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Makoto Endo Last modified date：2023.07.04

Lecturer / Orthopedic Surgery / Kyushu University Hospital


Papers
1. 薛 宇孝, 小田 義直, 田宮 貞史, 山元 英崇, 孝橋 賢一, 遠藤 誠, 高橋 祐介, 山田 裕一, 松田 秀一, 岩本 幸英, 恒吉 正澄, 軟部平滑筋肉腫におけるAkt/mTOR経路の活性化(Akt/mTOR pathway is activated independent of Akt1 mutation in soft tissue leiomyosarcoma), 日本癌学会総会記事, 69回, 480-481, 2010.08.
2. Clinicopathological features of synovial sarcoma.
3. 遠藤 誠, 小田 義直, 田宮 貞史, 山元 英崇, 孝橋 賢一, 薛 宇孝, 高橋 祐介, 山田 裕一, 松田 秀一, 岩本 幸英, 恒吉 正澄, 悪性末梢神経鞘腫瘍におけるp14、p15、p16不活性化と予後との関連についての包括的解析(Comprehensive and prognostic analysis of p14, p15 and p16 inactivation in malignant peripheral nerve sheath tumors), 日本癌学会総会記事, 69回, 225-225, 2010.08.
4. 薛 宇孝, 孝橋 賢一, 山元 英崇, 田宮 貞史, 遠藤 誠, 相島 慎一, 高橋 祐介, 山田 裕一, 松田 秀一, 岩本 幸英, 小田 義直, 軟部平滑筋肉腫においてリン酸化STAT3の発現は良好な予後と相関する(Phosphorylation of STAT3 in Soft Tissue Leiomyosarcoma is associated with a Better Prognosis), 日本癌学会総会記事, 70回, 455-455, 2011.09.
5. 小田 義直, 遠藤 誠, 薛 宇孝, 孝橋 賢一, 山元 英崇, 岩本 幸英, 肉腫の病理と治療標的探索 軟部肉腫における分子標的の探索(Topics of bone and soft part sarcoma Investigation of the molecular target in soft tissue sarcoma), 日本癌学会総会記事, 71回, 451-452, 2012.08.
6. 遠藤 誠, 松延 知哉, 松本 嘉寛, 播广谷 勝三, 孝橋 賢一, 山元 英崇, Nielsen Torsten O., 小田 義直, 岩本 幸英, 間葉系腫瘍におけるMCL1およびBCL2発現 どの腫瘍がnavitoclaxの治療ターゲットとして有望か?(MCL1 and BCL2 expressions in mesenchymal tumors: Which tumor is the best candidate for navitoclax therapy?), 日本癌学会総会記事, 72回, 180-180, 2013.10.
7. 井浦 国生, 孝橋 賢一, 石井 武彰, 前川 啓, 山田 裕一, 戸次 大史, 山元 英崇, 遠藤 誠, 岩本 幸英, 小田 義直, 癌精巣抗原PRAMEとNY-ESO-1の脂肪肉腫での発現と粘液/円形細胞型脂肪肉腫における臨床病理学的因子との関連(Expression of PRAME and NY-ESO-1 in liposarcomas and clinical outcome in myxoid/round cell liposarcoma), 日本癌学会総会記事, 73回, J-2086, 2014.09.
8. 専門医試験をめざす症例問題トレーニング 骨・軟部腫瘍.
9. Yasuhiko Kokubu, Toshifumi Fujiwara, Koh Nakagawa, Nokitaka Setsu, Makoto Endo, Jun-Ichi Fukushi, Yoshihiro Matsumoto, Yasuharu Nakashima, Postoperative clinical and functional outcomes in patients with tumor and tumor-like lesion of foot and ankle., Journal of foot and ankle research, 10.1186/s13047-022-00582-z, 15, 1, 75-75, 2022.10, BACKGROUND: Tumors and tumor-like lesions of the foot and ankle are relatively rare and their postoperative clinical outcome has not been well reported. METHODS: This study retrospectively reviewed medical records of all patients who underwent excision of tumors and tumor-like lesions of the foot and ankle from 2008 to 2020. Preoperative and postoperative clinical outcomes were evaluated by the Japanese Society for Surgery of the Foot (JSSF) scales (pain, function, and alignment). RESULTS: A total of 117 consecutive patients were analyzed in this study. Bone lesions accounted for 51 patients (benign: 45, intermediate malignancy: 1, malignant: 5), and soft tissue lesions accounted for 66 patients (benign: 57, intermediate malignancy: 2, malignant: 7). Four patients (8%) presenting with bone tumor and six (9%) soft tissue tumors resulted in recurrence. Eight (67%) patients with malignant lesions were alive continuously disease free and followed for a median of 50.5 (range: 18 to 82) months. Amputation at the first operation was done for five cases (33%) of malignant or intermediate malignancy (below-knee amputation: 1, Chopart disarticulation: 1, forefoot amputation: 3). Postoperative JSSF scores resulted in a significant 'positive' increase (bone lesion, 75.9 ± 13.7 to 91.4 ± 14.9, p 
10. Atsushi Kimura, Yu Toda, Yoshihiro Matsumoto, Hidetaka Yamamoto, Kenichiro Yahiro, Eijiro Shimada, Masaya Kanahori, Ryunosuke Oyama, Suguru Fukushima, Makoto Nakagawa, Nokitaka Setsu, Makoto Endo, Toshifumi Fujiwara, Tomoya Matsunobu, Yoshinao Oda, Yasuharu Nakashima, Nuclear β-catenin translocation plays a key role in osteoblast differentiation of giant cell tumor of bone., Scientific reports, 10.1038/s41598-022-17728-5, 12, 1, 13438-13438, 2022.08, Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment..
11. Shin Ishihara, Hidetaka Yamamoto, Takeshi Iwasaki, Yu Toda, Takeo Yamamoto, Masato Yoshimoto, Yoshihiro Ito, Yousuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Yuichi Yamada, Kenichi Kohashi, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yuko Kakuda, Yasuharu Nakashima, Yoshinao Oda, Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation., Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 10.1038/s41379-021-00972-x, 35, 5, 640-648, 2022.05, In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases..
12. Yu Toda, Hidetaka Yamamoto, Takeshi Iwasaki, Shin Ishihara, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Daisuke Kiyozawa, Yuichi Yamada, Kenichi Kohashi, Atsushi Kimura, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda, Expression of SATB2, RUNX2, and SOX9 and possible osteoblastic and chondroblastic differentiation in chondroblastoma., Pathology, research and practice, 10.1016/j.prp.2022.154239, 241, 154239-154239, 2022.11, Chondroblastoma (CB) is histologically characterized by oval to polygonal-shaped mononuclear neoplastic cells, multinucleated osteoclastic giant cells, and eosinophilic matrix with occasional calcification. Genetically, the majority of CBs harbor H3F3B p.K36M mutation. Despite the historical nomenclature, it has been reported that the matrix of CB is similar to osteoid rather than true cartilage; however, it remains unclear whether neoplastic cells in CB have the potential for osteoblastic differentiation. To clarify this issue, we immunohistochemically examined the expression of osteogenic and chondrogenic markers (SATB2, RUNX2, p63, and SOX9) as well as H3K36M mutant protein in 33 cases of CB. All 33 cases