen specimens revealed that 98% of tumors were positive for one or more of cathepsin-B (85%), cathepsin-K (50%), cathepsin-L (63%), and -S (10%). Strong cathepsin-K expression was associated with greater risks of local recurrence (hazard ratio, 3.78; p = 0.044) and disease-specific mortality (hazard ratio, 3.70; p = 0.025). Immunohistochemical analysis of 33 formalin-fixed paraffin-embedded block samples revealed that 97% were positive for cathepsin-B (88%), cathepsin-K (76%), cathepsin-L (52%), or -S (52%) at the tumor periphery; cathepsin-K positivity correlated with a radiographic tail-like sign (p = 0.004) and microscopic infiltrative growth (p = 0.020). We conclude that cathepsins are broadly overexpressed in myxofibrosarcoma and UPS, and cathepsin-K may be an immunohistochemical marker of local infiltration and poorer prognosis that could be used to guide precision surgery.

DOI： 10.1016/j.humpath.2022.12.006

[Ⅲ. The Role of Comprehensive Genomic Profiling in Sarcoma].

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Shinichi Toyooka, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Akira Hirasawa, Mashu Futagawa, Masahiro Tabata

Gan to kagaku ryoho. Cancer & chemotherapy 50 ( 3 ) 314 - 320 2023年3月

Musculoskeletal Tumor 骨・軟部腫瘍骨・軟部腫瘍におけるがん遺伝子プロファイリング検査骨・軟部腫瘍診療におけるがん遺伝子パネルの役割

中田英二, 藤原智洋, 国定俊之, 尾崎敏文, 豊岡伸一, 遠西大輔, 山本英喜, 二宮貴一朗, 冨田秀太, 平沢晃, 二川摩周, 田端雅弘

癌と化学療法 50 ( 3 ) 314 - 320 2023年3月

肉腫におけるがんゲノム医療の現状と未来がん遺伝子パネル検査から同定されるGermline Findingsへの対応

二川摩周, 中田英二, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 97 ( 2 ) S446 - S446 2023年3月

悪性末梢神経鞘腫瘍におけるPRRX1の治療標的分子としての可能性

たき平将太, 中田英二, 大曽根達則, 山田大祐, 高尾知佳, 佐藤浩平, 畑利彰, 藤原智洋, 国定俊之, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 97 ( 3 ) S1040 - S1040 2023年3月

遺伝性骨・軟部腫瘍外来におけるNF-1の診療

中田英二, 二川摩周, 藤原智洋, 国定俊之, 山本英喜, 平沢晃, 尾崎敏文

日本レックリングハウゼン病学会学術大会プログラム・抄録集 14回 33 - 33 2023年2月

神経線維腫症1型における院内レジストリの構築と定期的なサーベイランスの実施

二川摩周, 中田英二, 十川麗美, 加藤芙美乃, 浦川優作, 山本英喜, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本レックリングハウゼン病学会学術大会プログラム・抄録集 14回 34 - 34 2023年2月

悪性末梢神経鞘腫瘍におけるPRRX1の悪性化因子としての役割

たき平将太, 中田英二, 山田大祐, 片山晴喜, 畑利彰, 藤原智洋, 高尾知佳, 国定俊之, 宝田剛志, 尾崎敏文

日本レックリングハウゼン病学会学術大会プログラム・抄録集 14回 16 - 16 2023年2月

Treatment-related thoracic soft tissue sarcomas in survivors of breast cancer. 国際誌

Xianglin Hu, Tomohiro Fujiwara, Yangbai Sun, Wending Huang, Wangjun Yan

The Lancet. Oncology 24 ( 1 ) e6 2023年1月

腫瘍用人工骨頭による股関節置換術を施行した転移性前立腺癌の1例

和田里章悟, 久住倫宏, 藤原智洋, 山本哲也, 柳井広之, 白石裕雅, 徳永素, 窪田理沙, 市川孝治, 津島知靖

西日本泌尿器科 85 ( 2 ) 47 - 51 2022年12月

記述言語：日本語出版者・発行元：(一社)西日本泌尿器科学会

症例は57歳,男性。腰部と右大腿部の痛みを主訴に近医を受診した。単純X線写真での骨硬化像とPSA高値から骨転移を伴う前立腺癌を疑われ当科紹介となった。初診時,PSAは433ng/dLであり直腸診で前立腺は石様硬に触れた。画像検査では腰椎,仙骨,恥骨,右大腿骨頸部から転子部にかけて転移を疑う像を認めたが,リンパ節腫大と他臓器の占拠性病変はなかった。初診より7日目に経直腸式前立腺生検の迅速病理で腺癌の組織を確認し,即時の外科的去勢術を施行した。病理結果を以てGleason score 4+5の前立腺癌cT3bN0M1bと診断した。腰椎及び仙骨と右大腿骨の転移性骨腫瘍にはそれぞれ30Gyの放射線治療とビスフォスフォネート製剤の投与を行い,外来通院でアビラテロン内服を開始した。初診より5ヵ月後,PSAは低下傾向にあったが,右大腿骨頸部の病的骨折により入院となった。Activities of Daily Livingが著しく低下し,骨腫瘍切除術と腫瘍用人工骨頭による再建術を施行した。荷重部の転移性骨腫瘍については切迫骨折のリスクを評価し,免荷を指示するかあるいは,病的骨折を発症する前の外科的介入も検討する必要がある。(著者抄録)

Limb salvage surgery has a higher complication rate than amputation but is still beneficial for patients younger than 10 years old with osteosarcoma of an extremity. 国際誌

Yoichi Kaneuchi, Shinichirou Yoshida, Tomohiro Fujiwara, Scott Evans, Adesegun Abudu

Journal of pediatric surgery 57 ( 11 ) 702 - 709 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/PURPOSE: Limb preserving surgery for the treatment of patients with osteosarcoma younger than 10 years old is challenging and some authors have advocated amputation to reduce the risk of complications. The aim of this study was to compare the clinical outcomes and surgical complications of patients with osteosarcoma of the extremity aged <10 years old who were treated with limb salvage and amputation. PATIENTS AND METHODS: Retrospective review of patients aged <10 years old who were treated for primary osteosarcoma of bone between 2000 and 2018. RESULTS: We analyzed 82 consecutive patients (32 males, 50 females; median age 8, range 3-9 yrs). Limb-salvage surgery (LSS; n = 65, 79%) and amputation (n = 17, 21%) were performed. Fourteen patients had metastasis at surgery. In patients without metastasis at surgery, the metastasis-free and overall survival rates at 5 years following LSS vs. amputation were 75% vs. 58% (p = 0.162) and 71% vs. 55% (p = 0.516), respectively. The 2-year and 5-year OS rates of the LSS and amputation groups of patients with metastasis at surgery were 88% versus 83% and 50% versus 0%, respectively (p = 0.180). The overall complication rates were 46% post-LSS with 31% requiring re-operation versus 12% post-amputation, with 6% requiring re-operation (p = 0.010). CONCLUSION: The prognosis of patients with localized osteosarcoma aged <10 years undergoing LSS is similar to those treated with amputation, but LSS is associated with a higher risk of complications and subsequent re-operation. LEVEL OF EVIDENCE: Level III.

DOI： 10.1016/j.jpedsurg.2022.04.001

Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts. 国際誌

Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey, Nicola Fabbri

Hip international : the journal of clinical and experimental research on hip pathology and therapy 33 ( 2 ) 11207000221130270 - 11207000221130270 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Metastatic disease of the periacetabular region is a common problem in orthopaedic oncology, associated with severe pain, decreased mobility, and substantial decline of the quality of life. Conservative management includes optimisation of pain management, activity modification, and radiation therapy. However, patients with destructive lesions affecting the weight-bearing portion of the acetabulum often require reconstructive surgery to decrease pain and restore mobility. The goal of surgery is to provide an immediately stable and durable construct, allowing immediate postoperative weight-bearing and maintaining functional independence for the remaining lifetime of the patient. A variety of surgical techniques have been reported, most of which are based upon cemented total hip arthroplasty, but also include porous tantalum implants and percutaneous cementoplasty. This review discusses the various reconstructive concepts and options, including their respective indications and outcome. A reconstructive algorithm incorporating different techniques and strategies based upon location and quality of remaining bone is also presented.

DOI： 10.1177/11207000221130270

軟部肉腫に対する薬物療法がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 国定俊之, 平沢晃, 遠西大輔, 尾崎敏文

中部日本整形外科災害外科学会雑誌 65 ( 秋季学会 ) 77 - 77 2022年10月

がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 平沢晃, 二川摩周, 遠西大輔, 山本英喜, 冨田秀太, 久保寿夫, 田端雅弘, 国定俊之, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 60回 O49 - 4 2022年10月

がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 平沢晃, 二川摩周, 遠西大輔, 山本英喜, 冨田秀太, 久保寿夫, 田端雅弘, 国定俊之, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 60回 O49 - 4 2022年10月

Clinicopathological and histological analysis of secondary malignant giant cell tumors of bone without radiotherapy. 国際誌

Eiji Nakata, Hotaka Kawai, Tomohiro Fujiwara, Toshiyuki Kunisada, Hirofumi Inoue, Mashu Futagawa, Haruyoshi Katayama, Takuto Itano, Toshifumi Ozaki

Oncology letters 24 ( 3 ) 319 - 319 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Giant cell tumor of bone (GCTB) is an intermediate bone tumor that rarely undergoes malignant transformation. Secondary malignant GCTB (SMGCTB) is defined as a lesion in which high-grade sarcoma occurs at the site of previously treated GCTB. The present study retrospectively reviewed the medical records of patients with GCTB treated at Okayama University Hospital between April 1986 and April 2020. The clinicopathological and histological features of patients with SMGCTB without prior radiotherapy were investigated. A total of three patients (4%) with SMGCTB were detected, and the tumor sites were the distal ulna, distal femur and sacrum. Two of the patients had been treated with curettage and bone graft, and one had been treated with denosumab. In all cases, the lesions were made up of two components, the conventional GCTB component and the malignant component. The Ki67 labeling index was higher in the malignant components of SMGCTB and metastatic lesions compared with that in primary and recurrent conventional GCTB, or the conventional GCTB component of SMGCTB. Moreover, p53 expression was higher in these same components in patients who underwent curettage and bone grafting; however, there was no difference in the patient that received denosumab treatment. In this patient, clinical cancer genomic profiling revealed loss of CDKN2A, CDKN2B and MTAP expression. All three patients developed distant metastasis. The patients with SMGCTB in the ulna and femur died 13 and 54 months after detection of malignant transformation, respectively. The patient with SMGCTB in the sacrum received carbon-ion radiotherapy to the sacrum and pazopanib; the treatment was effective and the patient was alive at the last follow-up 3 years later. In conclusion, p53 may be associated with malignant transformation in GCTB. Future studies should investigate the association of between denosumab treatment and malignant transformation, as well as molecular targeted therapy to improve the clinical outcomes of SMGCTB.

DOI： 10.3892/ol.2022.13439

がんゲノム医療において遺伝性骨・軟部肉腫を同定する臨床的意義(Clinical significance of identifying hereditary bone and soft tissue sarcomas in precision medicine)

二川摩周, 中田英二, 十川麗美, 加藤芙美乃, 浦川優作, 植野さやか, 山本英喜, 藤原智洋, 国定俊之, 尾崎敏文, 平沢晃

日本癌学会総会記事 81回 P - 3121 2022年9月

骨・軟部腫瘍の基礎科学のトピックスクリニカルシークエンスによる肉腫のゲノム医療

中田英二, 藤原智洋, 国定俊之, 二川摩周, 遠西大輔, 久保寿夫, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 96 ( 8 ) S1533 - S1533 2022年9月

骨・軟部肉腫に対するがんゲノムプロファイリング検査から検出されるpresumed germline pathogenic variantsの意義

二川摩周, 中田英二, 十川麗美, 加藤芙美乃, 浦川優作, 河内麻里子, 山本英喜, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 96 ( 8 ) S1770 - S1770 2022年9月

骨・軟部腫瘍の基礎科学のトピックス転移性骨肉腫は臓器指向性サイトカインの分泌を介して微小環境を変化させ前転移ニッチを形成する

近藤宏也, 田澤大, 藤原智洋, 近藤彩奈, 片山晴喜, 佐藤浩平, 畑利彰, 中田英二, 国定俊之, 藤原俊義, 尾崎敏文

日本整形外科学会雑誌 96 ( 8 ) S1532 - S1532 2022年9月

悪性軟部腫瘍に対する抗CSF-1R阻害薬の有効性抗腫瘍効果と微小環境へ与える影響(Antitumor effect of CSF-1/CSF-1R blockade in soft-tissue sarcomas)

近藤彩奈, 藤原智洋, 吉田晶, 畑利彰, 近藤宏也, 国定俊之, 尾崎敏文

日本癌学会総会記事 81回 J - 1062 2022年9月

転移性骨肉腫細胞はCCL2によるM2マクロファージの腫瘍内浸潤を誘導して肺転移を促進する(Metastatic osteosarcoma cells facilitate lung metastasis by inducing CCL2-mediated tumor infiltration of M2 macrophages)

近藤宏也, 田澤大, 久禮美穂, 藤原智洋, 国定俊之, 尾崎敏文, 藤原俊義

日本癌学会総会記事 81回 J - 2087 2022年9月

Geographic Access to High-Volume Care Providers and Survival in Patients with Bone Sarcomas: Nationwide Patterns in the United States. 国際誌

Tomohiro Fujiwara, Koichi Ogura, Motaz Alaqeel, John H Healey

The Journal of bone and joint surgery. American volume 104 ( 16 ) 1426 - 1437 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Clinical practice guidelines recommend centralized care for patients with bone sarcoma. However, the relationship between the distance that patients travel to obtain care, institutional treatment volume, and survival is unknown. METHODS: We used the National Cancer Database to examine associations between travel distance and survival among 8,432 patients with bone sarcoma diagnosed from 2004 to 2015. Associations were identified using multivariable Cox regression analyses that controlled for sociodemographic, clinical, and hospital-level factors; subgroup analyses stratified patients by histological diagnosis, tumor stage, and pediatric or adult status. RESULTS: Mortality risk was lower among patients who traveled ≥50 miles (≥80.5 km) than among patients who traveled ≤10 miles (≤16.1 km) (hazard ratio [HR], 0.69 [95% confidence interval (CI), 0.63 to 0.76]). Among hospital-level factors, facility volume independently affected survival: mortality risk was lower among patients at high-volume facilities (≥20 cases per year) than at low-volume facilities (≤5 cases per year), with an HR of 0.72 (95% CI, 0.66 to 0.80). The proportion of patients who received care at high-volume facilities varied by distance traveled (p < 0.001); it was highest among patients who traveled ≥50 miles (53%) and lower among those who traveled 11 to 49 miles (17.7 to 78.9 km) (32%) or ≤10 miles (18%). Patients who traveled ≥50 miles to a high-volume facility had a lower risk of mortality (HR, 0.65 [95% CI, 0.56 to 0.77]) than those who traveled ≤10 miles to a low-volume facility. In subgroup analyses, this association was evident among patients with all 3 major histological subtypes; those with stage-I, II, and IV tumors; and adults. CONCLUSIONS: This national study showed that greater travel burden was associated with higher survival rates in adults, a finding attributable to patients traveling to receive care at high-volume facilities. Despite the burdens associated with travel, modification of referral pathways to specialized centers may improve survival for patients with bone sarcoma. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.21.01140

Effect of bacterium in the malignant wounds of soft tissue sarcoma 国際誌

Eiji Nakata, Tomohiro Fujiwara, Haruyoshi Katayama, Takuto Itano, Toshiyuki Kunisada, Toshifumi Ozaki

Oncology Letters 24 ( 4 ) 345 - 345 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Spandidos Publications

Malignant wounds (MWs) are rare skin lesions, which accompany ulceration, necrosis and infection caused by infiltration or damage by malignant tumor. The present study aimed to investigate the bacterial etiology implicated in MW in soft tissue sarcoma (STS), and the effectiveness of culture-guided perioperative antibacterial administration. A retrospective evaluation was conducted on medical records of patients who presented with MW between 2006 and 2020. A total of seven patients were included in the present study, in whom all tumors were relatively large (>5 cm) and high-grade. Subsequently, five patients underwent limb-sparing surgery, and three patients had distant metastases with a 5-year overall survival of 71%. Preoperative microbiological sampling from the wound identified 11 different bacterial strains in five patients. The infections were polymicrobial with an average of 2.6 strains isolated per patient (1 aerobic, 1.6 anaerobic bacteria). They were predominantly methicillin-sensitive Staphylococcus aureus. Patients with MWs from STS reported symptoms, including bleeding (71%), exudation (71%) and malodorous wound (43%) at the initial presentation; these completely resolved after surgery. All but one patient reported pain at the MW site with an average numeric rating scale of 4.4 at presentation that decreased to 1.4 (P=0.14) and 0.6 (P=0.04) one and two weeks after surgery, respectively. The patients had elevated C-reactive protein (71%), anemia (57%), low albumin (86%) and renal/liver dysfunction (14-29%). One patient was diagnosed with sepsis. Surgical resection afforded symptomatic relief and resolution of abnormal laboratory values. Although selected antibiotics were administered in four patients based on the preoperative antibiotic sensitivity test, surgical site infection (SSI) occurred in three patients. Therefore, the effectiveness of the selected antibiotics based on the results of the preoperative culture in preventing SSI needs to be investigated in the future. In conclusion, physicians should keep in mind that although surgical resection can improve the symptoms and abnormal values in laboratory examination form MW, it is accompanied with a high rate of SSI and poor prognosis.

DOI： 10.3892/ol.2022.13465

Alveolar soft part sarcoma: progress toward improvement in survival? A population-based study. 国際誌

Tomohiro Fujiwara, Eiji Nakata, Toshiyuki Kunisada, Toshifumi Ozaki, Akira Kawai

BMC cancer 22 ( 1 ) 891 - 891 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare histological subtype of soft-tissue sarcoma, which remains refractory to conventional cytotoxic chemotherapy. We aimed to characterize ASPS and investigate whether the oncological outcome has improved over the past decade. METHODS: One hundred and twenty patients with newly diagnosed ASPS from 2006 to 2017, identified from the Bone and Soft-Tissue Tumor Registry in Japan, were analyzed retrospectively. RESULTS: The study cohort comprised 34 (28%) patients with localized ASPS and 86 (72%) with metastatic disease at presentation. The 5-year disease-specific survival (DSS) was 68% for all patients and 86% and 62% for localized and metastatic disease, respectively (p = 0.019). Metastasis at presentation was the only adverse prognostic factor for DSS (hazard ratio [HR]: 7.65; p = 0.048). Patients who were > 25 years (80%; p = 0.023), had deep-seated tumors (75%; p = 0.002), and tumors > 5 cm (5-10 cm, 81%; > 10 cm, 81%; p < 0.001) were more likely to have metastases at presentation. In patients with localized ASPS, adjuvant chemotherapy or radiotherapy did not affect survival, and 13 patients (45%) developed distant metastases in the lung (n = 12, 92%) and brain (n = 2, 15%). In patients with metastatic ASPS (lung, n = 85 [99%]; bone, n = 12 [14%]; and brain n = 9 [11%]), surgery for the primary or metastatic site did not affect survival. Prolonged survival was seen in patients who received pazopanib treatment (p = 0.045), but not in those who received doxorubicin-based cytotoxic chemotherapy. Overall, improved DSS for metastatic ASPS has been observed since 2012 (5-year DSS, from 58 to 65%) when pazopanib was approved for advanced diseases, although without a statistically significant difference (p = 0.117). CONCLUSION: The national study confirmed a unique feature of ASPS with frequent metastasis to the lung and brain but an indolent clinical course. An overall trend toward prolonged survival after the introduction of targeted therapy encourages continuous efforts to develop novel therapeutic options for this therapeutically resistant soft-tissue sarcoma.

DOI： 10.1186/s12885-022-09968-5

Neoplastic synovial lining cells that coexpress podoplanin and CD90 overproduce CSF-1, driving tenosynovial giant cell tumor. 国際誌

Andrew C Chandler, Mohamed Yakoub, Tomohiro Fujiwara, Laura T Donlin, Paul Edward Purdue, John H Healey

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 40 ( 8 ) 1918 - 1925 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tenosynovial giant cell tumor (TCGT) is a rare neoplasm affecting the synovium of joints, bursae, and tendon sheaths. The overproduction of colony-stimulating factor-1 (CSF-1) by a minority of the tumor population works in a paracrine fashion to drive tumor growth. Pathology of the reactive, monocytic component has been well elucidated, whereas the populations of neoplastic cells and all the sources of CSF-1 overproduction are incompletely characterized. Podoplanin (PDPN), or gp38, is a cell surface glycoprotein that is expressed on fibroblast-like synovial cells and upregulated in rheumatoid arthritis and many cancers; it governs cell mobility, epithelial-mesenchymal transition, and other functions and is associated with lymphangiogenesis and poor prognosis in many solid tumors, which underscores its local and possible systemic effects. We found higher PDPN expression in TGCT than in internal controls of patients' healthy synovium. Flow cytometry partitioned PDPNhigh cells into PDPNhigh CD90+ and PDPNhigh CD14+ populations. Quantitative real-time polymerase chain reaction analysis of the PDPNhigh CD90+ cells revealed that CSF-1 expression was 10-fold higher than in PDPNhigh CD14+ cells. Therefore, we conclude that the lining fibroblast-like synovial cells, which express PDPNhigh CD90+ , are responsible for the overproduction of CSF-1 and for driving tumor growth.

DOI： 10.1002/jor.25216

Impact of racial disparities and insurance status in patients with bone sarcomas in the USA : a population-based cohort study. 国際誌

Xianglin Hu, Tomohiro Fujiwara, Matthew T Houdek, Lingxiao Chen, Wending Huang, Zhengwang Sun, Yangbai Sun, Wangjun Yan

Bone & joint research 11 ( 5 ) 278 - 291 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Socioeconomic and racial disparities have been recognized as impacting the care of patients with cancer, however there are a lack of data examining the impact of these disparities on patients with bone sarcoma. The purpose of this study was to examine socioeconomic and racial disparities that impact the oncological outcomes of patients with bone sarcoma. METHODS: We reviewed 4,739 patients diagnosed with primary bone sarcomas from the Surveillance, Epidemiology and End Results (SEER) registry between 2007 and 2015. We examined the impact of race and insurance status associated with the presence of metastatic disease at diagnosis, treatment outcome, and overall survival (OS). RESULTS: Patients with Medicaid (odds ratio (OR) 1.41; 95% confidence interval (CI) 1.15 to 1.72) and uninsured patients (OR 1.90; 95% CI 1.26 to 2.86) had higher risks of metastatic disease at diagnosis compared to patients with health insurance. Compared to White patients, Black (OR 0.63, 95% CI 0.47 to 0.85) and Asian/Pacific Islander (OR 0.65, 95% CI 0.46 to 0.91) were less likely to undergo surgery. In addition, Black patients were less likely to receive chemotherapy (OR 0.67, 95% CI 0.49 to 0.91) compared to White patients. In patients with chondrosarcoma, those with Medicaid had worse OS compared to patients with insurance (hazard ratio (HR) 1.65, 95% CI 1.06 to 2.56). CONCLUSION: In patients with a bone sarcoma, the cancer stage at diagnosis varied based on insurance status, and racial disparities were identified in treatment. Further studies are needed to identify modifiable factors which can mitigate socioeconomic and racial disparities found in patients with bone sarcomas. Cite this article: Bone Joint Res 2022;11(5):278-291.

DOI： 10.1302/2046-3758.115.BJR-2021-0258.R2

Impact of the national sarcoma guidelines on the prevalence and outcome of inadvertent excisions of soft tissue sarcomas: An observational study from a UK tertiary referral centre. 国際誌

Tomohiro Fujiwara, Scott Evans, Jonathan Stevenson, Yusuke Tsuda, Jonathan Gregory, Robert Grimer, Adesegun Abudu

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 48 ( 3 ) 533 - 540 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: This study aims to investigate the impact of the national guideline on the prevalence and outcome in patients with soft-tissue sarcoma (STS) who had undergone inadvertent excisions. METHODS: A total of 2336 patients were referred to a tertiary sarcoma centre from six regions (North East, North West, East Midlands, West Midlands, Wales, and South West) in the United Kingdom with a diagnosis of STS between 1996 and 2016, of whom 561 patients (24.0%) had undergone inadvertent excisions. Patients were categorised into two groups of 10-year periods pre and post the National Institute for Health and Clinical Excellence (NICE) guideline implementation in 2006. RESULTS: The proportion of inadvertent excisions decreased after the NICE guideline implementation: 27.2% (pre-NICE) versus 19.8% (post-NICE) (p = 0.001). A substantial regional variation (17.4%-34.5%) in the proportion of inadvertent excisions in the pre-NICE era was reduced in the post-NICE era (14.3%-22.4%). The 5-year disease-specific survival was 77.7% (pre-NICE) versus 75.6% (post-NICE) (p = 0.961) and there was a trend toward lower incidence of local recurrence in the post-NICE era; 13.5% (pre-NICE) versus 10.5% (post-NICE) (p = 0.522). Multivariate analyses revealed that residual tumours in re-resection specimens were independently associated with an increased risk of disease-specific mortality (HR, 3.35; p < 0.001) and local recurrence (HR, 1.99; p = 0.017), which was significantly reduced after the NICE guideline implementation (53.2% versus 42.0%; p = 0.022). CONCLUSIONS: The NICE guideline implementation reduced the proportion of patients with STS who had undergone inadvertent excisions and residual tumour in re-resection specimens, indicating an improved pre-referral management of STSs.

DOI： 10.1016/j.ejso.2021.11.013

Long-Term Results of Kyocera Modular Limb Salvage System after Resection of Tumors in the Distal Part of the Femur: Report from Japanese Musculoskeletal Oncology Group Study. 国際誌

Tomoki Nakamura, Akihiko Matsumine, Yu Toda, Satoshi Takenaka, Hidetatsu Outani, Tomohiro Fujiwara, Yoshihiro Nishida, Satoshi Tsukushi, Yasunori Tome, Teruya Kawamoto, Munehisa Kito, Naohiro Shinohara, Masato Tomita, Tomoaki Torigoe, Akihiro Sudo, Hirotaka Kawano

Cancers 14 ( 4 ) 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The distal femur is a common site of bone tumors. After surgical resection, prosthetic replacement is a major reconstruction method. We aimed to elucidate the long-term outcomes of the Kyocera Modular Limb Salvage (KMLS) systems after resection of tumors in the distal part of the femur. METHODS: Between 1998 and 2014, 125 patients were treated at 14 institutions. There were 59 males and 66 females, with a mean age of 35 years. The mean follow-up period was 132 months. RESULTS: There had been 65 additional surgeries, including 56 revisions and 9 amputations: 15 for aseptic loosening, 14 for stem breakage, 13 for deep infection, 13 for rotator-hinge bushing failure, 5 for local recurrence, and 5 for others. Implant survival rates at 10 and 15 years were 58.5% and 39.4%. The cumulative incidence of 15-year revision for femoral stem breakage was 31.7% in patients with cementless fixation. The 15-year cumulative incidence of revision for aseptic loosening was 19.8% in patients with cement fixation. CONCLUSIONS: KMLS systems represent a reliable system with long-term results. Stem breakage should be considered in patients with cementless and/or smaller femoral stem sizes. Aseptic loosening should be considered in patients with cement systems after 10 years.

DOI： 10.3390/cancers14040870

Soft-tissue sarcoma in adolescents and young adults

Toshiyuki Kunisada, Eiji Nakata, Tomohiro Fujiwara, Ako Hosono, Shota Takihira, Hiroya Kondo, Toshifumi Ozaki

International Journal of Clinical Oncology 28 ( 1 ) 1 - 11 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Soft-tissue sarcoma is a rare cancer that accounts for approximately 1% of all malignant tumors. Although they occur in various age groups, soft-tissue sarcomas account for 8% of all malignant tumors developing in adolescents and young adults, suggesting that they are not rare in this age group. This study aimed to evaluate the clinical and pathological characteristics of soft-tissue sarcoma in adolescents and young adults. According to the Bone and Soft-Tissue Tumor Registry in Japan, myxoid liposarcoma is the most common type of soft-tissue sarcoma found in adolescents and young adults; alveolar soft part sarcoma, extraskeletal Ewing sarcoma, epithelioid sarcoma, clear cell sarcoma and synovial sarcoma occur predominantly in this age group among soft-tissue sarcomas. The analysis based on this registry demonstrated that age was not a prognostic factor for poor survival of soft-tissue sarcoma, although the prognosis in adolescents and young adults was better than that in older patients in the US and Scandinavia. Adolescent and young adult patients with soft-tissue sarcoma have age-specific problems, and a multidisciplinary approach to physical, psychological, and social issues is necessary to improve the management of these young patients both during and after treatment.

DOI： 10.1007/s10147-022-02119-7

その他リンク： https://link.springer.com/article/10.1007/s10147-022-02119-7/fulltext.html

The Role of Imaging in Computer-Assisted Tumor Surgery of the Sacrum and Pelvis. 国際誌

Andrea Sambri, Tomohiro Fujiwara, Michele Fiore, Claudio Giannini, Riccardo Zucchini, Luca Cevolani, Davide Maria Donati, Massimiliano De Paolis

Current medical imaging 18 ( 2 ) 137 - 141 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

The use of a navigation system allows precise resection of a tumor and accurate reconstruction of the resultant defect thereby sparing important anatomical structures and preserving function. It is an "image-based" system where the imaging (computed tomography and magnetic resonance imaging) is required to supply the software with data. The fusion of the preoperative imaging provides pre-operative information about local anatomy and extent of the tumor, so that it allows an accurate preoperative planning. Accurate pre-operative imaging is mandatory in order to minimize CATS errors, thus performing accurate tumor resections.

DOI： 10.2174/1573405617666210303105735

Periacetabular reconstruction following limb-salvage surgery for pelvic sarcomas. 国際誌

Tomohiro Fujiwara, Koichi Ogura, Alexander Christ, Meredith Bartelstein, Shachar Kenan, Nicola Fabbri, John Healey

Journal of bone oncology 31 100396 - 100396 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Limb-salvage surgery for pelvic sarcomas remains one of the most challenging surgical procedures for musculoskeletal oncologists. In the past several decades, various surgical techniques have been developed for periacetabular reconstruction following pelvic tumor resection. These methods include endoprosthetic reconstruction, allograft or autograft reconstruction, arthrodesis, and hip transposition. Each of these procedures has its own advantages and disadvantages, and there is no consensus or gold standard for periacetabular reconstruction. Consequently, this review provides an overview of the clinical outcomes for each of these reconstructive options following pelvic tumor resections. Overall, high complication rates are associated with the use of massive implants/grafts, and deep infection is generally the most common cause of reconstruction failure. Functional outcomes decline with the occurrence of severe complications. Further efforts to avoid complications using innovative techniques, such as antibiotic-laden devices, computer navigation, custom cutting jigs, and reduced use of implants/grafts, are crucial to improve outcomes, especially in patients at a high risk of complications.

DOI： 10.1016/j.jbo.2021.100396

Extra-articular resection of the hip joint for pelvic sarcomas: Are there any oncological and functional risks compared with intra-articular resection? 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Jonathan Stevenson, Michael Parry, Lee Jeys

Journal of bone oncology 31 100401 - 100401 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: While extra-articular resection (EAR) of the knee and shoulder joint is associated with poorer clinical outcomes, the oncological and functional risks of EAR of the hip joint are unknown. We aimed to compare these risks between EAR of the hip joint and intra-articular resection (IAR). Methods: We conducted a comparative study of 75 patients who underwent en-bloc tumour resection and limb-salvage reconstruction for bone sarcomas of the peri-acetabulum between 1996 and 2016. We divided patients into two groups for analyses; EAR (n = 21) and IAR (n = 54). Results: There was no statistical difference in oncological outcomes; the 5-year cumulative incidence of disease-specific death was 34% and 35% in the EAR and IAR groups, respectively (p = 0.943), and the 5-year cumulative incidence of LR was 26% and 34%, respectively (p = 0.482). The most common complications were dislocation (28%) and deep infection (28%); there was equally no difference between the groups. The mean Musculoskeletal Tumour Society score was 66% and 65% in the EAR and IAR groups, respectively (p = 0.795), and were significantly lower in patients with deep infection (52% vs. 69%; p = 0.013). In a sub-analysis on the outcomes in patients who underwent PI-uninvolved PII-resection for chondrosarcoma, no major differences in oncologic and functional outcomes were confirmed. Conclusion: Patients undergoing EAR and limb-salvage reconstructions of the hip joint have undistinguishable oncological, clinical and functional outcomes compared to those undergoing IAR and reconstructions. If preoperative imaging suggests articular tumour involvement, there appears to be no detrimental effect of undertaking EAR to optimise local control.

DOI： 10.1016/j.jbo.2021.100401

What are the Results of Resection of Forearm Soft Tissue Sarcoma? 国際誌

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Ryuichi Nakahara, Toshiyuki Watanabe, Toshifumi Ozaki

Journal of orthopaedic surgery and research 18 ( 1 ) 599 - 599 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Research Square Platform LLC

Abstract

Only few reports have assessed the characteristics and oncological and functional outcomes of forearm soft tissue sarcomas (STS). Then, we aimed to investigate the clinical features and survival-related factors for forearm STS who underwent surgical excision at our institution. There were 38 patients. Fourteen patients (41%) were referred to our institution after an unplanned excision and tumor size and grade were significantly associated with the receipt of it. The postoperative median Musculoskeletal Tumor Society rating scale (MSTS) score was 28. Bone resection or major nerve palsy was the only factor influencing the postoperative MSTS score (P < 0.001). There was no significant difference in MSTS scores according to the reconstruction procedures (the use of flap or tendon reconstruction). The 5-year local recurrence-free survival (LRFS) rate was 86%. Univariate analysis revealed that the histological diagnosis of myxofibrosarcoma was the only factor that influenced LRFS (P = 0.047). The 5-year metastasis-free survival rate was 77%. The 5-year overall survival (OS) rate was 94%. Age was the only factor that influenced OS (P = 0.01). In conclusion, reconstruction of the skin and tendon can compensate for function. Careful follow-up is important, especially in patients with myxofibrosarcoma, due to its likelihood of local recurrence.

DOI： 10.21203/rs.3.rs-1028963/v1

その他リンク： https://www.researchsquare.com/article/rs-1028963/v1.html

Surgical outcomes of bone sarcoma of the foot. 国際誌

Yusuke Tsuda, Tomohiro Fujiwara, Jonathan D Stevenson, Adesegun Abudu

Japanese journal of clinical oncology 51 ( 10 ) 1541 - 1546 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Limb-salvage following resection of bone sarcomas of the foot are challenging due to the complicated anatomy, adjacent neurovascular structures and few durable reconstruction options. METHODS: We retrospectively analysed 50 patients with primary malignant bone sarcoma of the foot who underwent surgery including chondrosarcoma (n = 23), Ewing's sarcoma (n = 14) and osteosarcoma (n = 13). RESULTS: Median follow-up was 68 months. The primary sites were metatarsal (n = 18), phalanges (n = 15), calcaneus (n = 13) and others (n = 4). The 5-year disease-specific survivals were 100, 83 and 83% in chondrosarcoma, Ewing's sarcoma and osteosarcoma, respectively. Below knee amputation, ray/toe amputation, excision and curettage were performed in 21, 24, 2 and 3 patients, respectively. Below knee amputation was performed in 94% of mid/hindfoot tumours. Surgical margins were wide/radical, marginal and intralesional margin in 42, 5 and 3 patients. Three patients (6%) developed local recurrence, whereas, local recurrence was not observed in patients with wide/radical margins. Postoperative complications occurred in 3 patients (6%; surgical site infection n = 2 and delayed wound healing n = 1). Mean MSTS functional score was 26 points (range, 19-30). CONCLUSIONS: Good local control was achieved with acceptable functional outcomes and post-operative complications; almost all mid/hindfoot tumours required below knee amputation achieving wide/radical margins without local recurrence.

DOI： 10.1093/jjco/hyab118

Pelvic Ewing sarcoma: Should all patients receive pre-operative radiotherapy, or should it be delivered selectively? 国際誌

Johnathan R Lex, Vineet Kurisunkal, Yoichi Kaneuchi, Tomohiro Fujiwara, Jenny Sherriff, Catrin Wigley, Jonathan D Stevenson, Michael C Parry, Lee M Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47 ( 10 ) 2618 - 2626 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Locally recurrent disease following surgical resection of Ewing sarcoma (ES) confers a poor prognosis. Limited evidence is available evaluating non-selective use of pre-operative radiotherapy (RT) for patients with pelvic ES and its effect on local control and survival. PATIENTS AND METHODS: 49 consecutive patients with pelvic ES were identified retrospectively from a prospectively collated database. Patients either received non-selective pre-operative RT and surgery (n = 27), or selective post-operative RT (n = 22) (surgery alone (n = 11) or surgery and post-operative RT (n = 11)). RESULTS: Patients who had non-selective pre-operative radiotherapy appeared to have a higher LRFS, 88.0% compared to 66.5% in the selective RT group (p = 0.096, Kaplan Meier; p = 0.028, Chi-squared). Administration of non-selective, pre-operative RT to all patients with pelvic ES elevates the LFRS to that of the good responder group (≥90% tumour necrosis and margins, p = 0.880). There was no difference in metastasis-free survival, 60.0% and 54.5% (p = 0.728) and overall survival (OS), 57.7% and 63.6% (p = 0.893). The majority of pre-operative RT patients had both good necrosis (≥90%) (p = 0.003) and widely excised tumours, 81.5% vs 59.1% (p = 0.080). Tumour volume ≥250 ml was associated with worse LRFS (p = 0.045) and post-operative complications (p = 0.017). There may be improved LRFS (p = 0.057) with pre-operative proton-beam RT compared to surgery and selective post-operative RT. CONCLUSION: Pre-operative photon or proton-beam RT to all pelvic ES may improve LRFS compared to the selective delivery of post-operative RT. Radiotherapy delivered to all patients results in a greater percentage of highly necrotic tumours at surgical excision, enabling a greater proportion of patients with wide resection margins.

DOI： 10.1016/j.ejso.2021.05.027

The critical difference in the DASH (Disabilities of the Arm, Shoulder, and Hand) outcome measure after essential upper extremity tumor surgery. 国際誌

Koichi Ogura, Mohamed A Yakoub, Alexander B Christ, Tomohiro Fujiwara, Zarko Nikolic, Patrick J Boland, Edward A Athanasian, John H Healey

Journal of shoulder and elbow surgery 30 ( 9 ) e602-e609 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The DASH (Disabilities of the Arm, Shoulder, and Hand) is a scored questionnaire that is widely used to evaluate the health-related quality of life of patients with upper limb musculoskeletal disorders. However, numerical changes in the measure scores lack clinical significance without meaningful threshold change values of outcome measures that are diagnostically specific. The minimal clinically important difference (MCID) is useful for the interpretation of scores by defining the smallest change that a patient would perceive. However, the MCIDs of the scores in orthopedic oncology patients has not been reported. We aimed to determine the MCIDs of the measure in orthopedic oncology patients. METHODS: Data from our health-related quality of life database from 1999 to 2005 were retrospectively reviewed after institutional review board approval. Seventy-eight patients who underwent surgery and completed 2 surveys during postoperative follow-up were evaluated. Two different methods were used to estimate the MCIDs: distribution-based and anchor-based approaches (the latter used receiver operating characteristic analysis). RESULTS: Using distribution-based methods, the MCIDs of the DASH questionnaire were 7.4 and 8.3 by half standard deviation and the 90% interval of minimal detectable change, respectively. By anchor-based method (receiver operating characteristic analysis), the MCID was 8.3. CONCLUSION: The MCID values calculated by each method validates that the results for upper extremity oncology patients were similar to those reported in other orthopedic conditions. These results identify the threshold for meaningful improvements in DASH scores in orthopedic oncology patients and establish the reference to evaluate health-related quality of life and the outcomes of upper extremity oncology surgery. These data should be further refined for disease- and reconstruction-specific analyses.

DOI： 10.1016/j.jse.2020.11.027

Regional variation in the survival of patients with a soft-tissue sarcoma of the extremity and trunk wall under a centralized care system : what has been the impact of national policies in the UK? 国際誌

Tomohiro Fujiwara, Scott Evans, Jonathan Stevenson, Yusuke Tsuda, Jonathan Gregory, Robert J Grimer, Seggy Abudu

The bone & joint journal 103-B ( 9 ) 1541 - 1549 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: While a centralized system for the care of patients with a sarcoma has been advocated for decades, regional variations in survival remain unclear. The aim of this study was to investigate regional variations in survival and the impact of national policies in patients with a soft-tissue sarcoma (STS) in the UK. METHODS: The study included 1,775 patients with a STS who were referred to a tertiary sarcoma centre. The geographical variations in survival were evaluated according to the periods before and after the issue of guidance by the National Institute for Health and Care Excellence (NICE) in 2006 and the relevant evolution of regional management. RESULTS: There had been a significant difference in survival between patients referred from the North East, North West, East Midlands, West Midlands, South West, and Wales in the pre-NICE era (five-year disease-specific survival (DSS); South West, 74% vs North East, 47% (p = 0.045) or West Midlands, 54% (p = 0.049)), which was most evident for patients with a high-grade STS. However, this variation disappeared in the post-NICE era, in which the overall DSS for high-grade STS improved from 47% to 68% at five years (p < 0.001). Variation in the size of the tumour closely correlated with the variation in DSS, and the overall size of the tumour and incidence of metastasis at the time of diagnosis also decreased after the national policies were issued. CONCLUSION: The survival of patients with a STS improved and regional variation corrected after the introduction of national policies, as a result of a decreasing size of tumour and incidence of metastasis at the time of diagnosis, particularly in patients with a high-grade STS. This highlights the positive impact of national guidelines on regional variation in the presentation, management, and outcome in patients with a STS. Cite this article: Bone Joint J 2021;103-B(9):1541-1549.

DOI： 10.1302/0301-620X.103B9.BJJ-2020-2554.R1

Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression. 国際誌

Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Hiroya Kondo, Shuhei Osaki, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Koji Ueda, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer chemotherapy and pharmacology 88 ( 3 ) 513 - 524 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. MATERIALS AND METHODS: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. RESULTS: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. CONCLUSION: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.

DOI： 10.1007/s00280-021-04310-5

Long-term competing risks for overall and cause-specific failure of rotating-hinge distal femoral arthroplasty for tumour reconstruction. 国際誌

Koichi Ogura, Tomohiro Fujiwara, Carol D Morris, Patrick J Boland, John H Healey

The bone & joint journal 103-B ( 8 ) 1405 - 1413 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Rotating-hinge knee prostheses are commonly used to reconstruct the distal femur after resection of a tumour, despite the projected long-term burden of reoperation due to complications. Few studies have examined the factors that influence their failure and none, to our knowledge, have used competing risk models to do so. The purpose of this study was to determine the risk factors for failure of a rotating-hinge knee distal femoral arthroplasty using the Fine-Gray competing risk model. METHODS: We retrospectively reviewed 209 consecutive patients who, between 1991 and 2016, had undergone resection of the distal femur for tumour and reconstruction using a rotating-hinge knee prosthesis. The study endpoint was failure of the prosthesis, defined as removal of the femoral component, the tibial component, or the bone-implant fixation; major revision (exchange of the femoral component, tibial component, or the bone-implant fixation); or amputation. RESULTS: Multivariate Fine-Gray regression analyses revealed different hazards for each Henderson failure mode: percentage of femoral resection (p = 0.001) and extent of quadriceps muscle resection (p = 0.005) for overall prosthetic failure; extent of quadriceps muscle resection (p = 0.002) and fixation of femoral component (p = 0.011) for type 2 failure (aseptic loosening); age (p = 0.009) and percentage of femoral resection (p = 0.019) for type 3 failure (mechanical failure); and type of joint resection (p = 0.037) for type 4 (infection) were independent predictors. A bone stem ratio of > 2.5 reliably predicted aseptic loosening. CONCLUSION: We identified independent risk factors for overall and cause-specific prosthetic failure after rotating-hinge knee distal femoral arthroplasty using a competing risk Fine-Gray model. A bone stem ratio > 2.5 reliably predicts aseptic loosening. An accurate knowledge of the risks of distal femoral arthroplasty after resection for tumour assists surgical planning and managing patient expectations. Cite this article: Bone Joint J 2021;103-B(8):1405-1413.

DOI： 10.1302/0301-620X.103B8.BJJ-2020-2323.R1

CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. 国際誌

Tomohiro Fujiwara, Mohamed A Yakoub, Andrew Chandler, Alexander B Christ, Guangli Yang, Ouathek Ouerfelli, Vinagolu K Rajasekhar, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Hiroshi Tazawa, Yildirim Dogan, Malcolm A S Moore, Toshiyoshi Fujiwara, Toshifumi Ozaki, Ed Purdue, John H Healey

Molecular cancer therapeutics 20 ( 8 ) 1388 - 1399 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.

DOI： 10.1158/1535-7163.MCT-20-0591

Compliant Compression Reconstruction of the Proximal Femur Is Durable Despite Minimal Bone Formation in the Compression Segment. 国際誌

Alexander B Christ, Tomohiro Fujiwara, Nicola Fabbri, John H Healey

Clinical orthopaedics and related research 479 ( 7 ) 1577 - 1585 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Compliant compression fixation was developed to promote permanent bone-prosthesis osteointegration while preserving bone stock in patients needing endoprosthetic reconstructions. This has demonstrated durability in the distal femur, with reliable cortical hypertrophy adjacent to the implant. However, the extent of bone formation and prosthetic survivorship of proximal femoral replacements with compliant compression fixation has not been established. QUESTIONS/PURPOSES: (1) How much bone formation occurs across the compression segment in patients treated with a proximal femoral replacement implant using compliant compression fixation? (2) What were the Musculoskeletal Tumor Society (MSTS) scores at minimum 24-month follow-up of patients who received this reconstruction? (3) What is the implant survivorship free from implant removal or revision for any reason at final follow-up? METHODS: From 2006 to 2018, we performed 213 proximal femoral replacements in patients with oncologic conditions of the proximal femur where the trochanters could not be preserved. Of these, 6% (12 of 213) were performed with an implant that used compliant compression fixation. We used this device in primary oncologic reconstructions in patients younger than 65 years of age without metastases who had nonirradiated bone with the requisite ≥ 2.5 mm of cortical thickness in the hope that it would provide more durable fixation and bone stock preservation than conventional reconstructions. All patients were followed for longer than 2 years except one who died in that interval. Median (range) follow-up was 6 years (2 to 10 years). Seven patients received diagnosis-specific chemotherapy in a consistent manner based on Children's Oncology Group chemotherapy protocols. Using the NIH-developed ImageJ open-access software, we measured the area of bone under compression on 3-, 6-, 9-, 12-, 18-, and 24-month radiographs and the length of the traction bar potential-compression distance, reconciling independent measures from two investigators using the identical method as published for the distal femur with compression fixation. The duration of prosthesis retention was evaluated using a competing risk analysis for the 11 surviving patients. RESULTS: Bone hypertrophy in the compression segment was scant. At the final analysis, cortical bone formation was a median (range) of 4 (-7 to 14) above baseline. The median (range) MSTS score was 27 (19 to 30). One implant failed after trauma, and the patient underwent revision of the implant. CONCLUSION: Despite scant bone formation across the compression segment and drastically less formation than reported for distal femoral replacements, compliant compression fixation of the proximal femur demonstrated good survivorship in patients 65 years or younger with localized sarcoma and nonirradiated, adequate bone stock in this small, retrospective series. Patients achieved good functional outcomes at final follow-up. The potential benefit of this reconstruction method should be weighed against the initial period of limited weightbearing and the life expectancy of the patient. LEVEL OF EVIDENCE: Level IV, cohort study.

DOI： 10.1097/CORR.0000000000001663

The role of surgical margin quality in myxofibrosarcoma and undifferentiated pleomorphic sarcoma. 国際誌

Tomohiro Fujiwara, Vaiyapuri Sumathi, Michael Parry, Jonathan Stevenson, Yusuke Tsuda, Yoichi Kaneuchi, Lee Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47 ( 7 ) 1756 - 1762 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: The effect of margin quality as a barrier against infiltration of soft-tissue sarcomas (STSs) has been unclear. We aimed to investigate the effect of margin quantity and quality on local control for myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). METHODS: 278 patients with a localised MFS and UPS were studied. Margin quality was categorized into five types; type 1, pseudocapsule/reactive zone; type 2, fat/fibrofatty tissue; type 3, muscle; type 4, fascia; type 5, periosteum. RESULTS: The 5-year cumulative LR incidence was 22% and 13% in patients with positive and 0.1-9.9 mm margins, respectively, but decreased to 3% with ≥10.0 mm margins (p = 0.009); the cumulative LR incidence was significantly lower in patients with ≥10.0 mm margins than those with positive margins (p = 0.033) but was not significantly different in those with 0.1-9.9 mm margins (p = 0.183). In patients with 0.1-9.9 mm margins, the cumulative LR incidence was affected by margin quality; type 4 and 5 provided an LR risk less than 5% (p < 0.001), which was similar to those with margins ≥10.0 mm. Combining these two factors together, the LR risk in patients with positive or 0.1-9.9 mm margins without fascia/periosteum was approximately 11 × higher than patients with 0.1-9.9 mm margins with fascia/periosteum or margins ≥10.0 mm (p = 0.002). CONCLUSIONS: A resection margin of 0.1-9.9 mm with fascia or periosteum provided a similar LR risk profile to ≥10 mm margins with any margin quality, which provided the lowest LR risk. The quality of fascial or periosteal tissue margins may be equivalent to a margin quantity of 10 mm as a barrier to LR.

DOI： 10.1016/j.ejso.2020.11.144

Pelvic reconstruction using an ice-cream cone prosthesis: correlation between the inserted length of the coned stem and surgical outcome.

Tomohiro Fujiwara, Jonathan Stevenson, Michael Parry, Louis-Romée Le Nail, Yusuke Tsuda, Robert Grimer, Lee Jeys

International journal of clinical oncology 26 ( 6 ) 1139 - 1146 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Acetabular reconstruction using an ice-cream cone prosthesis has been a reliable reconstruction option following pelvic tumour resection. However, it remains unknown which factor determines the success of this procedure. We aimed to determine risk factors for complications and functional loss in acetabular reconstruction using an ice-cream cone prosthesis. PATIENTS AND METHODS: Fifty-four patients with malignant bone tumours who underwent acetabular reconstruction using an ice-cream cone prosthesis between 2004 and 2016 were studied. The bone-stem ratio was calculated as the ratio of the inserted length into the bone per the entire stem length. RESULTS: A total of 26 (48%) patients had at least one complication and 11 patients (20%) required surgical interventions. The complication rates were 71% and 40% with a bone-stem ratio ≤ 50% and > 50%, respectively (p = 0.026), and the bone-stem ratio significantly stratified the risk of complications (≤ 50%: OR, 4.67 versus > 50%; p = 0.048). The mean MSTS score at the final follow-up was 60% (range 23-97%): the scores were significantly lower in patients with complications/leg-length discrepancy (52%) than in those without (79%; p = 0.002). The mean score with a bone-stem ratio ≤ 50% was significantly lower than the score with a ratio > 50%, especially in patients who underwent non-navigated reconstructions (33% versus 64%; p = 0.001). CONCLUSION: The inserted length of the coned stem into residual bone was predictive of complications and functional outcome. Surgical indication for this procedure should be considered with the size of the remaining ilium to stabilise the prosthesis with a coned stem longer than half length.

DOI： 10.1007/s10147-021-01882-3

Is 2 mm a wide margin in high-grade conventional chondrosarcomas of the pelvis? 国際誌

Vineet Kurisunkal, Minna K Laitinen, Yoichi Kaneuchi, Bilal Kapanci, Jonathan Stevenson, Michael C Parry, Aleksi Reito, Tomohiro Fujiwara, Lee M Jeys

The bone & joint journal 103-B ( 6 ) 1150 - 1154 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Controversy exists as to what should be considered a safe resection margin to minimize local recurrence in high-grade pelvic chondrosarcomas (CS). The aim of this study is to quantify what is a safe margin of resection for high-grade CS of the pelvis. METHODS: We retrospectively identified 105 non-metastatic patients with high-grade pelvic CS of bone who underwent surgery (limb salvage/amputations) between 2000 and 2018. There were 82 (78%) male and 23 (22%) female patients with a mean age of 55 years (26 to 84). The majority of the patients underwent limb salvage surgery (n = 82; 78%) compared to 23 (22%) who had amputation. In total, 66 (64%) patients were grade 2 CS compared to 38 (36%) grade 3 CS. All patients were assessed for stage, pelvic anatomical classification, type of resection and reconstruction, margin status, local recurrence, distant recurrence, and overall survival. Surgical margins were stratified into millimetres: < 1 mm; > 1 mm but < 2 mm; and > 2 mm. RESULTS: The disease--specific survival (DSS) at five years was 69% (95% confidence interval (CI) 56% to 81%) and 51% (95% CI 31% to 70%) for grade 2 and 3 CS, respectively (p = 0.092). The local recurrence-free survival (LRFS) at five years was 59% (95% CI 45% to 72%) for grade 2 CS and 42% (95% CI 21% to 63%) for grade 3 CS (p = 0.318). A margin of more than 2 mm was a significant predictor of increased LRFS (p = 0.001). There was a tendency, but without statistical significance, for a > 2 mm margin to be a predictor of improved DSS. Local recurrence (LR) was a highly significant predictor of DSS, analyzed in a competing risk model (p = 0.001). CONCLUSION: Obtaining wide margins in the pelvis remains challenging for high-grade pelvic CS. On the basis of our study, we conclude that it is necessary to achieve at least a 2 mm margin for optimal oncological outcomes in patients with high-grade CS of the pelvis. Cite this article: Bone Joint J 2021;103-B(6):1150-1154.

DOI： 10.1302/0301-620X.103B6.BJJ-2020-1869.R1

Patients with an increased time to treatment initiation have a poorer overall survival after definitive surgery for localized high-grade soft-tissue sarcoma in the extremity or trunk : report from the National Cancer Database. 国際誌

Koichi Ogura, Tomohiro Fujiwara, John H Healey

The bone & joint journal 103-B ( 6 ) 1142 - 1149 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Time to treatment initiation (TTI) is generally defined as the time from the histological diagnosis of malignancy to the initiation of first definitive treatment. There is no consensus on the impact of TTI on the overall survival in patients with a soft-tissue sarcoma. The purpose of this study was to determine if an increased TTI is associated with overall survival in patients with a soft-tissue sarcoma, and to identify the factors associated with a prolonged TTI. METHODS: We identified 23,786 patients from the National Cancer Database who had undergone definitive surgery between 2004 and 2015 for a localized high-grade soft-tissue sarcoma of the limbs or trunk. A Cox proportional hazards model was used to examine the relationship between a number of factors and overall survival. We calculated the incidence rate ratio (IRR) using negative binomial regression models to identify the factors that affected TTI. RESULTS: Patients in whom the time to treatment initiation was prolonged had poorer overall survival than those with a TTI of 0 to 30 days. These were: 31 to 60 days (hazard ratio (HR) 1.08, p = 0.011); 61 to 90 days (HR 1.11, p = 0.044); and 91 days (HR 1.22; p = 0.003). The restricted cubic spline showed that the hazard ratio increased substantially with a TTI longer than 50 days. Non-academic centres (vs academic centres; IRR ranging from 0.64 to 0.86; p < 0.001) had a shorter TTI. Those insured by Medicaid (vs private insurance; IRR 1.34), were uninsured (vs private insurance; IRR 1.17), or underwent a transition in care (IRR 1.62) had a longer TTI. CONCLUSION: A time to treatment initiation of more than 30 days after diagnosis was independently associated with poorer survival. The hazard ratio showed linear increase, especially if the TTI was more than 50 days. We recommend starting treatment within 30 days of diagnosis to achieve the highest likelihood of cure for localized high-grade soft-tissue sarcomas in the limbs and trunk, even when a patient needs to be referred to a specialist centre. Cite this article: Bone Joint J 2021;103-B(6):1142-1149.

DOI： 10.1302/0301-620X.103B6.BJJ-2020-2087.R1

Prevalence of Psychological Distress and Its Risk Factors in Patients with Primary Bone and Soft Tissue Tumors. 国際誌

Masato Ise, Eiji Nakata, Yoshimi Katayama, Masanori Hamada, Toshiyuki Kunisada, Tomohiro Fujiwara, Ryuichi Nakahara, Shouta Takihira, Kohei Sato, Yoshiteru Akezaki, Masuo Senda, Toshifumi Ozaki

Healthcare (Basel, Switzerland) 9 ( 5 ) 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Psychological distress is common in patients with soft tissue and bone tumors. We first investigated its frequency and the associated risk factors in patients with pre-operative bone and soft tissue tumors. Participants included 298 patients with bone and soft tissue tumors who underwent surgery in our institution between 2015 and 2020. Psychological distress was evaluated by the Distress and Impact Thermometer (DIT) that consists of two types of questions (questions about the severity of the patient's distress (DIT-D) and its impact (DIT-I)). We used a cut-off point of 4 on the DIT-D and 3 on the DIT-I for screening patients with psychological distress. We therefore investigated: (1) the prevalence of psychological distress as assessed with DIT or distress thermometer (DT), which can be decided by DIT-D ≥ 4, (2) what are the risk factors for the prevalence of psychological distress, and (3) what is the number of patients who consulted a psychiatrist for psychological distress in patients with pre-operative bone and soft tissue tumors. With DIT and DT, we identified 64 patients (21%) and 95 patients (32%), respectively, with psychological distress. Multivariate logistic regression revealed that older age, sex (female), malignancy (malignant or intermediate tumor), a lower Barthel Index, and higher numeric rating scale were risk factors for psychological distress. Two patients (3%) consulted a psychiatrist after surgery. In conclusion, careful attention to psychological distress is needed, especially for female patients, older patients, and those with malignant soft or bone tissue tumors who have more than moderate pain.

DOI： 10.3390/healthcare9050566

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma. 国際誌

Suguru Yokoo, Tomohiro Fujiwara, Aki Yoshida, Koji Uotani, Takuya Morita, Masahiro Kiyono, Joe Hasei, Eiji Nakata, Toshiyuki Kunisada, Shintaro Iwata, Tsukasa Yonemoto, Koji Ueda, Toshifumi Ozaki

Cancers 13 ( 8 ) 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1+CD9+ EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1+CD9+ EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1+CD9+ EVs and indicates the therapeutic potential of MCT1 in SS.

DOI： 10.3390/cancers13081823

Immunotherapy for sarcomas. 国際誌

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Tastuo Ito, Shota Takihira, Toshifumi Ozaki

Japanese journal of clinical oncology 51 ( 4 ) 523 - 537 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sarcomas are a heterogeneous group of malignancies of mesenchymal origin; their molecular and genomic mechanisms differ with regard to histology. These characteristics lead to the presentation of varied immunological profiles based on the tumor microenvironment. Various immunotherapies are considered for the treatment of sarcoma. These treatments are performed either in isolation or in combination with other methods such as cytotoxic chemotherapy or the use of molecular target agents. Among these, two recently emerging immunotherapies include T-cell receptor gene therapy and immune checkpoint inhibitor therapy, which are expected to be effective for many types of sarcoma. A sarcoma with a disease-specific translocation and a limited number of mutations, such as synovial sarcoma, expresses high levels of self-antigens, like the New York esophageal squamous cell carcinoma 1, which has been targeted in T-cell receptor gene therapy. On the other hand, sarcomas with a greater number of mutations, such as undifferentiated pleomorphic sarcomas, myxofibrosarcoma and dedifferentiated liposarcomas, can be good candidates for immune checkpoint inhibitors. Among immune checkpoint inhibitor therapies, programmed cell death-1 blockade (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte-associated antigen 4 blockade (ipilimumab) have been investigated most often in sarcoma. Although the sole use of immune checkpoint inhibitors provides limited efficacy, combined immunotherapy with immune checkpoint inhibitors or molecular target agents, especially antiangiogenic agents, has shown moderate results against some types of sarcoma, such as the alveolar soft part sarcoma. Several clinical trials utilizing immunotherapy, including T-cell receptor gene therapy and immune checkpoint inhibitors, in sarcomas are under progress. By clarifying the tumor microenvironment and biomarker-predictive capacity of immunotherapy in sarcomas, better clinical trials can be designed; this could lead to improved outcomes for immunotherapy in sarcoma.

DOI： 10.1093/jjco/hyab005

Anti-IL17 antibody Secukinumab therapy is associated with ossification in giant cell tumor of bone: a case report of pathologic similarities and therapeutic potential similar to Denosumab. 国際誌

Andrew Chandler, Meredith K Bartelstein, Tomohiro Fujiwara, Cristina R Antonescu, John H Healey, Max Vaynrub

BMC musculoskeletal disorders 22 ( 1 ) 320 - 320 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage. CASE PRESENTATION: One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB. CONCLUSIONS: Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease.

DOI： 10.1186/s12891-021-04182-z

【骨・軟部腫瘍のマネジメント(その1)】総論診療体制サルコーマセンター設立と腫瘍内科医との連携集約化と地域連携

国定俊之, 中田英二, 藤原智洋, 久保寿夫, 西森久和, 田端雅弘, 尾崎敏文

別冊整形外科 ( 79 ) 7 - 12 2021年4月

記述言語：日本語出版者・発行元：(株)南江堂

＜文献概要＞はじめにわが国では歴史的に整形外科が中心となって肉腫(サルコーマ)の治療方針を決め,主に手術と化学療法を担当してきた.一方,欧米では腫瘍内科が肉腫の化学療法を担当することが一般的であり,わが国の治療状況とは大きく異なる.肉腫治療例の増加とともに進行例が増加し,新規治療薬も開発され,整形外科医のみで治療していくことがむずかしくなってきた.また,化学療法以外にも,肉腫の診断,手術には多くの診療科の協力が必要で,多職種による集学的医療チームによる治療が重要である.当院では肉腫患者によりよい治療を提供する目的で,2014年4月に大学病院の診療部門としては日本ではじめてサルコーマセンターを設立した.本稿では,当院サルコーマセンターの活動を紹介する.

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04037&link_issn=&doc_id=20210514600002&doc_link_id=10.15106%2Fj_besei79_7&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_besei79_7&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

【骨・軟部腫瘍のマネジメント(その1)】診断組織・遺伝子診断肉腫におけるがんゲノム医療の意義

中田英二, 藤原智洋, 国定俊之, 尾崎敏文, 遠西大輔, 冨田秀太, 平沢晃, 二川摩周, 武田達明

別冊整形外科 ( 79 ) 75 - 83 2021年4月

記述言語：日本語出版者・発行元：(株)南江堂

＜文献概要＞はじめにがんにはさまざまな遺伝子異常を認め,同一のがん種でも発現する遺伝子が異なることが少なくない.最近,次世代シークエンサー(next generation sequencer:NGS)を用いて遺伝子異常を同時多重性(マルチプレックス)に検出するがん遺伝子パネルが登場した.がんゲノム医療では,がん遺伝子パネルで同定した遺伝子変異に基づいて薬剤を選択する,精密医療(precision medicine)が行われる.本稿では,肉腫におけるゲノム医療の意義について述べる.

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04037&link_issn=&doc_id=20210514600016&doc_link_id=10.15106%2Fj_besei79_75&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_besei79_75&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

【骨・軟部腫瘍のマネジメント(その1)】治療総論免疫療法肉腫における免疫療法

中田英二, 藤原智洋, たき平将太, 国定俊之, 尾崎敏文

別冊整形外科 ( 79 ) 149 - 157 2021年4月

記述言語：日本語出版者・発行元：(株)南江堂

＜文献概要＞はじめに肉腫における免疫療法の歴史は古く,1891年,William Coley博士は切除不能で転移性の肉腫の患者において免疫療法の効果を最初に示した.その後,免疫調節薬,ワクチンなどさまざまな免疫療法が開発され,最近は免疫チェックポイント阻害薬(immune-check point inhibitor:ICI)や活性化自己リンパ球輸注療法などの有望な治療法が登場している(表1).本稿では肉腫の免疫療法についてレビューを行う.

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04037&link_issn=&doc_id=20210514600029&doc_link_id=10.15106%2Fj_besei79_149&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_besei79_149&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Limb-salvage reconstruction following resection of pelvic bone sarcomas involving the acetabulum. 国際誌

Tomohiro Fujiwara, Manuel Ricardo Medellin Rincon, Andrea Sambri, Yusuke Tsuda, Rhys Clark, Jonathan Stevenson, Michael C Parry, Robert J Grimer, Lee Jeys

The bone & joint journal 103-B ( 4 ) 795 - 803 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Limb salvage for pelvic sarcomas involving the acetabulum is a major surgical challenge. There remains no consensus about what is the optimum type of reconstruction after resection of the tumour. The aim of this study was to evaluate the surgical outcomes in these patients according to the methods of periacetabular reconstruction. METHODS: The study involved a consecutive series of 122 patients with a periacetabular bone sarcoma who underwent limb-salvage surgery involving a custom-made prosthesis in 65 (53%), an ice-cream cone prosthesis in 21 (17%), an extracorporeal irradiated autograft in 18 (15%), and nonskeletal reconstruction in 18 (15%). RESULTS: The rates of major complications necessitating further surgery were 62%, 24%, 56%, and 17% for custom-made prostheses, ice-cream cone prostheses, irradiated autografts and nonskeletal reconstructions, respectively (p = 0.001). The ten-year cumulative incidence of failure of the reconstruction was 19%, 9%, 33%, and 0%, respectively. The major cause of failure was deep infection (11%), followed by local recurrence (6%). The mean functional Musculoskeletal Tumour Society (MSTS) scores were 59%, 74%, 64%, and 72%, respectively. The scores were significantly lower in patients with major complications than in those without complications (mean 52% (SD 20%) vs 74% (SD 19%); p < 0.001). For periacetabular resections involving the ilium, the mean score was the highest with custom-made prostheses (82% (SD 10%)) in patients without any major complication; however, nonskeletal reconstruction resulted in the highest mean scores (78% (SD 12%)) in patients who had major complications. For periacetabular resections not involving the ilium, significantly higher mean scores were obtained with ice-cream cone prostheses (79% (SD 17%); p = 0.031). CONCLUSION: Functional outcome following periacetabular reconstruction is closely associated with the occurrence of complications requiring further surgery. For tumours treated with periacetabular and iliac resection, skeletal reconstruction may result in the best outcomes in the absence of complications, whereas nonskeletal reconstruction is a reasonable option if the risk of complications is high. For tumours requiring periacetabular resection without the ilium, reconstruction using an ice-cream cone prosthesis supported by antibiotic-laden cement is a reliable option. Cite this article: Bone Joint J 2021;103-B(4):795-803.

DOI： 10.1302/0301-620X.103B4.BJJ-2020-0665.R1

【骨・軟部腫瘍のマネジメント(その1)】診断組織・遺伝子診断骨・軟部腫瘍におけるリキッドバイオプシーの開発

藤原智洋, 中田英二, 国定俊之, 尾崎敏文

別冊整形外科 ( 79 ) 63 - 69 2021年4月

記述言語：日本語出版者・発行元：(株)南江堂

＜文献概要＞はじめに-リキッドバイオプシーとはリキッドバイオプシーとは,血液,尿,唾液などの体液中に含まれる細胞,核酸,蛋白質,代謝物などの生体分子の解析から病態の把握をめざす病態診断技術の総称である.この用語は,2010年代に血液中に存在する循環腫瘍細胞(circulating tumor cells:CTC)の検出による診断法に与えられたものであり,その後,核酸,蛋白質,代謝物などのさまざまな生体分子を対象とした解析法に対しても用いられるようになっている.現在では,循環腫瘍DNA(circulating tumor DNA:ctDNA),疾患特異的なマイクロRNA(microRNA:miRNA)などの核酸分子や,癌細胞由来のエクソソームの検出による疾患診断法の開発が精力的にすすめられている(図1).リキッドバイオプシーは非侵襲的かつ簡便に施行することができ,同一症例に対して繰り返し施行することが可能であるため,診断だけでなく治療効果や予後の予測に有用であり,次世代の診断技術の基盤として期待が集まっている.骨・軟部腫瘍には,消化器癌,前立腺癌,婦人科癌などの存在診断,治療効果予測,再発リスクの予測,術後再発のモニタリングなどに用いられる血液腫瘍マーカーがきわめて少ない.2012年の『軟部腫瘍診療ガイドライン』では,「臨床検査値で異常を示す腫瘍は?」というクリニカルクエスチョンに対して「軟部腫瘍で特異的な腫瘍マーカーは一般的にはない」と記載されている.癌腫と同様に乳酸脱水素酵素(LDH)の上昇を認めることがあるが,一般的には腫瘍サイズの大きな高悪性度軟部肉腫,あるいは多発性に転移して進行した軟部肉腫に限られる.このような背景から,肉腫細胞由来の生体分子を用いたリキッドバイオプシーの開発は,骨・軟部腫瘍の診療における新しいブレイクスルーとなる可能性があり,研究開発が精力的に行われている.本稿では,リキッドバイオプシーの骨・軟部腫瘍における研究開発の動向を生体分子別に述べ,本法の将来展望について論じる.

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04037&link_issn=&doc_id=20210514600014&doc_link_id=10.15106%2Fj_besei79_63&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_besei79_63&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Role of Tumor-Associated Macrophages in Sarcomas. 国際誌

Tomohiro Fujiwara, John Healey, Koichi Ogura, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Miho Kure, Hiroshi Tazawa, Eiji Nakata, Toshiyuki Kunisada, Toshiyoshi Fujiwara, Toshifumi Ozaki

Cancers 13 ( 5 ) 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.

DOI： 10.3390/cancers13051086

【希少がん-がん診療の新たな課題-】希少がん疾患各論骨軟部腫瘍・肉腫骨肉腫

国定俊之, 中田英二, 藤原智洋, 尾崎敏文

日本臨床 79 ( 増刊1 希少がん ) 454 - 461 2021年3月

Impact of NICE guidelines on the survival of patients with soft-tissue sarcomas. 国際誌

Tomohiro Fujiwara, Robert J Grimer, Scott Evans, Manuel Ricardo Medellin Rincon, Yusuke Tsuda, Louis-Romée Le Nail, Seggy Abudu

The bone & joint journal 103-B ( 3 ) 569 - 577 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Urgent referral to a specialist centre for patients with a soft-tissue sarcoma (STS) has been recommended by the National Institute for Health and Care Excellence (NICE) in the UK since 2006. However, the impact of this recommendation on the prognosis for these patients remains unclear. We aimed to determine the impact of the NICE guidelines on the disease-specific survival (DSS) of patients with an STS. METHODS: A total of 2,427 patients with an STS referred to a supraregional centre in the ten-year periods before (n = 1,386) and after (n = 1,041) the issue of the NICE guidelines were evaluated. RESULTS: The mean size of the tumour was significantly smaller at the time of diagnosis (10.3 cm (SD 6.5) vs 9.1 cm (SD 6.2); p < 0.001) and the number of patients who had undergone an inadvertent excision significantly decreased (28% (n = 389) vs 20% (n = 204); p < 0.001) following the introduction of the NICE guidelines. The five-year DSS was 63% in the pre-NICE and 71% in post-NICE groups (p < 0.001). The improved survival was more significant for those with a high-grade tumour (pre-NICE, 48%; post-NICE, 68%; p < 0.001). In those with a high-grade tumour, the mean size of the tumour (11.6 cm (SD 6.2) vs 9.6 cm (SD 5.8); p < 0.001) and the number of patients with metastasis at the time of diagnosis (15% (n = 124 vs 10% (n = 80); p = 0.007) significantly decreased in the post-NICE group. CONCLUSION: An improvement in survival was seen after the introduction of the NICE guidelines, especially in patients with a high-grade STS. More patients were referred at an earlier stage, indicating a clearer pathway after the issue of national policy for the management of STSs in the UK. Cite this article: Bone Joint J 2021;103-B(3):569-577.

DOI： 10.1302/0301-620X.103B3.BJJ-2020-0743.R1

How Are Indeterminate Pulmonary Nodules at Diagnosis Associated with Survival in Patients with High-Grade Osteosarcoma? 国際誌

Kim M Tsoi, Martin Lowe, Yusuke Tsuda, Johnathan R Lex, Tomohiro Fujiwara, Ghassan Almeer, Jonathan Gregory, Jonathan Stevenson, Scott E Evans, Rajesh Botchu, Lee M Jeys

Clinical orthopaedics and related research 479 ( 2 ) 298 - 308 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Pulmonary metastases are a poor prognostic factor in patients with osteosarcoma; however, the clinical significance of subcentimeter lung nodules and whether they represent a tumor is not fully known. Because the clinician is faced with decisions regarding biopsy, resection, or observation of lung nodules and the potential impact they have on decisions about resection of the primary tumor, this remains an area of uncertainty in patient treatment. Surgical management of the primary tumor is tailored to prognosis, and it is unclear how aggressively patients with indeterminate pulmonary nodules (IPNs), defined as nodules smaller than 1 cm at presentation, should be treated. There is a clear need to better understand the clinical importance of these nodules. QUESTIONS/PURPOSES: (1) What percentage of patients with high-grade osteosarcoma and spindle cell sarcoma of bone have IPNs at diagnosis? (2) Are IPNs at diagnosis associated with worse metastasis-free and overall survival? (3) Are there any clinical or radiologic factors associated with worse overall survival in patients with IPN? METHODS: Between 2008 and 2016, 484 patients with a first presentation of osteosarcoma or spindle cell sarcoma of bone were retrospectively identified from an institutional database. Patients with the following were excluded: treatment at another institution (6%, 27 of 484), death related to complications of neoadjuvant chemotherapy (1%, 3 of 484), Grade 1 or 2 on final pathology (4%, 21 of 484) and lack of staging chest CT available for review (0.4%, 2 of 484). All patients with abnormalities on their staging chest CT underwent imaging re-review by a senior radiology consultant and were divided into three groups for comparison: no metastases (70%, 302 of 431), IPN (16%, 68 of 431), and metastases (14%, 61 of 431) at the time of diagnosis. A random subset of CT scans was reviewed by a senior radiology registrar and there was very good agreement between the two reviewers (κ = 0.88). Demographic and oncologic variables as well as treatment details and clinical course were gleaned from a longitudinally maintained institutional database. The three groups did not differ with regard to age, gender, subtype, presence of pathological fracture, tumor site, or chemotherapy-induced necrosis. They differed according to local control strategy and tumor size, with a larger proportion of patients in the metastases group presenting with larger tumor size and undergoing nonoperative treatment. There was no differential loss to follow-up among the three groups. Two percent (6 of 302) of patients with no metastases, no patients with IPN, and 2% (1 of 61) of patients with metastases were lost to follow-up at 1 year postdiagnosis but were not known to have died. Individual treatment decisions were determined as part of a multidisciplinary conference, but in general, patients without obvious metastases received (neo)adjuvant chemotherapy and surgical resection for local control. Patients in the no metastases and IPN groups did not differ in local control strategy. For patients in the IPN group, staging CT images were inspected for IPN characteristics including number, distribution, size, location, presence of mineralization, and shape. Subsequent chest CT images were examined by the same radiologist to reevaluate known nodules for interval change in size and to identify the presence of new nodules. A random subset of chest CT scans were re-reviewed by a senior radiology resident (κ = 0.62). The association of demographic and oncologic variables with metastasis-free and overall survival was first explored using the Kaplan-Meier method (log-rank test) in univariable analyses. All variables that were statistically significant (p < 0.05) in univariable analyses were entered into Cox regression multivariable analyses. RESULTS: Following re-review of staging chest CTs, IPNs were found in 16% (68 of 431) of patients, while an additional 14% (61 of 431) of patients had lung metastases (parenchymal nodules 10 mm or larger). After controlling for potential confounding variables like local control strategy, tumor size, and chemotherapy-induced necrosis, we found that the presence of an IPN was associated with worse overall survival and a higher incidence of metastases (hazard ratio 1.9 [95% CI 1.3 to 2.8]; p = 0.001 and HR 3.6 [95% CI 2.5 to 5.2]; p < 0.001, respectively). Two-year overall survival for patients with no metastases, IPN, or metastases was 83% [95% CI 78 to 87], 65% [95% CI 52 to 75] and 45% [95% CI 32 to 57], respectively (p = 0.001). In 74% (50 of 68) of patients with IPNs, it became apparent that they were true metastatic lesions at a median of 5.3 months. Eighty-six percent (43 of 50) of these patients had disease progression by 2 years after diagnosis. In multivariable analysis, local control strategy and tumor subtype correlated with overall survival for patients with IPNs. Patients who were treated nonoperatively and who had a secondary sarcoma had worse outcomes (HR 3.6 [95% CI 1.5 to 8.3]; p = 0.003 and HR 3.4 [95% CI 1.1 to 10.0]; p = 0.03). The presence of nodule mineralization was associated with improved overall survival in the univariable analysis (87% [95% CI 39 to 98] versus 57% [95% CI 43 to 69]; p = 0.008), however, because we could not control for other factors in a multivariable analysis, the relationship between mineralization and survival could not be determined. We were unable to detect an association between any other nodule radiologic features and survival. CONCLUSION: The findings show that the presence of IPNs at diagnosis is associated with poorer survival of affected patients compared with those with normal staging chest CTs. IPNs noted at presentation in patients with high-grade osteosarcoma and spindle cell sarcoma of bone should be discussed with the patient and be considered when making treatment decisions. Further work is required to elucidate how the nodules should be managed. LEVEL OF EVIDENCE: Level III, prognostic study.

DOI： 10.1097/CORR.0000000000001491

Interlocking reconstruction-mode stem-sideplates preserve at-risk hips with short residual proximal femora. 国際誌

Alexander B Christ, Tomohiro Fujiwara, Mohamed A Yakoub, John H Healey

The bone & joint journal 103-B ( 2 ) 398 - 404 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: We have evaluated the survivorship, outcomes, and failures of an interlocking, reconstruction-mode stem-sideplate implant used to preserve the native hip joint and achieve proximal fixation when there is little residual femur during large endoprosthetic reconstruction of the distal femur. METHODS: A total of 14 patients underwent primary or revision reconstruction of a large femoral defect with a short remaining proximal femur using an interlocking, reconstruction-mode stem-sideplate for fixation after oncological distal femoral and diaphyseal resections. The implant was attached to a standard endoprosthetic reconstruction system. The implant was attached to a standard endoprosthetic reconstruction system. None of the femoral revisions were amenable to standard cemented or uncemented stem fixation. Patient and disease characteristics, surgical history, final ambulatory status, and Musculoskeletal Tumor Society (MSTS) score were recorded. The percentage of proximal femur remaining was calculated from follow-up radiographs. RESULTS: All 14 at-risk native hip joints were preserved at a mean final follow-up of 6.0 years (SD 3.7), despite a short residual femur, often after proximal osteotomies through the lesser trochanter. Overall, 13 of 14 stems had long-term successful fixation. Eight patients required no reoperation. Three patients required reoperation due to implant-related issues, and three patients required reoperation for wound healing problems or infection. There were no dislocations or fractures. At final follow-up the mean MSTS score was 24.9 (SD 4.1). Nine patients required no ambulation aids, and only one had a Trendelenburg gait. CONCLUSION: This interlocking, reconstruction-mode stem-sideplate reliably preserves native hip joint anatomy and function after large femoral resection with a short remaining proximal femur, both in the primary and revision setting. This is particularly important for preventing or delaying total femoral arthroplasty in young patients after oncological reconstruction. Hip abductor strength and function could be maintained by this method, and the risk of dislocation eliminated. The success of this technique in this modest series should be verified in a larger collaborative study and will be of interest to revision surgeons and oncologists. Cite this article: Bone Joint J 2021;103-B(2):398-404.

DOI： 10.1302/0301-620X.103B2.BJJ-2020-0654.R1

The adequacy of resection margin for non-infiltrative soft-tissue sarcomas. 国際誌

Tomohiro Fujiwara, Jonathan Stevenson, Michael Parry, Yusuke Tsuda, Yoichi Kaneuchi, Lee Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47 ( 2 ) 429 - 435 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: There remains no consensus on what constitutes an adequate margin of resection for non-infiltrative soft-tissue sarcomas (STSs). We aimed to investigate the role of resection margins in millimetres for non-infiltrative STSs. METHODS: 502 patients who underwent surgical resection for a localized, non-infiltrative, high-grade STSs were studied. The prognostic significance of margin width was analysed and compared with the conventional R- and R+1-classification of surgical margins. RESULTS: The overall local recurrence (LR) rate was 13%; 9% and 27% with negative and positive margins, respectively (p < 0.001). In patients with negative margins, the LR rates were greater than 10% in patients with margins ≤5.0 mm but reduced to less than 4% with margins >5.0 mm. When classified by the R- (or R+1)-classification, the 5-year cumulative LR incidence was 8%, 23% (16%), and 31% for R0, R1, and R2, respectively, which did not stratify the LR risk with negative margins. On the other hand, an accurate risk stratification was possible by metric distance; the 5-year cumulative incidence of LR was 29%, 10%, and 1% with 0 mm, 0.1-5.0 mm, and >5.0 mm, respectively (p < 0.001). This classification also stratified the LR risk in patients with or without adjuvant radiotherapy. CONCLUSION: While a negative margin is essential to optimize local control in patients with non-infiltrative STSs, surgical margin width greater than 5 mm minimises the risk of local failure regardless of the use of adjuvant radiotherapy.

DOI： 10.1016/j.ejso.2020.06.020

Navigation-assisted pelvic resections and reconstructions for periacetabular chondrosarcomas. 国際誌

Tomohiro Fujiwara, Yoichi Kaneuchi, Jonathan Stevenson, Michael Parry, Vineet Kurisunkal, Rhys Clark, Yusuke Tsuda, Minna Laitinen, Robert Grimer, Lee Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47 ( 2 ) 416 - 423 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Survival in patients with chondrosarcomas has not improved over 40 years. Although emerging evidence has documented the efficacy of navigation-assisted surgery, the prognostic significance in chondrosarcomas remains unknown. We aimed to assess the clinical benefit of navigation-assisted surgery for pelvic chondrosarcomas involving the peri-acetabulum. METHODS: We studied 50 patients who underwent limb-sparing surgery for periacetabular chondrosarcomas performed with navigation (n = 13) without it (n = 37) at a referral musculoskeletal oncology centre between 2000 and 2015. RESULTS: The intralesional resection rates in the navigated and non-navigated groups were 8% (n = 1) and 19% (n = 7), respectively; all bone resection margins were clear in the navigated group. The 5-year cumulative incidence of local recurrence was 23% and 56% in the navigated and non-navigated groups, respectively (p = 0.035). There were no intra-operative complications related to use of navigation. There was a trend toward better functional outcomes in the navigated group (mean MSTS score, 67%) than the non-navigated group (mean MSTS score, 60%; p = 0.412). At a mean follow-up of 63 months, the 5-year disease-specific survival was 76% and 53% in the navigated and non-navigated group, respectively (p = 0.085), whilst the 5-year progression-free survival was 62% and 28% in the navigated and non-navigated group, respectively (p = 0.032). CONCLUSION: This study confirmed improved local control and progression-free survival with the use of computer navigation in patients with limb-salvage surgery for periacetabular chondrosarcomas, although the advancement in other treatment modalities is required for improvement of disease-specific survival.

DOI： 10.1016/j.ejso.2020.05.025

Postradiation Fractures after Combined Modality Treatment in Extremity Soft Tissue Sarcomas. 国際誌

Meredith K Bartelstein, Divya Yerramilli, Alexander B Christ, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, Nicola Fabbri, John H Healey

Sarcoma 2021 8877567 - 8877567 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Soft tissue sarcoma (STS) of the extremities is typically treated with limb-sparing surgery and radiation therapy; with this treatment approach, high local control rates can be achieved. However, postradiation bone fractures, fractures occurring in the prior radiation field with minimal or no trauma, are a serious late complication that occurs in 2-22% of patients who receive surgery and radiation for STS. Multiple risk factors for sustaining a postradiation fracture exist, including high radiation dose, female sex, periosteal stripping, older age, femur location, and chemotherapy administration. The treatment of these pathological fractures can be difficult, with complications including delayed union, nonunion, and infection posing particular challenges. Here, we review the mechanisms, risk factors, and treatment challenges associated with postradiation fractures in STS patients.

DOI： 10.1155/2021/8877567

Myxofibrosarcoma: Clinical and Prognostic Value of MRI Features. 国際誌

Paolo Spinnato, Andrea Sambri, Tomohiro Fujiwara, Luca Ceccarelli, Roberta Clinca, Manuel R Medellin, Massimiliano De Paolis, Davide M Donati, Giuseppe Bianchi

Current medical imaging 17 ( 2 ) 217 - 224 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Myxofibrosarcoma is one of the most common soft tissue sarcomas in the elderly. It is characterized by an extremely high rate of local recurrence, higher than other soft tissue tumors, and a relatively low risk of distant metastases.Magnetic resonance imaging (MRI) is the imaging modality of choice for the assessment of myxofibrosarcoma, which plays a key role in the preoperative setting of these patients. MRI features associated with the high risk of local recurrence are: high myxoid matrix content (water-like appearance of the lesions), high grade of contrast enhancement and presence of an infiltrative pattern ("tail sign"). On the other hand, MRI features associated with worse sarcoma specific survival are: large size of the lesion, deep location, high grade of contrast enhancement. Recognizing the above-mentioned imaging features of myxofibrosarcoma may be helpful in stratifying the risk for local recurrence and disease-specific survival. Moreover, the surgical planning should be adjusted according to the MRI features.

DOI： 10.2174/1573405616999200729152135

Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression. 国際誌

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

PloS one 16 ( 4 ) e0250643 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

DOI： 10.1371/journal.pone.0250643

Greater travel distance to specialized facilities is associated with higher survival for patients with soft-tissue sarcoma: US nationwide patterns. 国際誌

Tomohiro Fujiwara, Koichi Ogura, John Healey

PloS one 16 ( 6 ) e0252381 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: The survival impact of geographic access to specialized care remains unknown in patients with soft-tissue sarcomas (STS). This study aimed to clarify the association between the patient travel distance and survival outcome and investigate the factors lying behind it. METHODS: A total of 34 528 patients with STS registered in the National Cancer Data Base, diagnosed from 2004-2016, were investigated. RESULTS: Tumor stage correlated with travel distance: patients with metastatic disease stayed closer to home. However, the type of facility showed greatest variation: 37.0%, 51.0%, 73.5%, and 75.9% of patients with ≤10 miles, 10.1-50 miles, 50.1-100 miles, and >100 miles, respectively (P<0.001), had a sarcoma care at academic/research centers. On a multivariable analysis, reduced mortality risk was associated with longer (versus short) travel distance (>100 miles: HR = 0.877; P = 0.001) and management at academic/research (versus non-academic/research) centers (HR = 0.857; P<0.001). The greatest divergence was seen in patients traveling very long distance (>100 miles) to an academic/research center, with a 26.9% survival benefit (HR = 0.731; P<0.001), compared with those traveling short distance (≤10 miles; 95.4% living in metropolitan area) to a non-academic/research center. There was no significant correlation between travel distance and survival in patients who had care at academic/research centers, whereas a survival benefit of management at academic/research centers was observed in every group of travel distance, regardless of tumor stage. CONCLUSIONS: This national study demonstrated that increased travel distance was associated with superior survival, attributable to a higher proportion of patients receiving sarcoma care at distant academic/research centers. These data support centralized care for STS. Overcoming referral and travel barriers may enable more patients to be treated at specialized centers and may further improve survival rates for patients with STS, even when it imposes an increased travel burden.

DOI： 10.1371/journal.pone.0252381

Radiographic and clinical assessment of unidirectional porous hydroxyapatite to treat benign bone tumors. 国際誌

Toshiyuki Kunisada, Joe Hasei, Tomohiro Fujiwara, Eiji Nakata, Suguru Yokoo, Koji Demiya, Toshifumi Ozaki

Scientific reports 10 ( 1 ) 21578 - 21578 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Unidirectional porous hydroxyapatite (UDPHAp) was developed as an excellent scaffold with unidirectional pores oriented in the horizontal direction with interpore connections. The purpose of this study was to assess radiographic changes and clinical outcomes and complications following UDPHAp implantation to treat benign bone tumors. We retrospectively analyzed 44 patients treated with intralesional resection and UDPHAp implantation for benign bone tumors between 2010 and 2015. Clinical and radiographic findings were evaluated postoperatively at regular follow-up visits. The mean follow-up was 49 months. Radiographic changes were classified into five stages based on bone formation in the implanted UDPHAp according to Tamai's classification. All patients showed excellent bone formation inside and around implanted UDPHAp. Absorption of UDPHAp and bone marrow cavity remodeling was identified in 20 patients at a mean of 17 months postoperatively, and was significantly more common in young patients. Preoperative cortical thinning was completely regenerated in 26 of 31 patients on average 10 months after surgery. There were no cases of delayed wound healing, postoperative infection, or allergic reaction related to implanted UDPHAp. UDPHAp is a useful bone-filling substitute for treating benign bone tumor, and the use of this material has a low complication rate.

DOI： 10.1038/s41598-020-78409-9

Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma. 国際誌

Yusuke Tsuda, Kim Tsoi, Jonathan D Stevenson, Minna Laitinen, Peter C Ferguson, Jay S Wunder, Anthony M Griffin, Michiel A J van de Sande, Veroniek van Praag, Andreas Leithner, Tomohiro Fujiwara, Hideo Yasunaga, Hiroki Matsui, Michael C Parry, Lee M Jeys

The bone & joint journal 102-B ( 12 ) 1752 - 1759 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma. METHODS: The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot. RESULTS: In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit. CONCLUSION: Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: Bone Joint J 2020;102-B(12):1752-1759.

DOI： 10.1302/0301-620X.102B12.BJJ-2020-0810.R1

Low-grade soft-tissue sarcomas: What is an adequate margin for local disease control? 国際誌

Tomohiro Fujiwara, Yoichi Kaneuchi, Yusuke Tsuda, Jonathan Stevenson, Michael Parry, Lee Jeys

Surgical oncology 35 303 - 308 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Whilst the resection margin is an established factor predictive of local control of soft-tissue sarcomas (STSs), the adequacy of margin width for low-grade STSs has been rarely described. We aimed to investigate the margin adequacy and its prognostic relevance in low-grade STSs. METHODS: 109 patients who underwent surgical treatment for a low-grade STS were studied. The prognostic value of margin status was evaluated according to the R-, R+1-classification, and width in millimetres. RESULTS: The 10-year local recurrence (LR) rates were 6%, 27%, 54% in R0, R1, and R2, respectively (p < 0.001), according to the R-classification. The R+1-classification resulted in a decreased LR rate in R1, but no major differences in LR rates in R0 and R2; 7%, 14%, 54% in R0, R1, and R2, respectively (p < 0.001). When classified by metric distance, 10-year LR rates were 0%, 8%, and 38% by ≥ 2.0 mm, 0.1-1.9 mm, and 0 mm margins, respectively (p < 0.001). Patients with close margins (0.1-1.9 mm) who received adjuvant radiotherapy had a trend toward lower LR risk than those without radiotherapy (10-year, 4% vs. 12%; p = 0.406). The 5 and 10-year disease-specific mortality was 9% and 13%, respectively; margin width was not associated with disease-specific mortality but LR was a poor prognostic factor for survival (p = 0.003). CONCLUSION: Whilst negative margin provided local control over 90%, excellent local control was achieved with microscopic margins ≥2 mm. The role of margins is more important than radiotherapy in local control. Margins do not determine survival, but LR is associated with a poor prognosis.

DOI： 10.1016/j.suronc.2020.08.022

What Are the Minimum Clinically Important Differences in SF-36 Scores in Patients with Orthopaedic Oncologic Conditions? 国際誌

Koichi Ogura, Mohamed A Yakoub, Alexander B Christ, Tomohiro Fujiwara, Zarko Nikolic, Patrick J Boland, John H Healey

Clinical orthopaedics and related research 478 ( 9 ) 2148 - 2158 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The SF-36 is widely used to evaluate the health-related quality of life of patients with musculoskeletal tumors. The minimum clinically important difference (MCID) is useful for interpreting changes in functional scores because it defines the smallest change each patient may perceive. Since the MCID is influenced by the population characteristics, MCIDs of the SF-36 should be defined to reflect the specific conditions of orthopaedic oncology patients. QUESTIONS/PURPOSES: (1) What is the MCID of SF-36 physical component summary (PCS) and mental component summary (MCS) scores in patients with orthopaedic oncologic conditions when calculated with distribution-based methods? (2) What is the MCID of SF-36 PCS and MCS scores in patients with orthopaedic oncologic conditions when calculated by anchor-based methods? METHODS: Of all 960 patients who underwent surgery from 1999 to 2005, 32% (310) of patients who underwent musculoskeletal oncologic surgery and completed two surveys during postoperative follow-up were reviewed. We evaluated a dataset that ended in 2005, completing follow-up of data accrued as part of the cooperative effort between the American Academy of Orthopaedic Surgeons and the Council of Musculoskeletal Specialty Societies to create patient reported quality of life instruments for lower extremity conditions. This effort, started in 1994 was validated and widely accepted by its publication in 2004. We believe the findings from this period are still relevant today because (1) this critical information has never been available for clinicians and researchers to distinguish real differences in outcome among orthopaedic oncology patients, (2) the SF-36 continues to be the best validated and widely used instrument to assess health-related quality of life, and unfortunately (3) there has been no significant change in outcome for oncology patients over the intervening years. SF-36 PCS and MCS are aggregates of the eight scale scores specific to physical and mental dimension (scores range from 0 to 100, with higher scores representing better health). Their responsiveness has been shown postoperatively for several surgical procedures (such as, colorectal surgery). Two different methods were used to calculate the MCID: the distribution-based method, which was based on half the SD of the change in score and standard error of the measurement at baseline, and anchor-based, in which a receiver operating characteristic (ROC) curve analysis was performed. The anchor-based method uses a plain-language question to ask patients how their individual conditions changed when compared with the previous survey. Answer choices were "much better," "somewhat better," "about the same," "somewhat worse," or "much worse." The ROC curve-derived MCIDs were defined as the change in scores from baseline, with sensitivity and specificity to detect differences in patients who stated their outcome was, about the same and those who stated their status was somewhat better or somewhat worse. This approach is based on each patient's perception. It considers that the definition of MCID is the minimal difference each patient can perceive as meaningful. RESULTS: Using the distribution-based method, we found that the MCIDs of the PCS and MCS were 5 and 5 by half the SD, and 6 and 5 by standard error of the measurement. In the anchor-based method, the MCIDs of the PCS and MCS for improvement/deterioration were 4 (area under the curve, 0.82)/-2 (area under the curve, 0.79) and 4 (area under the curve, 0.72)/ (area under the curve, 0.68), respectively. CONCLUSIONS: Since both anchor-based and distribution-based MCID estimates of the SF-36 in patients with musculoskeletal tumors were so similar, we have confidence in the estimates we made, which were about 5 points for both the PCS and the MCS subscales of the SF-36. This suggests that interventions improving SF-36 by less than that amount are unlikely to be perceived by patients as clinically important. Therefore, those interventions may not justify exposing patients to risk, cost, or inconvenience. When applying new interventions to orthopaedic oncology patients going forward, it will be important to consider these MCIDs for evaluation purposes. LEVEL OF EVIDENCE: Level III, diagnostic study.

DOI： 10.1097/CORR.0000000000001341

Chondrosarcoma of bone in children and adolescents. 国際誌

Yoichi Kaneuchi, Tomohiro Fujiwara, Yusuke Tsuda, Shinichirou Yoshida, Jonathan D Stevenson, Adesegun Abudu

Journal of children's orthopaedics 14 ( 4 ) 330 - 334 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Purpose: Chondrosarcomas typically present in adults during the fifth to seventh decades and are rare in young patients. The biological behaviour and oncological outcomes may be different in children and adolescents. Methods: We retrospectively evaluated the outcomes of all patients with chondrosarcoma of bone who were younger than 18 years of age at the time of diagnosis and were treated at our centre between 1995 and 2018. Results: The 15 consecutive patients studied included nine male and six female cases, with a mean age at diagnosis of 13 years (7 to 17). The median follow-up was 117 months (30 to 277). The tumours were primary and secondary in ten and five patients, respectively. The tumours were central in 13 and surface in two patients. The tumour locations were the humerus in five, digits in five, femur in three, radius in one and pelvis in one patient. The histological grades were grade I in seven, grade II in seven and grade III in one patient. The surgical treatments were limb salvage in ten patients and ray amputation in five patients. The surgical margins were wide in eight, marginal in two and intralesional in five patients. All the patients were alive and continuously free of disease at the time of the last follow-up. No patient developed metastases or local recurrence. Conclusion: Chondrosarcoma of bone in children and adolescent patients has a very good prognosis and is less aggressive compared with published outcomes in older patients. Level of evidence: IV.

DOI： 10.1302/1863-2548.14.200046

The role of radiotherapy in the treatment of superficial soft-tissue sarcomas. 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Louis-Romée Le Nail, Scott Evans, Jonathan Gregory, Roger Tillman, Adesegun Abudu

The bone & joint journal 102-B ( 8 ) 1088 - 1094 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The existing clinical guidelines do not describe a clear indication for adjuvant radiotherapy (RT) in the treatment of superficial soft tissue sarcomas (STSs). We aimed to determine the efficacy of adjuvant RT for superficial STSs. METHODS: We retrospectively studied 304 patients with superficial STS of the limbs and trunk who underwent surgical resection at a tertiary sarcoma centre. The efficacy of RT was investigated according to the tumour size and grade: group 1, ≤ 5 cm, low grade; group 2, ≤ 5cm, high grade; group 3, > 5 cm, low grade; group 4, > 5 cm, high grade. RESULTS: The five- and ten-year local recurrence-free survival (LRFS) for all patients was 88% and 81%, respectively. While the efficacy of adjuvant RT was not proven in local control of all patients (five-year LRFS; RT+, 90% versus RT-, 83%; p = 0.074), the LRFS was significantly improved by adjuvant RT in group 2 (five-year LRFS; RT+, 96% versus RT-, 82%; p = 0.019), and group 4 (five-year LRFS; RT+, 87% versus RT-, 73%; p = 0.027). In groups 2 and 4, adjuvant RT significantly reduced the LR risk if the resection margin was clear but less than 5 mm; the LR rate was 7% with adjuvant RT compared with 26% with surgery alone (p = 0.003). There was no statistical relationship with the use of adjuvant RT and survival in every group. CONCLUSION: Adjuvant RT reduces the risk of local recurrence in patients with superficial high-grade STS regardless of tumour size, especially when resection margin is less than 5 mm. Cite this article: Bone Joint J 2020;102-B(8):1088-1094.

DOI： 10.1302/0301-620X.102B8.BJJ-2020-0043.R1

Clinical relevance and functional significance of cell-free microRNA-1260b expression profiles in infiltrative myxofibrosarcoma. 国際誌

Takuya Morita, Tomohiro Fujiwara, Aki Yoshida, Koji Uotani, Masahiro Kiyono, Suguru Yokoo, Joe Hasei, Toshiyuki Kunisada, Toshifumi Ozaki

Scientific reports 10 ( 1 ) 9414 - 9414 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Infiltrative tumor growth into adjacent soft tissues is a major cause of the frequent recurrence and tumor-related death of myxofibrosarcoma (MFS), but no useful biomarkers reflecting tumor burden and infiltrative growth are available. While emerging evidence suggests a diagnostic and functional role of extracellular/circulating microRNA (miRNA) in various malignant diseases, their significance in MFS patients remains unknown. Global miRNA profiling identified four upregulated miRNAs in MFS patient sera and culture media of MFS cells. Among these, serum miR-1260b level was significantly upregulated in patient serum discriminating from healthy individuals and closely correlated with clinical status and tumor dynamics in MFS-bearing mice. In addition, high miR-1260b expression in serum was correlated with radiological tail-like patterns, characteristic of the infiltrative MFS. The extracellular miR-1260b was embedded in tumor-derived extracellular vesicles (EVs) and promoted cellular invasion of MFS through the downregulation of PCDH9 in the adjacent normal fibroblasts. Collectively, circulating miR-1260b expression may represent a novel diagnostic target for tumor monitoring of this highly aggressive sarcoma. Moreover, EV-miR-1260b could act as a transfer messenger to adjacent cells and mediate the infiltrative growth of MFS, providing new insights into the mechanism of infiltrative nature via crosstalk between tumor cells and their microenvironment.

DOI： 10.1038/s41598-020-66120-8

Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma. 国際誌

Yusuke Tsuda, Kim Tsoi, Michael C Parry, Jonathan D Stevenson, Tomohiro Fujiwara, Vaiyapuri Sumathi, Lee M Jeys

The bone & joint journal 102-B ( 6 ) 795 - 803 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: To assess the correlation between the histological response to preoperative chemotherapy and event-free survival (EFS) or overall survival (OS) in patients with high-grade localized osteosarcoma. METHODS: Out of 625 patients aged ≤ 40 years treated for primary high-grade osteosarcoma between 1997 and 2016, 232 patients without clinically detectable metastases at the time of diagnosis and treated with preoperative high-dose methotrexate, adriamycin and cisplatin (MAP) chemotherapy and surgery were included. Associations of chemotherapy-induced necrosis in the resected specimen and EFS or OS were assessed using Cox model and the Pearson's correlation coefficients (r). Time-dependent receiver operating characteristic analysis was applied to determine the optimal cut-off value of chemotherapy-induced necrosis for EFS and OS. RESULTS: OS was 74% (95% confidence interval (CI) 67 to 79) at five years. Median chemotherapy-induced necrosis was 85% (interquartile range (IQR) 50% to 97%). In multivariate Cox model, chemotherapy-induced necrosis was significantly associated with EFS and OS (hazard ratio (HR) = 0.99 (95% CI 0.98 to 0.99); p < 0.001 and HR = 0.98 (95% CI 0.97 to 0.99); p < 0.001, respectively). Positive correlation was observed between chemotherapy-induced necrosis and five-year EFS and five-year OS (r = 0.91; p < 0.001, and r = 0.85; p < 0.001, respectively). The optimal cut-off value of chemotherapy-induced necrosis for five-year EFS and five-year OS was 85% and 72%, respectively. CONCLUSION: Chemotherapy-induced necrosis in the resected specimen showed positive correlation with EFS and OS in patients with high-grade localized osteosarcoma after MAP chemotherapy. In our analysis, optimal cut-off values of MAP chemotherapy-induced necrosis in EFS and OS were lower than the commonly used 90%, suggesting the need for re-evaluation of the optimal cut-off value through larger, international collaborative research. Cite this article: Bone Joint J 2020;102-B(6):795-803.

DOI： 10.1302/0301-620X.102B6.BJJ-2019-1307.R1

Is Microscopic Vascular Invasion in Tumor Specimens Associated with Worse Prognosis in Patients with High-grade Localized Osteosarcoma? 国際誌

Yusuke Tsuda, Kim Tsoi, Jonathan D Stevenson, Michael C Parry, Tomohiro Fujiwara, Vaiyapuri Sumathi, Lee M Jeys

Clinical orthopaedics and related research 478 ( 6 ) 1190 - 1198 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Other than metastases at diagnosis and histological response to preoperative chemotherapy, there are few reliable predictors of survival in patients with osteosarcoma. Microscopic vascular invasion (MVI) has been identified in the resection specimens of patients with osteosarcoma. However, it is unknown whether the MVI in resected specimens is associated with worse overall survival and higher cumulative incidence of local recurrence or metastasis in a large cohort of patients younger than 40 years with high-grade localized osteosarcoma. QUESTIONS/PURPOSES: (1) Is MVI associated with worse overall survival and higher cumulative incidence of events (local recurrence or metastasis) in patients younger than 40 years with high-grade localized osteosarcoma? (2) What clinical characteristics are associated with MVI in patients with high-grade localized osteosarcoma? METHODS: A total of 625 patients younger than 40 years with primary high-grade osteosarcoma between 1997 and 2016 were identified in our oncology database. We included patients younger than 40 years with primary high-grade osteosarcoma who underwent definitive surgery and preoperative and postoperative chemotherapy. The minimum follow-up period was 2 years after treatment. Patients with the following were excluded: metastasis at initial presentation (21%, n = 133), progression with preoperative chemotherapy precluding definitive surgery (6%, n = 38), surgery at another unit (2%, n = 13), lost to follow-up before 2 years but not known to have died (3%, n = 18), and death related to complications of preoperative chemotherapy (1%, n = 4). A retrospective pathologic and record review was conducted in the remaining 419 patients. The median follow-up period was 5 years (interquartile range [IQR] 3 to 9 years). The overall survival of the entire group (n = 419) was 67% [95% CI 63 to 72] at 5 years. Of the 419 patients, 10% (41) had MVI in their resection specimens. The Kaplan-Meier method was used to estimate overall survival. The cumulative incidence of events captured the first event of either metastasis or local recurrence. This analysis was completed with a competing risk framework: deaths without evidence of local recurrence or metastasis were regarded as a competing event. Clinical and histological variables (sex, age, tumor site, tumor largest dimension, surgical margin, chemotherapy-induced necrosis, type of surgery, histologic type of tumor, type of chemotherapy regimen, pathologic fracture, and MVI) were evaluated using the log-rank test or Gray test in the univariate analyses and Cox proportional hazard model or Fine and Gray model in the multivariate analyses. RESULTS: After adjusting for other factors, multivariate analyses showed that the presence of MVI in resection specimens was associated with worse overall survival and higher cumulative incidence of event (hazard ratio 1.88 [95% CI 1.22 to 2.89]; p = 0.004 and HR 2.33 [95% CI 1.56 to 3.49]; p < 0.001, respectively). A subgroup analysis demonstrated that the relationship between MVI and survival applied only to patients with a poor response to chemotherapy (less than 90% necrosis; overall survival at 5 years, MVI [+] = 24% [95% CI 11 to 39] versus MVI [-] = 60% [95% CI 52 to 66]; p < 0.001 and cumulative incidence of events at 5 years, MVI [+] = 86% [95% CI 68 to 94] versus MVI [-] = 54% [95% CI 46 to 61]; p < 0.001). The MVI (+) group had a higher proportion of patients with a poor response to chemotherapy (85% [35 of 41] versus 53% [201 of 378]; p < 0.001), involved margins (15% [6 of 41] versus 5% [18 of 378]; p = 0.021), and limb-ablative surgery (37% [15 of 41] versus 21% [79 of 378]; p = 0.022) than the MVI (-) group did. CONCLUSIONS: MVI is associated with lower overall survival and higher cumulative incidence of local recurrence or metastasis, especially in patients with a poor histologic response to preoperative chemotherapy. Future studies in patients treated for osteosarcoma should consider this observation when planning new trials. LEVEL OF EVIDENCE: Level III, therapeutic study.

DOI： 10.1097/CORR.0000000000001079

Acetabular reconstruction with an ice-cream cone prosthesis following resection of pelvic tumors: Does computer navigation improve surgical outcome? 国際誌

Tomohiro Fujiwara, Deepak V Sree, Jonathan Stevenson, Yoichi Kaneuchi, Michael Parry, Yusuke Tsuda, Louis-Romée Le Nail, Ricardo M Medellin, Robert Grimer, Lee Jeys

Journal of surgical oncology 121 ( 7 ) 1104 - 1114 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: Acetabular reconstruction with a coned-stem prosthesis has been one of the reliable procedures following pelvic tumor resections but is associated with a risk of complications and postoperative morbidity. We investigated whether navigated reconstruction could decrease the complication rate and optimize outcomes. METHODS: A retrospective study was conducted on 33 patients who underwent acetabular resection and reconstruction with ice-cream cone prostheses; outcomes were compared between the navigated and nonnavigated groups. RESULTS: A clear margin was obtained in 91% and 82% of the navigated and nonnavigated groups, respectively. The local recurrence (LR) rate was 12%, and all LRs occurred in the nonnavigated group. The rate of major complications requiring surgical intervention was significantly lower in the navigated group (9%) than in the nonnavigated group (50%; P = .024). Two implant failures occurred in the nonnavigated group. Functional outcomes were significantly correlated with the occurrence of major complications (P = .010) and the use of navigation (P = .043); superior functional scores were observed in the navigated group (Musculoskeletal Tumor Society, 73% vs 55%; Toronto Extremity Salvage Score, 73% vs 56%). CONCLUSION: Ice-cream cone prosthesis is an acceptable reconstruction modality following periacetabular tumor resections, and computer navigation are useful to facilitate proper resection margins and implant position.

DOI： 10.1002/jso.25882

Denosumab in giant cell tumour of bone in the pelvis and sacrum: Long-term therapy or bone resection?

Andrea Sambri, Manuel R Medellin, Costantino Errani, Laura Campanacci, Tomohiro Fujiwara, Davide Donati, Michael Parry, Robert Grimer

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 25 ( 3 ) 513 - 519 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Surgery of GCTB in sacrum and pelvis is challenging, with high rates of complications and local recurrence. Denosumab can consolidate the peripheral rim of the tumour, thus reducing the rate of morbidities of surgery. The aim of this paper is to evaluate the use of denosumab in pelvic/sacrum giant cell tumours of bone (GCTB). PATIENTS AND METHODS: We retrospectively reviewed a cohort of 26 patients with aggressive GCTB in sacrum or pelvis treated with denosumab at two referral centres. Clinical response and local recurrence were recorded and the radiologic responses were evaluated with the MDA criteria. RESULTS: 69% of the pelvic GCTB treated with denosumab presented partial or good radiologic responses (type 2A or 2B) after 49 weeks of treatment. Denosumab was administered as adjuvant therapy prior and after surgery in 11 patients (group A), and as the only treatment in 15 patients (group B). In group A, 62% of local recurrence was observed in patients treated with intralesional curettage. No recurrences were identified after en bloc resection. In group B, 9 patients were on continuous bimonthly long term denosumab administration with type 2A and 2B responses. Six patients stopped denosumab and 66% remained stable after 10 months of follow-up. CONCLUSIONS: Long-term denosumab therapy can be considered with curative intent for pelvic and sacrum GCTB. If surgical intervention is required wide resection may be advisable to reduce the risk of recurrence.

DOI： 10.1016/j.jos.2019.05.003

Extra-articular resection of shoulder joint for bone sarcomas: Oncologic and limb-salvage outcomes of 32 cases compared with shoulder disarticulation and forequarter amputation. 国際誌

Yusuke Tsuda, Tomohiro Fujiwara, Scott Evans, Yoichi Kaneuchi, Adesegun Abudu

Journal of surgical oncology 121 ( 4 ) 612 - 619 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: We aimed to identify the overall survival (OS), surgical complications, survival of reconstruction, and functional outcome of patients who underwent extra-articular resection of the shoulder joint for primary bone sarcomas. The OS and local recurrence rates in patients who underwent an amputation were also evaluated for comparison. METHODS: Thirty-two patients treated between 1988 and 2017 were studied. The tumours were located in the humerus in 22 (69%) and scapula in 10 patients (31%). The resection types were Malawer type IV in 6 (19%), type V in 21 (66%), and type VI in 5 patients (15%). Reconstruction was performed with endoprosthesis in 23 patients (72%) while excision arthroplasty with the suspension of the humerus to the clavicle was performed in 9 patients (28%). Surgical margins were wide in 16, marginal in 8, intralesional in 3, and not available in 5 patients. During the study period, 40 patients underwent a forequarter amputation and 11 patients underwent a shoulder disarticulation. RESULTS: The 5-year OS for patients who underwent extra-articular resection of the shoulder joint was 42% which was not statistically different compared with that of patients who underwent amputation (5-year OS = 30%; P = .091). The 5-year survival of the reconstruction was 94%, similar for endoprosthesis and excision arthroplasty. Local recurrence and complications developed in 6 (19%) and 10 patients (31%), respectively. Failures of the reconstruction requiring revision surgery occurred in two patients (6%). Limb salvage was achieved in 30 patients (94%). The median Musculoskeletal Tumour Society functional score was 61% (interquartile range, 57%-70%) and was similar in the endoprosthesis and excision arthroplasty group. CONCLUSIONS: Extra-articular resection of the shoulder joint for bone sarcomas is an effective limb-salvage method. However, local recurrence remains a principal concern.

DOI： 10.1002/jso.25838

Sacral chordoma: do the width of surgical margin and the use of photon/proton radiotherapy affect local disease control? 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Jonathan Stevenson, Michael Parry, Lee Jeys

International orthopaedics 44 ( 2 ) 381 - 389 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Chordoma is a rare but highly aggressive primary bone sarcoma that arises commonly from the sacrum. While en bloc resection has been the mainstay of the treatment, the role of resection margin in millimetres with/without adjuvant radiotherapy (RT) has been unknown. We investigated the prognostic impact of surgical margin width, adjuvant RT, and their combined factor for sacral chordoma. METHODS: Forty-eight patients who underwent surgical treatment between 1996 and 2016 were studied. Of these, 11 patients (23%) received adjuvant RT; photon RT in 7 (15%) and proton RT in 4 (8%). Margins were microscopically measured in millimetres from the resection surface to the closest tumour on histologic slides. RESULTS: The five year and ten year disease-specific survival was 88% and 58%, respectively, and the local recurrence (LR) rate was 48%. The LR rate with 0-mm, < 1.5-mm, and ≥ 1.5-mm margin was 50% (group 1), 50% (group 2: RT-, 61%; group 3: RT+, 14%), and 0% (group 4), respectively. We observed a significantly lower LR rate in patients with adjuvant photon/proton RT (18%) than without it (57%; p = 0.026), and no LR was observed after post-operative proton RT. The combined factor of margin with RT clearly stratified the LR risk: patients of group 1 (positive margin) and 2 (< 1.5-mm margin, RT-) had approximately 7.5× LR risk (p = 0.049) compared with those of group 3 (< 1.5-mm margin, RT+) and 4 (≥ 1.5-mm margin). CONCLUSION: This study identified the lowest risk of local failure in tumour resection with ≥ 1.5-mm margin or negative but < 1.5-mm margin with the use of adjuvant photon/proton radiotherapy for sacral chordoma. Early results of adjuvant proton RT demonstrated excellent local control.

DOI： 10.1007/s00264-019-04460-5

Surgical outcomes and prognostic factors of non-metastatic radiation-induced sarcoma of bone. 国際誌

Yusuke Tsuda, Martin Lowe, Scott Evans, Michael C Parry, Jonathan D Stevenson, Tomohiro Fujiwara, Yoichi Kaneuchi, Louis-Romee Le Nail, Lee M Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 46 ( 2 ) 293 - 298 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The survival and prognostic factors in non-metastatic, radiation-induced bone sarcomas of bone have not been described. Moreover, the quantitative data about surgical outcomes and complications after limb-salvage surgery versus amputation are quite limited. METHODS: Twenty-five patients with non-metastatic, radiation-induced sarcoma of bone who underwent definitive surgery were analysed. Histological diagnosis was osteosarcoma in 19 and undifferentiated pleomorphic sarcoma in six. The definitive surgery was limb-salvage surgery in 15 patients and an amputation in 10. RESULTS: The 5-year overall survival rate (OS) and the 5-year event-free survival rate (EFS) were 53% (95% CI 31%-70%) and 40% (21%-59%), respectively. Patients with wide or radical surgical margins (n = 13) showed significantly better OS compared with those with marginal (n = 8) or intralesional (n = 2) margins (5-year OS, radical or wide = 74%, marginal = 17%, intralesional = 0%, p = 0.044). The risk of local recurrence was significantly higher in the limb-salvage group compared to the amputation group (49% vs 0%, p = 0.011). OS and EFS were not significantly different between limb-salvage group and an amputation group (p = 0.188 and 0.912, respectively). CONCLUSIONS: We believe non-metastatic, radiation-induced sarcoma of bone should be resected with the aim of achieving wide or radical margins. Although limb-salvage surgery was related to higher rates of local recurrence compared with those of the amputation group, OS and EFS were not different among two groups. Surgeons need to discuss the higher risk of local recurrence in limb-salvage surgery.

DOI： 10.1016/j.ejso.2019.10.036

What is an adequate margin for infiltrative soft-tissue sarcomas? 国際誌

Tomohiro Fujiwara, Jonathan Stevenson, Michael Parry, Yusuke Tsuda, Kim Tsoi, Lee Jeys

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 46 ( 2 ) 277 - 281 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: What constitutes an adequate margin of resection for infiltrative subtypes of soft-tissue sarcomas remains unclear. We aimed to determine the prognostic significance of the margin in millimetres for myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). METHODS: 305 patients diagnosed with either a high-grade, localised MFS (n = 98) or UPS (n = 207) were included. The relationship of closest margin in millimetres to viable tumour and oncological outcomes was analysed. RESULTS: The overall local recurrence (LR) rate for all patients were 12%: 19% with positive margin and 10% with negative margin (p = 0.051). The LR rate was similar in patients with negative but <10 mm margin; 13%, 6%, 15%, 17% with 0.1-0.9 mm, 1.0-1.9 mm, 2.0-4.9 mm, and 5.0-9.9 mm margin, respectively. However, the LR rate decreased to 3% if the margin was ≥10 mm. By the R- or R+1-classification, the 10-year cumulative probability of LR was 9%, 15%, 48% for R0, R1, R2 resections, respectively, which was not sensitive enough to stratify the LR risk in patients with negative margins. However, the cumulative probability of LR was significantly stratified by metric distance; the 10-year cumulative LR probability was 3%, 14%, 25% with ≥10.0 mm, 0.1-9.9 mm, and 0 mm, respectively (p = 0.026). A trend towards improved local control by adjuvant radiotherapy was seen in patients with 0-9.9 mm margin (p = 0.078). CONCLUSION: The resection margin, when measured as a metric distance, correlates with a reduction in LR, and appears to be more significant on local control than radiotherapy. To minimise the risk of LR, a margin distance of at least 10 mm is advocated for MFS and UPS.

DOI： 10.1016/j.ejso.2019.10.005

Extendable Endoprostheses in Skeletally Immature Patients: A Study of 124 Children Surviving More Than 10 Years After Resection of Bone Sarcomas. 国際誌

Yusuke Tsuda, Kim Tsoi, Jonathan D Stevenson, Tomohiro Fujiwara, Roger Tillman, Adesegun Abudu

The Journal of bone and joint surgery. American volume 102 ( 2 ) 151 - 162 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Extendable endoprostheses are used to reconstruct segmental defects following resection of bone sarcomas in skeletally immature patients. However, there remains a paucity of studies with regard to long-term outcomes. METHODS: We retrospectively reviewed 124 skeletally immature children who underwent an extendable endoprosthetic replacement and survived more than 10 years after the surgical procedures. Anatomical sites included the distal part of the femur (n = 66), the proximal part of the femur (n = 13), the proximal part of the tibia (n = 29), and the proximal part of the humerus (n = 16). Complications and implant survival were classified according to the modified Henderson criteria. RESULTS: The mean follow-up was 24 years (range, 10 to 36 years). The mean age at the time of the extendable endoprosthetic replacement was 9 years (range, 2 to 16 years). All patients had reached skeletal maturity at the last follow-up. The 10-year endoprosthetic failure-free survival rate was 28%. A total of 243 complications occurred in 90% of patients; these complications were most frequently related to soft-tissue problems (27% of complications). The incidence of and cumulative survival with respect to each failure mode varied between anatomical sites. Soft-tissue failures occurred most frequently in the proximal part of the femur (77%; p = 0.003), and the distal part of the femur was the most frequent site of aseptic loosening (52%; p = 0.014) and structural failure (55%; p = 0.001). Excluding lengthening procedures, 105 patients (85%) underwent an additional surgical procedure, with a mean of 2.7 surgical procedures per patient (range, 0 to 7 surgical procedures per patient). The mean limb-length discrepancy at the final follow-up was 1 cm (range, 0 to 9 cm). Limb salvage was achieved in 113 patients (91%). The mean Musculoskeletal Tumor Society functional score (the percentage of a total score of 30 points) was 82% (range, 40% to 100%) in 115 patients with available data at the last follow-up. CONCLUSIONS: Extendable endoprostheses are associated with a high complication rate and a need for additional surgical procedures over time. Despite this, successful limb salvage with reasonable function and small limb-length discrepancy is achievable in the long term. Our study provides benchmark data for individual anatomical sites for further improvements of outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

DOI： 10.2106/JBJS.19.00621

The long-term results of extendable endoprostheses of the humerus in children after the resection of a bone sarcoma. 国際誌

Yusuke Tsuda, Tomohiro Fujiwara, Jonathan D Stevenson, Michael C Parry, Roger Tillman, Adesegun Abudu

The bone & joint journal 102-B ( 1 ) 64 - 71 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The purpose of this study was to report the long-term results of extendable endoprostheses of the humerus in children after the resection of a bone sarcoma. METHODS: A total of 35 consecutive patients treated with extendable endoprosthetic replacement of the humerus in children were included. There were 17 boys and 18 girls in the series with a median age at the time of initial surgery of nine years (interquartile range (IQR) 7 to 11). RESULTS: The median follow-up time was 10.6 years (IQR 3.9 to 20.4). The overall implant survival at ten years was 75%. Complications occurred in 13 patients (37%). Subluxation at the proximal humerus occurred in 19 patients (54%) but only six (17%) were symptomatic. Subluxation was seen more commonly in children under the age of nine years (86%) than in those aged nine years or more (33%) (p = 0.002). Implant failure occurred in nine patients (26%): the most common cause was aseptic loosening (four patients, 11%). Lengthening of the implant was carried out in 23 patients (66%). At final follow up, three patients had a limb that was shortened by 5 cm or more. The mean Musculoskeletal Tumor Society (MSTS) functional score was 79% (73% to 90%). CONCLUSION: Extendable endoprosthetic replacement is a reliable method of reconstructing humerus after excision of a bone sarcoma. Children who are less than nine years old have a high risk of subluxation. Cite this article: Bone Joint J 2020;102-B(1):64-71.

DOI： 10.1302/0301-620X.102B12.BJJ-2020-0124.R1

The long-term outcomes of modified Harrington procedure using antegrade pins for periacetabular metastasis and haematological diseases. 国際誌

Roger Tillman, Yusuke Tsuda, Manoj Puthiya Veettil, Peter S Young, Deepak Sree, Tomohiro Fujiwara, Adesegun Abudu

The bone & joint journal 101-B ( 12 ) 1557 - 1562 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The aim of this study was to present the long-term surgical outcomes, complications, implant survival, and causes of implant failure in patients treated with the modified Harrington procedure using antegrade large diameter pins. PATIENTS AND METHODS: A cohort of 50 consecutive patients who underwent the modified Harrington procedure for periacetabular metastasis or haematological malignancy between January 1996 and April 2018 were studied. The median follow-up time for all survivors was 3.2 years (interquartile range 0.9 to 7.6 years). RESULTS: The five-year overall survival rate was 33% for all the patients. However, implant survival rates were 100% and 46% at five and ten years, respectively. Eight patients survived beyond five years. There was no immediate perioperative mortality or complications. A total of 15 late complications occurred in 11 patients (22%). Five patients (10%) required further surgery to treat complications. The most frequent complication was pin breakage without evidence of acetabular loosening (6%). Two patients (4%) underwent revision for aseptic loosening at 6.5 and 8.9 years after surgery. Ambulatory status and pain level were improved in 83% and 89%, respectively. CONCLUSION: The modified Harrington procedure for acetabular destruction has low complication rates, good functional outcome, and improved pain relief in selected patients Cite this article: Bone Joint J 2019;101-B:1557-1562.

DOI： 10.1302/0301-620X.101B12.BJJ-2019-0265.R1

Extra-articular resection for bone sarcomas involving the hip joint. 国際誌

Tomohiro Fujiwara, Yusuke Tsuda, Scott Evans, Jonathan Stevenson, Michael Parry, Lee Jeys, Adesegun Abudu

Journal of surgical oncology 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: The aim of this study was to determine the oncologic, functional, and clinical outcomes after the extra-articular resection and limb-salvage reconstruction of the hip joint. METHODS: A retrospective study of 34 patients who underwent extra-articular resection of the hip joint for bone sarcomas between 1996 and 2016 was conducted. The primary tumor site was pelvis in 26 patients (76%) and femur in eight (24%). RESULTS: The surgical margins achieved were clear in 31 (91%) patients, and seven (21%) patients developed local recurrence; mostly occurring in pelvic tumors (n = 6). The 3-year overall survival was 63% with a median follow-up of 38 months (range, 5-219), which showed no statistical difference in tumor location. The most common complication was deep infection (n = 7) and dislocation (n = 7), mostly seen in pelvic tumors. Implant failure was seen in two patients with pelvic tumors, while no failure was noted in patients with femoral tumors. The median Musculoskeletal Tumour Society score was 69%; 67% for pelvic tumors and 73% for femoral tumors (P = .535). CONCLUSION: Despite complex surgery, extra-articular resection of the hip joint can achieve oncologically and functionally acceptable outcomes. While tumors of the pelvis are associated with a higher incidence of infection and local recurrence after resection, resection of tumors involving the femur are well tolerated.

DOI： 10.1002/jso.25769

Surgical treatment for pelvic Ewing sarcoma: What is a safe and functional acetabular reconstruction when combined with modern multidisciplinary treatments? 国際誌

Tomohiro Fujiwara, Johnathan R Lex, Jonathan D Stevenson, Yusuke Tsuda, Rhys Clark, Michael C Parry, Robert J Grimer, Lee M Jeys

Journal of surgical oncology 120 ( 6 ) 985 - 993 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: The purpose of this study was to clarify which local treatment is oncologically and functionally effective in pelvic Ewing sarcoma (ES). METHODS: A consecutive series of patients who underwent pelvic resections and acetabular reconstructions after chemotherapy between 1986 and 2016 at a supra-regional center were evaluated. RESULTS: The cohort consisted of 35 patients. The 5-year overall survival (OS) and local recurrence-free survival (LRFS) was 61% and 72%, respectively. Preoperative radiotherapy (RT) and surgery provided an excellent/good histological response in 92% and achieved significantly better OS (5 years, 64%) and LRFS (5 years, 100%) than surgery alone or surgery with postoperative RT. The Musculoskeletal Tumor Society functional scores were significantly better in patients with hip transposition than those with structural reconstructions (74% vs 57%; P = .031) using custom-made prostheses, irradiated autografts, and ice-cream cone prostheses. These scores were significantly lower if patients had deep infection (P = .035), which was the most common complication (28%) in structural reconstructions but did not occur in hip transposition even when performed after preoperative RT. CONCLUSION: Acetabular reconstruction with hip transposition resulted in no deep infection and superior function in patients with pelvic ES even when combined with preoperative RT, which improved tumor necrosis and rate of local control and survival.

DOI： 10.1002/jso.25660

Is the Width of a Surgical Margin Associated with the Outcome of Disease in Patients with Peripheral Chondrosarcoma of the Pelvis? A Multicenter Study. 国際誌

Yusuke Tsuda, Scott Evans, Jonathan D Stevenson, Michael Parry, Tomohiro Fujiwara, Minna Laitinen, Hidetatsu Outani, Lee Jeys

Clinical orthopaedics and related research 477 ( 11 ) 2432 - 2440 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: We attempted to resect peripheral chondrosarcoma of the pelvis with clear margins. Because of the proximity of vessels or organs, there is still concern that narrow surgical margins may have an adverse effect on disease outcomes. Although current guidelines recommend resection of histologic Grade II or Grade III chondrosarcomas with a "wide" margin, there are no specific recommendations for the adequate width of a surgical margin. QUESTIONS/PURPOSES: (1) What is the disease-specific and local recurrence-free survival of patients with peripheral chondrosarcoma of the pelvis treated with resection or amputation? (2) Is the width of a surgical margin associated with the outcome of disease in patients with peripheral chondrosarcoma of the pelvis? (3) Does the histologic grade as determined with a preoperative biopsy correlate with the final grade after resection? (4) What are surgical complications in these patients? METHODS: We retrospectively reviewed records from three international collaborating hospitals. Between 1983 and 2017, we resected 262 pelvic chondrosarcomas of all types. After reviewing the pathologic reports of these patients, we included 52 patients with peripheral chondrosarcomas of the pelvis who had an osteochondroma-like lesion at the base of the tumor and a cartilage cap with malignant cells in resected specimens. To be eligible for this study, a patient had to have a minimum of 1 year of follow-up. Two patients were excluded because they had less than 1 year of follow-up, leaving 50 patients for inclusion in this study. The median follow-up duration was 7.0 years (interquartile range 2.1-10 years). The median age was 37 years (IQR 29-54 years). The ilium was the most frequently affected bone (in 36 of 50 patients; 72%). The histologic status of the surgical margin was defined as microscopically positive (0 mm), negative < 1 mm, or negative ≥ 1 mm. Thirteen of the 50 patients (26%) had local recurrence. Seven of 34 patients had Grade I tumors, five of 13 had Grade II tumors, and one of three had a Grade III tumor. Nine of 16 patients had multiple local recurrences. Two patients with Grade I tumors and two with Grade II tumors died because of pressure effects caused by local recurrence. RESULTS: The 10-year disease-specific and local recurrence-free survival rates were 90% (95% confidence interval, 70-97) and 69% (95% CI, 52-81), respectively. A surgical margin ≥ 1 mm (n = 16) was associated with a better local recurrence-free survival rate than a surgical margin < 1 mm (n = 17) or 0 mm (n = 11) (10-year local recurrence-free survival: resection margin ≥ 1 mm = 100% versus < 1 mm = 52% [95% CI, 31 to 70]; p = 0.008). No patients with a surgical margin ≥ 1 mm had local recurrence, metastasis, or disease-related death, irrespective of tumor grade. Patients with local recurrence (n = 13) showed worse disease-specific survival than those without local recurrence (n = 37) (10-year disease-specific survival: local recurrence [+] = 59% [95% CI, 16 to 86] versus local recurrence [-] = 100%; p=0.001]). The preoperative biopsy results correctly determined the tumor grade in 15 of 41 patients (37%). The most frequent complication after surgery was local recurrence (13 of 50 patients, 26%). Deep infection was the most frequent nononcologic complication (four patients). CONCLUSIONS: We found a high local recurrence rate after surgical treatment of a peripheral pelvic chondrosarcoma, which was related to the width of the surgical margin. These local recurrences led to inoperable recurrent tumors and death. The tumor grade as determined by preoperative biopsy was inaccurate in 2/3 of patients compared with the final histologic assessment. Therefore, we believe every attempt should be made to achieve a negative margin during the initial resection to lessen the likelihood of local recurrence of peripheral chondrosarcoma of the pelvis of all grades. A margin of 1 mm or more appeared to be sufficient in these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

DOI： 10.1097/CORR.0000000000000926

The Clinical Outcomes of Hemicortical Extracorporeal Irradiated Autologous Bone Graft After Tumor Resection of Bone and Soft Tissue Sarcoma. 国際誌

Tomoki Nakamura, Tomohiro Fujiwara, Yusuke Tsuda, Adesegun Abudu, Yoshihito Nomoto, Akinori Takada, Yutaka Toyomasu, Tomohito Hagi, Kunihiro Asanuma, Akihiro Sudo

Anticancer research 39 ( 10 ) 5605 - 5610 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/AIM: We analyzed the process of healing at osteotomy sites and timing of achievement of full weight-bearing in sarcoma patients who underwent hemicortical or intercalary reconstruction using the extracorporeal irradiated autologous bone graft technique. PATIENTS AND METHODS: We studied 10 patients who had undergone tumor resection and reconstruction with hemicortical extracorporeal irradiated autologous bone graft at mid-shaft femur or tibia. The control group consisted of 30 patients who received the reconstruction using intercalary bone graft. RESULTS: Full weight-bearing was achieved in all 10 patients at a median time of 4.8 months. Function was excellent in all patients. When comparing the clinical outcome among the patients who received intercalary and hemicortical grafts, the duration to full weight-bearing achievement in patients who received hemicortical graft was shorter than that in those with intercalary graft. CONCLUSION: Early full weight-bearing may be achieved in patients undergoing hemicortical resection and reconstruction using extracorporeal irradiated autologous bone graft.

DOI： 10.21873/anticanres.13755

Secondary chondrosarcoma arising from osteochondroma: outcomes and prognostic factors. 国際誌

Yusuke Tsuda, Jonathan J Gregory, Tomohiro Fujiwara, Seggy Abudu

The bone & joint journal 101-B ( 10 ) 1313 - 1320 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: The aim of this study was to report the outcomes of patients who underwent definitive surgery for secondary chondrosarcomas arising from osteochondromas. PATIENTS AND METHODS: A total of 51 patients with secondary chondrosarcomas occurring from osteochondromas were reviewed. Median age was 36 years (interquartile range (IQR) 15 to 82). Median follow-up was 6.9 years (IQR 2.8 to 10.6). The pelvis was the most commonly affected site (59%). Histological grades were grade I in 35 (69%), grade II in 13 (25%), and grade III in three patients (6%). RESULTS: Preoperative biopsy histology correctly predicted the final histological grade in 27% of patients. The ten-year disease-specific survival (DSS) for all patients was 89.4%. Local recurrence occurred in 15 patients (29%), more commonly in pelvic tumours (37%) compared with limb tumours (19%). Four patients with pelvic tumours died from progression of local recurrence. No patient with limb tumours died of disease. Wide/radical margin was associated with improved local recurrence-free survival (p = 0.032) and local recurrence was associated with worse DSS (p = 0.005). CONCLUSION: We recommend that a secondary chondrosarcoma arising from osteochondroma of the pelvis is resected with wide/radical resection margins. The balance between the morbidity of surgery and risk of local recurrence needs to be considered in patients with limb secondary chondrosarcomas. Cite this article: Bone Joint J 2019;101-B:1313-1320.

DOI： 10.1302/0301-620X.101B9.BJJ-2019-0190.R1

Temporary External Fixation Can Stabilize Hip Transposition Arthroplasty After Resection of Malignant Periacetabular Bone Tumors. 国際誌

Toshiyuki Kunisada, Tomohiro Fujiwara, Joe Hasei, Eiji Nakata, Masuo Senda, Toshifumi Ozaki

Clinical orthopaedics and related research 477 ( 8 ) 1892 - 1901 2019年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The choice of reconstructive procedure to restore limb function is challenging after internal hemipelvectomy. Hip transposition arthroplasty, also known as resection arthroplasty, removes a malignant or aggressive tumor of the pelvis and acetabulum after which the remaining femoral head is moved proximally to the lateral surface side of the sacrum or the underside of the resected ilium after internal hemipelvectomy. It may provide reasonable functional results and have some advantages such as lowering the risk of an infected implant compared with other reconstructions because no foreign implants are used. Hip transposition is generally managed with prolonged bed rest or immobilization postoperatively to stabilize the soft tissue surrounding the remaining femur. Because enabling patients to be mobile while the soft tissues heal might be advantageous, we reviewed our experience with an external fixation for this procedure. QUESTIONS/PURPOSES: (1) Does temporary external fixation facilitate postoperative physiotherapy in patients who undergo hip transposition arthroplasty? (2) What functional Musculoskeletal Tumor Society (MSTS) scores were achieved at short term in a small series of patients treated with hip transposition and temporary external fixation? (3) What were the complications of using external fixation in a small series of patients who received it for malignant tumors? METHODS: Between 2008 and 2012, we treated seven patients (three men and four women; median age, 37 years; age range, 18-53 years) with acetabular resection for malignant bone tumors; all were managed with a hip transposition, initially stabilized using external fixation. No other types of procedures were used for this indication in this period. Minimum followup in this retrospective study was 45 months, except for one patient who died at 18 months (range of followup duration, 18-90 months; median followup, 57 months), and no patients were lost to followup. The pins for external fixation were inserted into the affected side of the femur and the healthy contralateral ilium. External fixation was removed 6 weeks postoperatively and weightbearing was started at that time. Preoperative chemotherapy was administrated in four patients, but postoperative chemotherapy was delayed since it was given after external fixation removal in three patients. The postoperative rehabilitation course and functional results were assessed by chart review, functional results were determined using MSTS scores, tallied by physiotherapists who were not part of the surgical team, and complications were ascertained through chart review. Major complications were defined as complications that were treated with additional operations, such as deep infection, or ones that could cause severe postoperative dysfunction, such as nerve injury. RESULTS: With temporary external fixation, standing next to a bed was achieved in median 7 days (range, 6-9 days) postoperatively, transferring to a wheel chair in median 8 days (range, 6-28 days), and gait training using parallel bars in median 15 days (range, 7-48 days). At most recent followup, three patients could walk without a crutch or cane, three could walk with a cane, and one could walk with a crutch. The median MSTS score at most recent followup (median, 57 months) was 63%. Two patients had complications that resulted in reoperations; one had a wound dehiscence, and one had an abdominal herniation that gradually developed, and which was reconstructed using polypropylene mesh 2 years after pelvic resection. Two patients had nerve palsies that recovered by the end of the first year. All patients had pin tract infections that resolved with nonsurgical approaches. CONCLUSIONS: Hip transposition with temporary external fixation can stabilize the bone soft tissue after pelvic resection. Although we did not have a comparison group of patients, we believe that external fixation facilitates early postoperative physiotherapy and rehabilitation and provides good functional results without major surgical complications. Because it delays the resumption of chemotherapy, more patients with longer followup are needed to determine whether this will be associated with poorer oncologic results. LEVEL OF EVIDENCE: Level IV, therapeutic study.

DOI： 10.1097/CORR.0000000000000764

Metformin induces CD11b+-cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects. 国際誌

Takenori Uehara, Shingo Eikawa, Mikako Nishida, Yuki Kunisada, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Heiichiro Udono

International immunology 31 ( 4 ) 187 - 198 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors.

DOI： 10.1093/intimm/dxy079

A rare manifestation of extraskeletal myxoid chondrosarcoma with a huge expanding hematoma.

Toshinori Omori, Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Aki Yoshida, Hiroyuki Yanai, Toshifumi Ozaki

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 24 ( 2 ) 377 - 381 2019年3月

Mini-open excision of osteoid osteoma using intraoperative O-arm/Stealth navigation.

Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Eiji Nakata, Yusuke Mochizuki, Masahiro Kiyono, Aki Yoshida, Toshifumi Ozaki

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 24 ( 2 ) 337 - 341 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Although osteoid osteomas have traditionally been treated by surgical excision, radiofrequency ablation (RFA) has gained favor as a less invasive procedure. However, RFA is contraindicated for osteoid osteomas close to the skin or crucial neurovascular structures, and is not covered by national health insurance in Japan. The aim of the present study was to evaluate the efficacy of surgical excision of osteoid osteomas using intraoperative navigation. METHODS: We performed a retrospective review of five patients with osteoid osteoma who underwent a mini-open excision using O-arm/Stealth navigation at our institution. The osteoid osteomas were excised using a cannulated cutter or curetted out with the assistance of navigation. RESULTS: Complete excision was achieved in all patients, which was confirmed by pathological examination. The mean skin incision was 2.1 cm (range, 1.5 to 3.0 cm) and the mean duration required for setup three-dimensional image was 15 min (range, 12 to 20 min). Although the mean visual analog scale score was 7 (range, 4 to 8) before surgery, all patients experienced relief from their characteristic pain immediately after surgery, with the mean scores of 2.2 (range, 1 to 3) and 0 at 2 days and 4 weeks after surgery, respectively. There was no intra-operative complication related to the navigation and no recurrence was observed during the mean follow-up period of 25 months (range, 13 to 33 months). CONCLUSIONS: Mini-open excision using intraoperative O-arm/Stealth navigation is a safe and accurate procedure for patients with osteoid osteoma, which could cover the limitation of RFA.

DOI： 10.1016/j.jos.2018.09.017

Identification of Circulating Exosomal Marker in Synovial Sarcoma

Suguru Yokoo, Tomohiro Fujiwara, Aki Yoshida, Masahiro Kiyono, Yusuke Mochizuki, Koji Demiya, Joe Hasei, Toshiyuki Kunisada, Yusuke Yoshioka, Koji Ueda, Takahiro Ochiya, Toshifumi Ozaki

CANCER SCIENCE 109 570 - 570 2018年12月

Intraoperative O-arm-navigated resection in musculoskeletal tumors.

Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Eiji Nakata, Ryuichi Nakahara, Aki Yoshida, Toshifumi Ozaki

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 23 ( 6 ) 1045 - 1050 2018年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Although emerging evidence has suggested that computer-assisted navigation allows surgeons to plan the optimal level of resection without compromising the surgical margins, the precise accuracy of the procedures has been unclear. The aim of this study was to investigate the accuracy and safety of the musculoskeletal tumor resection using O-arm/Stealth intraoperative navigation assistance. METHODS: A retrospective study of six patients with bone and soft tissue tumors who underwent surgical resection using O-arm/Stealth navigation system was performed. The histological diagnosis was osteosarcoma, metastatic bone tumor, leiomyosarcoma, undifferentiated sarcoma, and synovial sarcoma, respectively. Tumor resection was performed according to planned osteotomy planes determined on O-arm/Stealth three-dimensional intraoperative images. The resection accuracy, length of time for the procedures, surgical margins, and perioperative complications were evaluated. RESULTS: The distances between the entry and exit points for the planned and actual cuts were 1.5 ± 0.3 mm and 2.3 ± 0.3 mm, respectively, and the mean discrepancy of the osteotomy angle was 2.8 ± 1.2°. The mean length of time required for navigation was 14 min. A histological examination revealed clear margins in all patients. There were no complications related to navigation, and no patients developed local recurrence during a mean follow-up of 30.6 months. CONCLUSIONS: The O-arm/Stealth intraoperative CT navigation system provides safe and accurate osteotomy in musculoskeletal tumor resections. However, surgeons should keep in mind and be careful of minimal errors during osteotomy, which are around 2 mm from the planned line.

DOI： 10.1016/j.jos.2018.06.012

Autopsy Case of a Penetrating Wound to the Left Cerebral Hemisphere Caused by an Accidental Shooting With a Crossbow. 国際誌

Takeshi Kondo, Motonori Takahashi, Azumi Kuse, Mai Morichika, Kanako Nakagawa, Yoshihiro Tagawa, Tomoya Taniguchi, Yuji Taguchi, Tomohiro Fujiwara, Junpei Tsuchiya, Masahiko Nakamura, Makoto Sakurada, Migiwa Asano, Yasuhiro Ueno

The American journal of forensic medicine and pathology 39 ( 2 ) 164 - 168 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

A crossbow is a bow that shoots an arrow when a gun-like trigger is pulled. Deaths caused by accidental crossbow shootings are extremely rare. Here we describe an autopsy case of a penetrating wound to the left cerebral hemisphere caused by an accidental shooting with a crossbow. A man in his early 60s who lived with his wife and had used crossbows for 20 years as his hobby was found one early morning in the shed of his house, collapsed and bleeding from the head and neck. He was taken to a hospital and died after approximately 3 days of conservative treatment. At autopsy, a penetrating wound between the upper part of the left anterior neck and the left frontoparietal region was evident. Traumatic intracerebral hematoma was observed in the left frontal lobe, and severe traumatic subarachnoid hemorrhage was present throughout the brain. Cerebral contusion and hematoma without any organization were noted around the penetration. The cause of death was determined to be cerebral contusion and intracerebral hematoma due to the penetrating wound by the crossbow arrow. He was probably trying to load an arrow into the crossbow by placing it on the floor, pointing upward, and made a mistake in its operation that resulted in the shooting of the arrow. This case is unique because it was a rare accidental death caused by a crossbow arrow, and a detailed histopathological examination was performed.

DOI： 10.1097/PAF.0000000000000381

Clinical and Functional Significance of Intracellular and Extracellular microRNA-25-3p in Osteosarcoma.

Aki Yoshida, Tomohiro Fujiwara, Koji Uotani, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Joe Hasei, Eiji Nakata, Toshiyuki Kunisada, Toshifumi Ozaki

Acta medica Okayama 72 ( 2 ) 165 - 174 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although there is considerable evidence indicating that the dysregulation of microRNAs (miRNAs) in malignant tumors plays a role in tumor development, the overall function of miRNAs and their clinicopathological significance are not well understood. In this retrospective analysis of 45 biopsy specimens from osteosarcoma (OS) patients, we investigated the functional and clinical significance of miR-25-3p in OS, which we previously identified as a highly expressed miRNA in OS patients' serum. We observed that miR-25-3p dysregulation in human OS tissues was negatively correlated with the clinical prognosis, whereas the expression level of its target gene, Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), was positively correlated with the clinical prognosis. Endogenous miR-25-3p upregulation promoted tumor growth, invasion, and drug resistance, which was consistent with DKK3 silencing in OS cells. In addition, secretory miR-25-3p was embedded in tumor-derived exosomes, where it promoted capillary formation and the invasion of vascular endothelial cells. Overall, our results show that miR-25-3p has intracellular and extracellular oncogenic functions as well as clinicopathological relevance in OS, indicating its potential as a novel diagnostic and therapeutic tool for the clinical management of this disease.

DOI： 10.18926/AMO/55857

【運動器画像診療の最前線】部位別・疾患別画像診療の最前線骨腫瘍の画像診療

中田英二, 国定俊之, 長谷井嬢, 藤原智洋, 尾崎敏文

関節外科 37 ( 4月増刊 ) 130 - 143 2018年4月

記述言語：日本語出版者・発行元：(株)メジカルビュー社

＜画像診療のポイント＞●骨腫瘍の診療において、画像検査は鑑別診断や治療効果判定だけではなく、手術にも有用である。●鑑別診断について、初診医は一般整形外科医であることが多く、悪性を疑う所見を見逃さないことが重要である。●骨腫瘍にはそれぞれ特徴的な年齢分布や好発部位があり、年齢や既往歴などの臨床情報も踏まえ、複数の画像検査の情報を組み合わせて診断を行う。●単純X線像の読影では、腫瘍の局在と性状に注目する。●CTは、単純X線検査では評価が困難な部位の診断、微細な石灰化や骨化の有無の検出などを調べるのに適している。また、三次元的に骨病変を評価することができ、術前計画にも有用である。さらに、近年はコンピュータ支援手術により術中に短時間で高画質の2D・3D画像が取得でき、画像データをナビゲーションシステムに送信することで、より低侵襲かつ安全で確実な手術が可能となっている。●MRIは優れたコントラスト分解能をもち、腫瘍の進展や質的診断、治療効果判定などに有用である。●PET/CTは、良悪性の鑑別診断、病期診断、治療効果判定に有用である。●各画像検査には長所と短所があるため、その特徴を理解しておくことが重要である。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00282&link_issn=&doc_id=20180406150013&doc_link_id=10.18885%2FJ00282.2018192551&url=https%3A%2F%2Fdoi.org%2F10.18885%2FJ00282.2018192551&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Liquid biopsy using tumor-derived exosomes for Ewing sarcoma patients

Aki Yoshida, Tomohiro Fujiwara, Koji Uotani, Shintaro Iwata, Yusuke Yoshioka, Koji Ueda, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Joe Hasei, Toshiyuki Kunisada, Takahiro Ochiya, Toshifumi Ozaki

CANCER SCIENCE 109 312 - 312 2018年1月

Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma. 国際誌

Koji Uotani, Tomohiro Fujiwara, Aki Yoshida, Shintaro Iwata, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Kunihiko Numoto, Yutaka Nezu, Tsukasa Yonemoto, Takeshi Ishii, Akira Kawai, Takahiro Ochiya, Toshifumi Ozaki

Scientific reports 7 ( 1 ) 14634 - 14634 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs). Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel impact as biomarkers for patients with malignant diseases, but their significance in synovial sarcoma (SS) patients remains unknown. Initial global miRNA screening using SS patient serum and SS cell culture media identified a signature of four upregulated miRNAs. Among these candidates, miR-92b-3p secretion from SS cells was confirmed, which was embedded within tumour-derived exosomes rather than argonaute-2. Animal experiments revealed a close correlation between serum miR-92b-3p levels and tumour dynamics. Clinical relevance was validated in two independent clinical cohorts, and we subsequently identified that serum miR-92b-3p levels were significantly higher in SS patients in comparison to that in healthy individuals. Moreover, serum miR-92b-3p was robust in discriminating patients with SS from the other STS patients and reflected tumour burden in SS patients. Overall, liquid biopsy using serum miR-92b-3p expression levels may represent a novel approach for monitoring tumour dynamics of SS.

DOI： 10.1038/s41598-017-12660-5

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction. 国際誌

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

Cancer science 108 ( 9 ) 1870 - 1880 2017年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation.

DOI： 10.1111/cas.13316

Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma. 国際誌

Tomohiro Fujiwara, Koji Uotani, Aki Yoshida, Takuya Morita, Yutaka Nezu, Eisuke Kobayashi, Akihiko Yoshida, Takenori Uehara, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Ken Takeda, Toshiyuki Kunisada, Machiko Kawamura, Akira Kawai, Takahiro Ochiya, Toshifumi Ozaki

Oncotarget 8 ( 20 ) 33375 - 33392 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. METHODS: Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. RESULTS: Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. CONCLUSIONS: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

DOI： 10.18632/oncotarget.16498

Atypical manifestation of lung metastasis 17 years after initial diagnosis of low-grade central osteosarcoma.

Tomohiro Fujiwara, Mai Oda, Akihiko Yoshida, Koichi Ogura, Hirokazu Chuman, Masahiko Kusumoto, Akira Kawai

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 22 ( 2 ) 357 - 361 2017年3月

悪性骨盤腫瘍一時的創外固定を利用した早期リハビリテーション

国定俊之, 武田健, 藤原智洋, 野田知之, 尾崎敏文, 堅山佳美, 千田益生

日本創外固定・骨延長学会雑誌 28 147 - 147 2017年2月

腫瘍型人工関節置換術とそのリハビリテーション

国定俊之, 藤原智洋, 長谷井嬢, 堅山佳美, 千田益生, 尾﨑敏文

The Japanese journal of rehabilitation medicine = リハビリテーション医学 54 ( 3 ) 209 - 213 2017年

記述言語：日本語出版者・発行元：公益社団法人日本リハビリテーション医学会

<p>腫瘍型人工関節置換術は，術後のリハビリテーションを早期に開始することができるため，社会復帰が早いという利点がある．しかし，筋肉などの軟部組織の再建が症例ごとに異なっているため，変形性関節症などに対して行われる一般的な人工関節置換術とは異なるアプローチが必要である．腫瘍切除により，多くの筋肉が起始・停止部で切離されるため，これらの筋肉をできるだけ解剖学的位置に再建することが機能回復において重要となる．金属の人工関節と筋肉は生物学的な癒合が期待できないが，ポリプロピレンメッシュを使用することで，強固な固定力が獲得できる．本稿では，近位・遠位大腿骨，近位脛骨の腫瘍型人工関節のリハビリテーションについて解説する．</p>

DOI： 10.2490/jjrmc.54.209

その他リンク： http://search.jamas.or.jp/link/ui/2017296069

miR-135b, a key regulator of malignancy, is linked to poor prognosis in human myxoid liposarcoma 査読

Y. Nezu, K. Hagiwara, Y. Yamamoto, T. Fujiwara, K. Matsuo, A. Yoshida, A. Kawai, T. Saito, T. Ochiya

ONCOGENE 35 ( 48 ) 6177 - 6188 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Myxoid/round cell (RC) liposarcomas (MLS) were originally classified into two distinct populations based on histological differences; a myxoid component and a RC component. It is notable that, depending on an increase of the RC component, the prognosis significantly differs. Hence, the RC component is associated with metastasis and poor prognosis. However, the molecular mechanisms that contribute to the malignancy of the RC component still remain largely unknown. Here, we report microRNA-135b (miR-135b), a key regulator of the malignancy, highly expressed in the RC component and promoting MLS cell invasion in vitro and metastasis in vivo through the direct suppression of thrombospondin 2 (THBS2). Decreased THBS2 expression by miR-135b increases the total amount of matrix metalloproteinase 2 (MMP2) and influences cellular density and an extracellular matrix structure, thereby resulting in morphological change in tumor. The expression levels of miR-135b and THBS2 significantly correlated with a poor prognosis in MLS patients. Overall, our study reveals that the miR-135b/THBS2/MMP2 axis is tightly related to MLS pathophysiology and has an important clinical implication. This work provides noteworthy evidence for overcoming metastasis and improving patient outcomes, and sheds light on miR-135b and THBS2 as novel molecular targets for diagnosis and therapy in MLS.

DOI： 10.1038/onc.2016.157

網羅的解析による滑膜肉腫由来circulating cell-free microRNAの特定および検証

魚谷弘二, 藤原智洋, 吉田晶, 森田卓也, 大森敏規, 上原健敬, 杉生和久, 小松原将, 武田健, 国定俊之, 根津悠, 岩田慎太郎, 川井章, 落谷孝広, 尾崎敏文

日本整形外科学会雑誌 90 ( 8 ) S1560 - S1560 2016年8月

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

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 28953 - 28953 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

創外固定を利用した悪性骨盤腫瘍に対する早期リハビリテーション

国定俊之, 藤原智洋, 野田知之, 堅山佳美, 千田益生, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine ( JARM2016 ) I438 - I438 2016年6月

手・足部発生の類骨骨腫の治療経験

小松原将, 武田健, 森田卓也, 杉生和久, 魚谷弘二, 大森敏規, 上原健敬, 吉田晶, 藤原智洋, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 90 ( 6 ) S1396 - S1396 2016年6月

PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma. 国際誌

Mio Hirahata, Mitsuhiko Osaki, Yusuke Kanda, Yui Sugimoto, Yusuke Yoshioka, Nobuyoshi Kosaka, Fumitaka Takeshita, Tomohiro Fujiwara, Akira Kawai, Hisao Ito, Takahiro Ochiya, Futoshi Okada

Cancer medicine 5 ( 5 ) 892 - 902 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Despite recent improvements in the therapy for osteosarcoma, 30-40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR-143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR-143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor-1 (PAI-1) as a direct target gene of miR-143. To determine the role of PAI-1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI-1 expression. An in vitro study showed that downregulation of PAI-1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI-1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA-injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI-1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase-13 (MMP-13), which is also a target gene of miR-143 and a proteolytic enzyme that regulates tumor-induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR-143 expressing cases showed poor expression of PAI-1 in the primary tumor cells. All such cases belonged to the lung metastasis-negative group. Moreover, the frequency of lung metastasis-positive cases was significantly higher in PAI-1 and MMP-13 double-positive cases than in PAI-1 or MMP-13 single-positive or double-negative cases (P < 0.05). These results indicated that PAI-1, a target gene of miR-143, regulates invasion and lung metastasis via enhancement of MMP-13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.

DOI： 10.1002/cam4.651

Cancer stem cells of sarcoma

Tomohiro Fujiwara, Akira Kawai, Akihiko Yoshida, Toshifumi Ozaki, Takahiro Ochiya

Role of Cancer Stem Cells in Cancer Biology and Therapy 23 - 78 2016年4月

Limb salvage surgery for pelvic osteosarcoma 査読

Toshiyuki Kunisada, Ken Takeda, Tomohiro Fujiwara, Shinsuke Sugihara, Toshifumi Ozaki

Osteosarcoma 135 - 147 2016年1月

記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：Springer Japan

Patients with pelvic osteosarcoma have a poor outcome
treatment is one of the most challenging problems for the orthopedic oncologist. The reconstructive approach varies according to anatomic location, extent of resection, the patient’s functional demands, and individual surgeon preference. The choice of optimal technique for reconstruction after acetabular tumor resection depends on numerous parameters and includes iliofemoral arthrodesis or pseudoarthrodesis, combined use of hip arthroplasty with massive allograft or recycled autograft, and pelvic and saddle prosthesis. The type of reconstruction modality can influence the rate of infection. Hip transposition resulted in the least incidence of complications after resection of the acetabulum, compared to the use of prosthesis or prosthesis and allograft. The absence of large implants and allografts helps reduce surgical time, facilitates closure, and may decrease the incidence of infection and late revision due to implant failure. These can lead to early postoperative systemic treatment and functional recovery and are critical for patients with a high incidence of local recurrence and distant metastases. We believe that resection arthroplasty should be indicated for the patient with acetabular osteosarcoma.

DOI： 10.1007/978-4-431-55696-1_11

miR-125b and miR-100 Are Predictive Biomarkers of Response to Induction Chemotherapy in Osteosarcoma. 国際誌

Daisuke Kubota, Nobuyoshi Kosaka, Tomohiro Fujiwara, Akihiko Yoshida, Yasuhito Arai, Zhiwei Qiao, Fumitaka Takeshita, Takahiro Ochiya, Akira Kawai, Tadashi Kondo

Sarcoma 2016 1390571 - 1390571 2016年

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. We investigated miRNA expression in eight open biopsy samples to identify miRNAs predictive of response to induction chemotherapy and thus maybe used for risk stratification therapy. The samples were obtained from four patients with inferior necrosis (Huvos I/II) and four patients with superior necrosis (Huvos III/IV) following induction chemotherapy. We found six miRNAs, including miR-125b and miR-100, that were differentially expressed > 2-fold (p < 0.05) in patients who respond poorly to treatment. The association between poor prognosis and the abundance of miR-125b and miR-100 was confirmed by quantitative reverse transcriptase-polymerase chain reaction in 20 additional osteosarcoma patients. Accordingly, overexpression of miR-125b and miR-100 in three osteosarcoma cell lines enhanced cell proliferation, invasiveness, and resistance to chemotherapeutic drugs such as methotrexate, doxorubicin, and cisplatin. In addition, overexpression of miR-125b blocked the ability of these chemotherapy agents to induce apoptosis. As open biopsy is routinely performed to diagnose osteosarcoma, levels of miR-125b and miR-100 in these samples may be used as basis for risk stratification therapy.

Overcoming Therapeutic Resistance of Bone Sarcomas: Overview of the Molecular Mechanisms and Therapeutic Targets for Bone Sarcoma Stem Cells. 国際誌

Tomohiro Fujiwara, Toshifumi Ozaki

Stem cells international 2016 2603092 - 2603092 2016年

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone sarcomas are heterogeneous malignant tumors that exhibit clinical, histological, and molecular heterogeneity. Recent progress in their multimodal treatment has gradually improved patient prognosis; however, drug resistance and distant metastasis remain unresolved clinical problems. Recent investigations have suggested the existence of cancer stem-like cells (CSCs) in bone sarcomas, which represent a subpopulation of tumor cells with high tumor-forming ability. The hallmarks of CSCs include tumor- and metastasis-forming potential and drug resistance, which are responsible for poor prognoses of bone sarcoma patients. Therefore, elucidation of the molecular mechanisms of CSCs and identification of therapeutic targets could contribute to novel treatment strategies for bone sarcomas and improve patient prognosis. This paper provides an overview of the accumulating knowledge on bone sarcoma stem cells and preclinical analyses to overcome their lethal phenotypes, in addition to a discussion of their potential for novel therapeutics for bone sarcomas.

DOI： 10.1155/2016/2603092

Second primary osteosarcomas in patients with retinoblastoma. 国際誌

Tomohiro Fujiwara, Miyuki Fujiwara, Kunihiko Numoto, Koichi Ogura, Akihiko Yoshida, Tsukasa Yonemoto, Shigenobu Suzuki, Akira Kawai

Japanese journal of clinical oncology 45 ( 12 ) 1139 - 45 2015年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Second primary malignancies have become the leading cause of death in retinoblastoma survivors. Although osteosarcoma is the most common second malignancy, little is known about its clinical and therapeutic features. METHODS: We retrospectively reviewed a database of patients with retinoblastoma and osteosarcoma occurring as a second malignancy between 1964 and 2010 at the National Cancer Center Hospital of Japan. RESULTS: Among 857 patients with retinoblastoma registered in the database, 10 (1.1%) developed osteosarcoma as a second malignancy. The median age at the onset of retinoblastoma was 3 months, being bilateral in nine patients and unilateral in one. Systemic chemoreduction was performed in three patients and intra-arterial chemotherapy in six; all patients received external beam radiotherapy. The median age at the onset of second primary osteosarcoma was 11.2 years; four were radiation-related and six were located in an extremity. Among five patients treated at our institute, four patients with tumors on an extremity were treated by wide resection with neoadjuvant and adjuvant chemotherapy. Three of these four patients (75%) were good responders to high-dose methotrexate-based multi-agent chemotherapy and survived with no evidence of disease (median follow-up period, 17.3 years). One patient whose temporal bone was affected underwent radiotherapy with chemotherapy but died after local recurrence. CONCLUSIONS: The clinical outcomes of second primary osteosarcoma in an extremity occurring in retinoblastoma survivors may be more favorable than those of conventional osteosarcoma. Early diagnosis of radiation-related osteosarcoma arising in the craniofacial region should be made at a stage where complete resection is possible.

DOI： 10.1093/jjco/hyv140

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi-institutional study. 国際誌

Koichi Ogura, Tomohiro Fujiwara, Hideo Yasunaga, Hiroki Matsui, Dae-Geun Jeon, Wan Hyeong Cho, Hiroaki Hiraga, Takeshi Ishii, Tsukasa Yonemoto, Hiroto Kamoda, Toshifumi Ozaki, Eiji Kozawa, Yoshihiro Nishida, Hideo Morioka, Toru Hiruma, Shigeki Kakunaga, Takafumi Ueda, Yusuke Tsuda, Hirotaka Kawano, Akira Kawai

Cancer 121 ( 21 ) 3844 - 52 2015年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: In this era of individualized cancer treatment, data that could be applied to predicting the survival of patients with osteosarcoma are still limited because of the rarity of the disease and the difficulty in accumulating a sufficient number of patients. Therefore, a multi-institutional collaboration was implemented to develop and externally validate nomograms that would predict metastasis-free survival (MFS) and overall survival (OAS) for patients with nonmetastatic osteosarcoma. METHODS: This study retrospectively examined 1070 patients treated with neoadjuvant chemotherapy and surgery for nonmetastatic osteosarcoma. Data from Japanese patients (n = 557) were used to develop multivariate nomograms based on Cox regression. Six clinical and pathologic variables were built into nomograms estimating the probability of MFS and OAS 3 and 5 years after diagnosis. The model was internally validated for discrimination and calibration with bootstrap resampling and was externally validated with an independent patient cohort from Korea (n = 513). RESULTS: A patient's age, tumor site, and histologic response were found to have a stronger influence on MFS and OAS in the model than sex, tumor size, or pathologic fracture. The nomograms and calibration plots based on these results well predicted the probability of MFS (concordance index, 0.631) and OAS (concordance index, 0.679). The concordance indices for external validation were 0.682 for MFS and 0.665 for OAS. CONCLUSIONS: The nomograms were externally validated and verified to be useful for the prediction of MFS and OAS and for the assessment of the postoperative prognosis. They can be used for counseling patients and for establishing appropriate surveillance strategies after surgery.

DOI： 10.1002/cncr.29575

Diagnostic value of Thallium-201 scintigraphy in differentiating malignant bone tumors from benign bone lesions.

Ryota Inai, Takayoshi Shinya, Akihiro Tada, Shuhei Sato, Tomohiro Fujiwara, Ken Takeda, Toshiyuki Kunisada, Hiroyuki Yanai, Toshifumi Ozaki, Susumu Kanazawa

Annals of nuclear medicine 29 ( 8 ) 674 - 81 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: This retrospective study aims to evaluate the diagnostic capacity of thallium-201 (201Tl) scintigraphy for differentiating malignant bone tumors from benign bone lesions. METHODS: Between January 2006 and December 2012, 279 patients with bone lesions (51 malignant and 228 benign) underwent 201Tl scintigraphy before treatment. To evaluate 201Tl uptake, we investigated tumor-to-background contrast (TBC) as well as TBC washout rate (WR). The differences of TBC on early and delayed images and WR were estimated by the Mann-Whitney U test. Receiver operating characteristic (ROC) analyses were used to determine the cut-off TBC values for differentiating malignant bone tumors from benign bone lesions. RESULTS: There were statistically significant differences in median TBC between malignant tumors and benign lesions. These differences occurred for early imaging (1.57 vs. 0.09, p < 0.001) as well as for delayed imaging (0.83 vs. 0.07, p < 0.001). However, there was no statistical difference in WR between malignant tumors and benign lesions (44 vs. 43 %, NS). The chosen TBC cut-off value was 0.68 for early imaging and 0.38 for delayed imaging. Using these cut-off values, the prediction of malignancy had a 77 % sensitivity, 74 % specificity, and 75 % accuracy for early imaging and an 80 % sensitivity, 76 % specificity, and 77 % accuracy for delayed imaging. CONCLUSIONS: 201Tl scintigraphy may have the ability to distinguish malignant bone tumors from benign bone lesions.

DOI： 10.1007/s12149-015-0990-6

The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be favorable: experience of two cancer centers in Japan.

Tsukasa Yonemoto, Ako Hosono, Shintaro Iwata, Hiroto Kamoda, Yoko Hagiwara, Tomohiro Fujiwara, Akira Kawai, Takeshi Ishii

International journal of clinical oncology 20 ( 3 ) 613 - 6 2015年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Osteosarcoma as second malignancy of childhood cancers rarely occurs, and its clinical characteristics are unclear. METHODS: Patients with osteosarcoma occurring as second malignancy of childhood cancers were retrospectively surveyed. RESULTS: Of 323 patients with osteosarcoma registered in the database, 10 (3.1%) had a past history of childhood cancers. The mean age at the onset of the first childhood cancer was 2.7 years, and the diagnosis of the first childhood cancer was adrenocortical carcinoma, malignant teratoma, ovarian carcinoma, Ewing's sarcoma, and rhabdomyosarcoma in 1 patient each, and retinoblastoma in 5 patients. Osteosarcoma as second malignancy occurred 14.6 years after the first childhood cancer on average. Seven patients were alive and 3 died. In 1 patient, the cause of death was related to a complication of treatment for the first childhood cancer. Except for this patient, 7 (77.8%) of 9 patients survived with no disease (mean follow-up period: 10.9 years). CONCLUSIONS: Attention should be paid to complications of treatment for the first childhood cancer in the treatment for osteosarcoma occurring as second malignancy. The prognosis of osteosarcoma as second malignancy of childhood cancers may be more favorable than that of conventional osteosarcoma.

DOI： 10.1007/s10147-014-0729-8

仙骨骨巨細胞腫に対する治療戦略

藤原智洋, 国定俊之, 武田健, 山川泰明, 大森敏規, 上原健敬, 魚谷弘二, 杉生和久, 尾崎敏文

日本整形外科学会雑誌 89 ( 6 ) S1308 - S1308 2015年6月

Pelvic ring reconstruction with a double-barreled free vascularized fibula graft after resection of malignant pelvic bone tumor. 国際誌

Koichi Ogura, Minoru Sakuraba, Shimpei Miyamoto, Tomohiro Fujiwara, Hirokazu Chuman, Akira Kawai

Archives of orthopaedic and trauma surgery 135 ( 5 ) 619 - 25 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: In patients undergoing limb-salvage internal hemipelvectomy, pelvic ring reconstruction is mandatory to maintain the stability of the pelvis and the spinal column, which finally expected to achieve a good functional outcome. However, no optimal reconstruction method has been established. In addition, no previous reports have highlighted the long-term complications of pelvic ring reconstruction after internal hemipelvectomy. We aimed to analyze the outcome of pelvic ring reconstruction using a double-barreled free vascularized fibula graft (VFG) after internal hemipelvectomy with special reference to long-term complications. MATERIALS AND METHODS: We conducted a retrospective review of 9 consecutive patients (5 male, 4 female; mean age 31 years) who underwent pelvic ring reconstruction using a double-barreled free VFG after internal hemipelvectomy (P1, n = 4; P1 + 4, n = 3; P1 + 2, n = 2) at our institution between 1998 and 2013. The mean follow-up period was 55 months (range 3-131 months). RESULTS: The mean length of the bone defect was 9 cm. The methods of fixation included a Cotrel-Dubosset rod (n = 4), screw (n = 3), and screw and plate (n = 2). Bone union was achieved in 5 of 8 patients (63 %) over a 1-year follow-up. The mean period required for bone union was 5.4 months (range 3-7 months). There were 3 early postoperative complications: 2 deep infections resulting in graft removal and 1 implant failure resulting in non-union. Among 3 patients, 2 developed scoliosis within 5 years. One patient developed lumbar disc hernia as a result of scoliosis, for which surgical intervention was required. The mean Musculoskeletal Tumor Society score was 57 % at the last follow-up. CONCLUSIONS: In conclusion, this reconstruction method can achieve an early and high rate of bone union and provide good functional outcome. However, follow-up with careful attention to postoperative complications, including deep infection in the early postoperative period and spinal deformity in the long term, is necessary.

DOI： 10.1007/s00402-015-2197-7

The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. 国際誌

Yu Fujita, Shigehiro Yagishita, Keitaro Hagiwara, Yusuke Yoshioka, Nobuyoshi Kosaka, Fumitaka Takeshita, Tomohiro Fujiwara, Koji Tsuta, Hiroshi Nokihara, Tomohide Tamura, Hisao Asamura, Makoto Kawaishi, Kazuyoshi Kuwano, Takahiro Ochiya

Molecular therapy : the journal of the American Society of Gene Therapy 23 ( 4 ) 717 - 27 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1(high) drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.

DOI： 10.1038/mt.2015.10

骨温存のため液体窒素処理骨と腫瘍用人工関節術を併用した2例

上原健敬, 国定俊之, 大森敏規, 藤原智洋, 武田健, 尾崎敏文

中部日本整形外科災害外科学会雑誌 58 ( 春季学会 ) 224 - 224 2015年3月

原発性悪性骨・軟部腫瘍に対するpolypropylene meshを用いた腫瘍用人工関節置換術の治療成績

藤原智洋, 国定俊之, 武田健, 山川泰明, 上原健敬, 大森敏規, 魚谷弘二, 杉生和久, 尾崎敏文

日本整形外科学会雑誌 89 ( 3 ) S682 - S682 2015年3月

患肢温存術を行った15歳以下小児悪性骨腫瘍の治療成績

武田健, 国定俊之, 魚谷弘二, 杉生和久, 上原健敬, 大森敏規, 藤原智洋, 尾崎敏文

日本整形外科学会雑誌 89 ( 3 ) S687 - S687 2015年3月

骨軟部腫瘍における画像評価最前線シンチグラフィを用いた骨軟部腫瘍の機能的画像診断

国定俊之, 武田健, 藤原智洋, 上原健敬, 大森敏規, 尾崎敏文

臨床整形外科 50 ( 3 ) 229 - 235 2015年3月

記述言語：日本語出版者・発行元：(株)医学書院

骨軟部腫瘍の診断・治療では,骨シンチグラフィ,タリウムシンチグラフィが有用な画像診断法である.骨シンチグラフィは,骨腫瘍の活動性が評価可能であり,単発性・多発性発生の診断や悪性骨腫瘍では骨転移の診断に役立つ.タリウムシンチグラフィは腫瘍の活動性や悪性度を反映するため,術前治療の効果判定や良性・悪性の鑑別診断に有用である.術前治療が有効と判定可能であれば,縮小手術が可能となりうる.タリウムシンチグラフィとDMSAシンチグラフィを行うことで,軟骨系骨腫瘍の悪性度診断も可能とある.画像診断で良性・悪性の鑑別ができれば,外来診療での治療方針決定の一つの指標となる.(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01554&link_issn=&doc_id=20150304050011&doc_link_id=10.11477%2Fmf.1408200144&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1408200144&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

MicroRNAs in Bone and Soft Tissue Sarcomas and Their Value as Biomarkers 査読

Tomohiro Fujiwara, Yu Fujita, Yutaka Nezu, Akira Kawai, Toshifumi Ozaki, Takahiro Ochiya

Epigenetic Biomarkers and Diagnostics 613 - 642 2015年1月

記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：Elsevier Inc.

Bone and soft tissue sarcomas are malignant neoplasms that are histologically and genetically heterogeneous, and various subtypes of them have been identified. Evidence of microRNA (miRNA) dysregulation in bone and soft tissue sarcomas has been recently described. miRNA dysregulation that is associated with genetic abnormalities unique to the specific subtypes of sarcomas, functionally important, or correlated with clinical prognosis has been gradually identified. Furthermore, the discovery of circulating miRNAs in patient blood has accelerated interest in their potential to transform clinical applications. Considering the lack of useful bone and soft tissue sarcoma biomarkers, the discovery of miRNA dysregulation may provide a diagnostic method that can be used at early disease stages to detect tumors, predict tumor response to chemotherapy, or identify prognoses. Such interventions would address some of the most important challenges in sarcoma management. In this review, we summarize the emerging evidence of miRNA dysregulation in bone and soft tissue sarcomas and discuss their potential as novel biomarkers and therapeutics.

DOI： 10.1016/B978-0-12-801899-6.00030-9

Clinical Outcomes of Surgical Treatments for Primary Malignant Bone Tumors Arising in the Acetabulum. 国際誌

Tomohiro Fujiwara, Koichi Ogura, Eisuke Kobayashi, Yoshikazu Tanzawa, Fumihiko Nakatani, Hirokazu Chuman, Akira Kawai

Sarcoma 2015 430576 - 430576 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）

The functional and oncologic results of eighteen patients with primary malignant periacetabular tumors were reviewed to determine the impact of surgical treatment. The reconstruction procedures were endoprosthesis (11), hip transposition (4), iliofemoral arthrodesis (2), and frozen bone autograft (1). After a mean follow-up of 62 months, 13 patients were alive and 5 had died of their disease; the 5-year overall survival rate was 67.2%. The corresponding mean MSTS scores of patients with endoprosthesis (11) and other reconstructions (7) were 42% and 55% (49%, 68%, and 50%), respectively. Overall, postoperative complications including deep infection or dislocation markedly worsened the functional outcome. Iliofemoral arthrodesis provided better function than the other procedures, whereas endoprosthetic reconstruction demonstrated poor functional outcome except for patients who were reconstructed with the adequate soft tissue coverage. Avoiding postoperative complications is highly important for achieving better function, suggesting that surgical procedures with adequate soft tissue coverage or without the massive use of nonbiological materials are preferable. Appropriate selection of the reconstructive procedures for individual patients, considering the amount of remaining bone and soft tissues, would lead to better clinical outcomes.

DOI： 10.1155/2015/430576

microRNAs and Soft Tissue Sarcomas. 国際誌

Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Toshifumi Ozaki

Advances in experimental medicine and biology 889 179 - 99 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）

Soft tissue sarcomas are a highly heterogenous group of malignant tumors that originate from mesenchymal tissues including muscle, adipose and fibrous tissues, blood vessels, and peripheral nerves. A large variety of histological subtypes that current diagnostic approaches recognize present a diagnostic challenge because their clinical and histopathological characteristics are not always distinct. One of the important clinical problems is a lack of useful biomarkers; therefore, the discovery of biomarkers that can be used to detect tumors or predict tumor response to chemotherapy or radiotherapy could help clinicians provide more effective clinical management. Recent reports on microRNAs (miRNAs) in soft tissue sarcomas have provided clues to solve the problem. Evidence for miRNAs in tumor tissues as well as circulating miRNAs in patients' blood is accelerating the potential to transform clinical applications. In this chapter, we summarize the emerging evidence of dysregulated miRNAs in tumor tissues and patients' blood and discuss the potential of miRNAs as novel biomarkers and therapeutic targets.

DOI： 10.1007/978-3-319-23730-5_10

The Values and Limitations of FDG-PET/CT for Diagnosis of Hibernoma. 国際誌

Jong Hoon Park, Koichi Ogura, Tomohiro Fujiwara, Akihito Nagano, Kunihiko Numoto, Takashi Terauchi, Akihiko Yoshida, Akira Kawai

Case reports in orthopedics 2015 958690 - 958690 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）

Hibernoma is a rare benign lipogenic tumor of brown fat that develops in a wide variety of locations. Although the features of hibernoma demonstrated by MRI resemble those of liposarcoma, recent FDG-PET/CT studies have documented higher radiotracer uptake than liposarcoma, suggesting that FDG/PET/CT is useful for differentiating hibernoma from liposarcoma. Here we report two cases of hibernoma that showed relatively lower SUVs than those reported previously, lying within the range for liposarcoma. Our findings emphasize that hibernoma needs to be included in the differential diagnosis of any fat-containing tumor showing intense accumulation by FDG-PET/CT. Although it is unlikely that such a rare condition could be reasonably diagnosed on the basis of MRI and FDG-PET/CT alone due to possible SUV overlap between hibernoma and liposarcoma, it is important to recognize this extremely rare lipogenic tumor for accurate diagnosis and appropriate management.

DOI： 10.1155/2015/958690

Immunotherapy for Bone and Soft Tissue Sarcomas. 国際誌

Takenori Uehara, Tomohiro Fujiwara, Ken Takeda, Toshiyuki Kunisada, Toshifumi Ozaki, Heiichiro Udono

BioMed research international 2015 820813 - 820813 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）

Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

DOI： 10.1155/2015/820813

Intercalary reconstruction after wide resection of malignant bone tumors of the lower extremity using a composite graft with a devitalized autograft and a vascularized fibula. 国際誌

Koichi Ogura, Shimpei Miyamoto, Minoru Sakuraba, Tomohiro Fujiwara, Hirokazu Chuman, Akira Kawai

Sarcoma 2015 861575 - 861575 2015年

記述言語：英語掲載種別：研究論文（学術雑誌）

Introduction. Although several intercalary reconstructions after resection of a lower extremity malignant bone tumor are reported, there are no optimal methods which can provide a long-term reconstruction with fewest complications. We present the outcome of reconstruction using a devitalized autograft and a vascularized fibula graft composite. Materials and Methods. We conducted a retrospective review of 11 patients (7 males, 4 females; median age 27 years) undergoing reconstruction using a devitalized autograft (pasteurization (n = 6), deep freezing (n = 5)) and a vascularized fibula graft composite for lower extremity malignant bone tumors (femur (n = 10), tibia (n = 1)). Results. The mean period required for callus formation and bone union was 4.4 months and 9.9 months, respectively. Four postoperative complications occurred in 3 patients: 2 infections (1 pasteurized autograft, 1 frozen autograft) and 1 fracture and 1 implant failure (both in pasteurized autografts). Graft removal was required in 2 patients with infections. The mean MSTS score was 81% at last follow-up. Conclusions. Although some complications were noted in early cases involving a pasteurized autograft, our novel method involving a combination of a frozen autograft with a vascularized fibula graft and rigid fixation with a locking plate may offer better outcomes than previously reported allografts or devitalized autografts.

DOI： 10.1155/2015/861575

RPN2 Gene Confers Osteosarcoma Cell Malignant Phenotypes and Determines Clinical Prognosis. 国際誌

Tomohiro Fujiwara, Ryou-U Takahashi, Nobuyoshi Kosaka, Yutaka Nezu, Akira Kawai, Toshifumi Ozaki, Takahiro Ochiya

Molecular therapy. Nucleic acids 3 ( 9 ) e189 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Drug resistance and metastasis are lethal characteristics of tumors. We previously demonstrated that silencing of ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, efficiently induced apoptosis and reduced resistance to docetaxel in human breast cancer cells. Here, we report the clinical and functional correlations of RPN2 expression in osteosarcoma. Immunohistochemical evaluation of 35 osteosarcoma patient biopsies revealed that RPN2 was moderately to highly expressed in all specimens, and higher RPN2 mRNA expression was significantly correlated with poor prognosis. To investigate whether lethal phenotypes of osteosarcoma could be reduced by regulating the expression of RPN2, we conducted a study of RNAi-induced RPN2 knockdown in highly metastatic human osteosarcoma cells. The results indicated that RPN2 silencing reduced cell proliferation, sphere formation, cell invasion, and sensitized drug response in vitro. Mice bearing RPN2-silenced highly metastatic osteosarcoma xenografts showed reduced tumor growth and lung metastasis, and survived longer than mice bearing control tumor xenografts. Taken together, our data suggest that RPN2 silencing contributes to regulation of lethal osteosarcoma phenotypes and could be a novel target for RNAi-based therapeutics against osteosarcoma.

DOI： 10.1038/mtna.2014.35

切除縁評価法の問題点 : 悪性骨腫瘍 (パネルディスカッション切除縁評価法の問題点) 査読

国定俊之, 武田健, 藤原智洋

日本整形外科学会雑誌 88 ( 9 ) 588 - 594 2014年9月

記述言語：日本語出版者・発行元：日本整形外科学会

2005年〜2011年に治療した初診時遠隔転移を認めない高悪性骨腫瘍52例を対象に、最近の症例について検討し、悪性骨腫瘍の切除縁評価法に関する疑問点・問題点について検討した。組織型は骨肉腫34例、軟骨肉腫12例、Ewing肉腫3例等であった。52例の切除縁評価は2cm wide margin以上45例、1cm wide margin 4例、marginal margin以下3例であった。1cm wide marginとなった4例は血管温存目的(2例)および術前化学療法効果著効例での関節温存目的(2例)であった。marginal margin以下となった3例は骨盤発生、脊椎発生、大腿骨巨大腫瘍で、広範囲切除縁確保が困難であった。再発は4例に認め、2cm wide margin以上1例、marginal margin以下3例であった。最初の問題点は反応層の定義で、反応層をもう少し詳細に分類する必要がある。2番目の問題点は術前画像での切除縁設定の基準を決めることで、全国で統一した安全な切除縁設定の基準を決める必要があると思われた。

その他リンク： http://search.jamas.or.jp/link/ui/2015068034

Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma. 国際誌

Yasushi Totoki, Akihiko Yoshida, Fumie Hosoda, Hiromi Nakamura, Natsuko Hama, Koichi Ogura, Aki Yoshida, Tomohiro Fujiwara, Yasuhito Arai, Junya Toguchida, Hitoshi Tsuda, Satoru Miyano, Akira Kawai, Tatsuhiro Shibata

Genome research 24 ( 9 ) 1411 - 20 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors.

DOI： 10.1101/gr.160598.113

Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells. 国際誌

Tomohiro Fujiwara, Takeshi Katsuda, Keitaro Hagiwara, Nobuyoshi Kosaka, Yusuke Yoshioka, Ryou-U Takahashi, Fumitaka Takeshita, Daisuke Kubota, Tadashi Kondo, Hitoshi Ichikawa, Akihiko Yoshida, Eisuke Kobayashi, Akira Kawai, Toshifumi Ozaki, Takahiro Ochiya

Stem cells (Dayton, Ohio) 32 ( 4 ) 959 - 73 2014年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Novel strategies against treatment-resistant tumor cells remain a challenging but promising therapeutic approach. Despite accumulated evidence suggesting the presence of highly malignant cell populations within tumors, the unsolved issues such as in vivo targeting and clinical relevance remain. Here, we report a preclinical trial based on the identified molecular mechanisms underlying osteosarcoma-initiating cells and their clinical relevance. We identified key microRNAs (miRNAs) that were deregulated in a highly malignant CD133(high) population and found that miR-133a regulated the cell invasion that characterizes a lethal tumor phenotype. Silencing of miR-133a with locked nucleic acid (LNA) reduced cell invasion of this cell population, and systemic administration of LNA along with chemotherapy suppressed lung metastasis and prolonged the survival of osteosarcoma-bearing mice. Furthermore, in a clinical study, high expression levels of CD133 and miR-133a were significantly correlated with poor prognosis, whereas high expression levels of the four miR-133a target genes were correlated with good prognosis. Overall, silencing of miR-133a with concurrent chemotherapy would represent a novel strategy that targets multiple regulatory pathways associated with metastasis of the malignant cell population within osteosarcoma.

DOI： 10.1002/stem.1618

MicroRNAs in soft tissue sarcomas: overview of the accumulating evidence and importance as novel biomarkers. 国際誌

Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Koji Uotani, Aki Yoshida, Takahiro Ochiya, Toshifumi Ozaki

BioMed research international 2014 592868 - 592868 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）

Sarcomas are distinctly heterogeneous tumors and a variety of subtypes have been described. Although several diagnostic explorations in the past three decades, such as identification of chromosomal translocation, have greatly improved the diagnosis of soft tissue sarcomas, the unsolved issues, including the limited useful biomarkers, remain. Emerging reports on miRNAs in soft tissue sarcomas have provided clues to solving these problems. Evidence of circulating miRNAs in patients with soft tissue sarcomas and healthy individuals has been accumulated and is accelerating their potential to develop into clinical applications. Moreover, miRNAs that function as novel prognostic factors have been identified, thereby facilitating their use in miRNA-targeted therapy. In this review, we provide an overview of the current knowledge on miRNA deregulation in soft tissue sarcomas, and discuss their potential as novel biomarkers and therapeutics.

DOI： 10.1155/2014/592868

Secondary Chondrosarcoma of the Proximal Part of the Humerus Arising in a Four-Year-Old Boy with Ollier Disease: A Case Report. 国際誌

Koichi Ogura, Ken Takeda, Tomohiro Fujiwara, Akihiko Yoshida, Hirokazu Chuman, Akira Kawai

JBJS case connector 3 ( 4 Suppl 8 ) e131 2013年12月

[Update on microRNAs research in sarcoma: review the literature and proposal of the clinical application].

Tomohiro Fujiwara, Akira Kawai, N Kosaka, Toshifumi Ozaki, Takahiro Ochiya

Gan to kagaku ryoho. Cancer & chemotherapy 40 ( 3 ) 305 - 13 2013年3月

後頚部両側に発生し, 異なるMRI所見を呈したspindle cell lipomaの1例査読

滑川陽一, 小林英介, 藤原智洋, 丹澤義一, 川井章, 中馬広一

中部日本整形外科災害外科学会雑誌 56 ( 4 ) 865 - 866 2013年

記述言語：日本語出版者・発行元：(一社)中部日本整形外科災害外科学会

57歳男。10年前より頸部に母指頭大の腫瘤を自覚していたが、徐々に増大傾向を認めた。頸部の左右両側皮下に腫瘤を認めた。術前MRIでは、両腫瘤に連続性は認めず、右頸部腫瘤はT1で筋肉よりやや高信号、T2で高信号、ガドリニウムで不均一に造影された。左頸部腫瘤はT1で筋肉と等信号、T2で高信号、ガドリニウムでは造影されなかった。切除生検にて右頸部腫瘤はSpindle cell lipoma(SCL)と診断し、左頸部腫瘤は画像上lipomaが疑われたため、いずれの腫瘍にも辺縁切除を行った。免疫組織染色では、両腫瘍で紡錘形細砲がCD34に陽性を示し、ともにSCLと診断した。組織学的には右頸部腫瘍が脂肪成分に乏しいいわゆるlow-fat type SCLであったのに対し、左頸部腫瘍は脂肪成分に富んだSCLであった。術後経過は良好で、両腫瘍ともに術後5年の現在、再発を認めていない。

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00831&link_issn=&doc_id=20131009040038&doc_link_id=10.11359%2Fchubu.2013.865&url=https%3A%2F%2Fdoi.org%2F10.11359%2Fchubu.2013.865&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Extraskeletal myxoid chondrosarcoma: a review of 23 patients treated at a single referral center with long-term follow-up. 国際誌

Koichi Ogura, Tomohiro Fujiwara, Yasuo Beppu, Hirokazu Chuman, Akihiko Yoshida, Hirotaka Kawano, Akira Kawai

Archives of orthopaedic and trauma surgery 132 ( 10 ) 1379 - 86 2012年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma. Although it has been regarded as a low-grade sarcoma unassociated with tumor-related death, a recent study has suggested an insidious nature with a high propensity for relapse during a long disease course. The aim of this study was to clarify the long-term clinical features of EMC treated at a single referral center using state-of-the-art techniques. METHODS: A retrospective review of 23 consecutive patients (10 males, 13 females; mean age 58 years) treated between 1979 and 2008 (mean follow-up; 109 months) was performed. RESULTS: Surgery for the primary tumor was performed in 22 patients, and 7 cases recurred locally due to inadequate resection. Eleven patients had metastatic disease, either at diagnosis (3) or developing later (8). The 5/10-year overall survival rates were 91/84 %, and the 5/10-year local recurrence-free and metastasis-free survival rates for patients with localized disease were 89/62 and 89/61 %, respectively. Larger tumor size (>10 cm) and metastases at diagnosis were significant negative prognostic factors. Four patients received ifosfamide-based chemotherapy with no objective response. There was no local recurrence in three patients who underwent R1 resection followed by adjuvant radiotherapy. Clinical palliation and retarded progression of the metastatic disease were achieved in three patients who underwent radiotherapy. CONCLUSIONS: EMC is indolent but has a high propensity for relapse over 5 years of follow-up. Definitive initial surgery and careful monitoring for a prolonged period are important. Radiotherapy seems beneficial in an adjuvant setting and as palliative therapy for metastatic disease.

下腿骨幹部骨折術後非感染性偽関節の治療戦略査読

藤原智洋, 野田知之, 中原龍一, 島村安則, 尾崎敏文, 寺田忠司

骨折 34 ( 3 ) 702 - 706 2012年9月

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）出版者・発行元：(一社)日本骨折治療学会

下腿骨幹部骨折術後非感染性偽関節の治療にはインプラント選択を含めた再内固定方法、骨欠損および変形への対処法など様々な問題点が存在する。当科で経験した5例を検討した。全例男性、手術時平均年齢は46歳、偽関節タイプおよび前回手術法は肥厚型3例(プレート固定1例、血管柄付き骨移植2例)、萎縮型2例(創外固定1例、髄内釘固定1例)。偽関節手術法は、髄内釘固定および髄内釘入れ替えを2例、ロッキングプレート固定を3例に実施し、偽関節部新鮮化・骨移植を4例、部分腓骨切除を併用した変形矯正を3例に行った。全例に骨癒合が得られ、矯正位は良好であった。本偽関節に対しては、適切な手術手技による髄内釘入れ替えを第一選択とし、血管柄付き骨移植後などの髄腔狭小・閉鎖例にはロッキングプレート固定を第二選択として適応し、変形や骨欠損に対する部分腓骨切除や自家骨移植などの併用により治療成績の向上が期待できる。(著者抄録)

肉腫の病理と治療標的探索プロテオミクスを用いた骨軟部肉腫の分子標的探索(Topics of bone and soft part sarcoma Molecular markers of bone and soft tissue sarcomas revealed by proteomics)

川井章, 窪田大介, 藤原智洋, 菊田一貴, 末原義之, 小倉浩一, 薛宇孝, 浅野尚文, 小林英介, 中谷文彦, 中馬広一, 落谷孝広, 近藤格

日本癌学会総会記事 71回 452 - 452 2012年8月

microRNAマイクロアレイを用いた骨肉腫化学療法奏効性予測バイオマーカーの開発

窪田大介, 末原義之, 藤原智洋, 川井章, 金子和夫, 近藤格

日本整形外科学会雑誌 86 ( 6 ) S967 - S967 2012年6月

墜落外傷の原因による比較検討査読

八幡直志, 石井桂輔, 藤原智洋, 栗本久嗣

関東整形災害外科学会雑誌 43 ( 2 ) 111 - 114 2012年

記述言語：日本語出版者・発行元：関東整形災害外科学会

1999〜2008年の墜落外傷932例を対象に、自殺企画群551例(A群)と事故群381例(B群)に分け、受傷・高度別に人数や死亡数を比較した。その結果、収容時に心肺停止であった症例の占める割合は、A群40%、B群5.8%であった。墜落外傷者数の年次推移については、A群は2005年から増加し、2006年が最も多かった。B群は2001年と2006年を中心に2峰性を示し、2001年が最も多かった。墜落外傷の月別分布については、A群の4〜6月が有意差をもって多く収容されていた。受傷部位については、A群はB群に比べ下肢外傷の発生頻度が有意に高く、墜落高度が有意に高かった。B群はA群に比べ頭部外傷の発生頻度が有意に高かった。墜落階層による予後を比較すると、5階以下では退院時生存例が多く、6階以上では死亡例が退院時生存例を上回った。11階以上に生存者はいなかった。墜落外傷の原因の違いにより病像に差異があり、B群では頭部外傷が多く注意を要すると考えられた。

Cancer stem cells in breast cancer. 国際誌

Ryou-U Takahashi, Fumitaka Takeshita, Tomohiro Fujiwara, Makiko Ono, Takahiro Ochiya

Cancers 3 ( 1 ) 1311 - 28 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

The cancer stem cell (CSC) theory is generally acknowledged as an important field of cancer research, not only as an academic matter but also as a crucial aspect of clinical practice. CSCs share a variety of biological properties with normal somatic stem cells in self-renewal, the propagation of differentiated progeny, the expression of specific cell markers and stem cell genes, and the utilization of common signaling pathways and the stem cell niche. However, CSCs differ from normal stem cells in their chemoresistance and their tumorigenic and metastatic activities. In this review, we focus on recent reports regarding the identification of CSC markers and the molecular mechanism of CSC phenotypes to understand the basic properties and molecular target of CSCs. In addition, we especially focus on the CSCs of breast cancer since the use of neoadjuvant chemotherapy can lead to the enrichment of CSCs in patients with that disease. The identification of CSC markers and an improved understanding of the molecular mechanism of CSC phenotypes should lead to progress in cancer therapy and improved prognoses for patients with cancer.

DOI： 10.3390/cancers3011311

Roof impactionを伴う寛骨臼骨折の治療経験査読

藤原智洋, 野田知之, 中原龍一, 雑賀建多, 島村安則, 尾﨑敏文

骨折 33 ( 3 ) 637 - 642 2011年

担当区分：筆頭著者記述言語：日本語出版者・発行元：(一社)日本骨折治療学会

Roof impactionを伴う寛骨臼骨折3例の手術治療について検討した。本所見に伴う骨折型は前壁骨折1例、前柱骨折2例であった。前壁骨折に伴う1例に対してはilioinguinal approachの2nd windowから前壁骨片を翻転し陥没骨片を直視下に整復した。前柱骨折に伴う2例に対してはmodified Stoppa approachにlateral windowを併用し、1例は陥没骨片直上の骨折部から整復を、1例は骨片直上を開窓し整復した。いずれも内固定および人工骨充填によるsubchondral supportを行った。全例整復位・臨床評価ともに概ね良好な成績を得たが、うち1例はアプローチ選択に課題が残った。Roof impactionの存在は成績不良因子とされるが、個々の症例における術前の詳細な評価、アプローチ選択および整復固定法の工夫により治療成績の改善が期待できる。(著者抄録)

ロッキングプレートによる下肢長管骨非感染性偽関節の治療成績査読

藤原智洋, 野田知之, 西山武, 中原龍一, 雑賀建多, 島村安則, 尾崎敏文, 加原尚明, 宮澤慎一, 高城康師

中国・四国整形外科学会雑誌 22 ( 2 ) 355 - 361 2010年9月

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）出版者・発行元：中国・四国整形外科学会

2005〜2008年に当科と関連施設で下肢長管骨非感染性偽関節に対してロッキングプレートによる治療を行った15例の成績を報告した。男性7例、女性8例、手術時年齢21〜82歳、手術部位は大腿骨骨幹部2例、大腿骨遠位部3例、脛骨近位部7例、脛骨骨幹部2例、脛骨遠位部1例であった。偽関節の種類はhypertrophic non-unionが9例、atrophic non-unionが6例であった。手術では14例に自家骨移植を併施した。治療成績は全例で骨癒合が得られた。術直後から最終観察時までのアライメント変化の度合いは、単純X線正面像で平均1.13°(0〜10°)、側面像で平均0.35°(0〜5°)であり、ほとんどの症例で良好なアライメントが維持されていた。術後合併症として遷延治癒を5例(33%)、矯正損失を1例(7%)に認め、感染や皮膚壊死などの軟部組織合併症は認めなかった。合併症を認めた6例中4例がatrophic non-unionであった。

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J02438&link_issn=&doc_id=20101006220017&doc_link_id=10.11360%2Fjcsoa.22.355&url=https%3A%2F%2Fdoi.org%2F10.11360%2Fjcsoa.22.355&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

骨盤腫瘍に対する創外固定を併用したhip transposition法の治療経験

藤原智洋, 国定俊之, 森本裕樹, 井谷智, 佐々木剛, 尾崎敏文

中部日本整形外科災害外科学会雑誌 53 ( 春季学会 ) 129 - 129 2010年3月

骨盤腫瘍に対する創外固定を併用したhip transposition法の治療経験査読

藤原智洋, 国定俊之, 井谷智, 森本裕樹, 佐々木剛, 尾﨑敏文

中部日本整形外科災害外科学会雑誌 53 ( 4 ) 937 - 938 2010年

担当区分：筆頭著者記述言語：日本語出版者・発行元：中部日本整形外科災害外科学会

Enneking分類P2を含む骨盤腫瘍に対し、腫瘍切除後に創外固定を併用したhip transposition法を用いて再建を行った3例の短期成績を検討した。手術時年齢は平均38歳、術後経過観察期間は平均13ヵ月で、手術時間は平均6時間37分、出血量は平均4020gであった。全例が術翌日より坐位可能で、最終観察時の歩行状態は独歩1例、杖歩行2例、MSTS scoreは平均70%であった。平均5.2cmの脚長差が生じたが、術後感染症などの重篤な合併症はなかった。Enneking分類P2を含む骨盤腫瘍切除後の再建方法として、創外固定を併用したhip transposition法は有用であると考えられた。

DOI： 10.11359/chubu.2010.937

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J00831&link_issn=&doc_id=20100915110096&doc_link_id=10.11359%2Fchubu.2010.937&url=https%3A%2F%2Fdoi.org%2F10.11359%2Fchubu.2010.937&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

[Fundamental Study on Heavy Ion CT Using Pencil Beam Scanning Method].

Toshiyuki Kohno, Tomohiro Fujiwara, Yumiko Ohno, Naruhiro Matsufuji, Tatsuaki Kanai

Igaku butsuri : Nihon Igaku Butsuri Gakkai kikanshi = Japanese journal of medical physics : an official journal of Japan Society of Medical Physics 20 ( 2 ) 71 - 82 2000年

記述言語：日本語掲載種別：研究論文（学術雑誌）

The feasibility of heavy ion computed tomography was investigated. A cylindrical polyethylene sample of 50 mm in diameter was used to establish the pencil beam scanning method and estimate the performance of the system. The sample was irradiated with carbon ions of 290 MeV/u and 400 MeV/u, and helium ions of 150 MeV/u. The residual beam energy was measured by a BGO scintillator in coincidence with two small plastic scintillators placed in front of and behind the sample to restrict the beam path and improve the spatial resolution in the CT reconstruction. The projection data were obtained by moving the sample only in the transverse direction because of its symmetrical structure. A Lucite sample with many holes of different diameters was used to demonstrate the spatial resolution of this CT system. From the reconstructed images the spatial resolution was estimated to be less than 2 mm under the conditions in this work. The electron density ratios of ethyl alcohol, water, and Lucite to polyethylene were obtained, which are in good agreement with the calculated values.

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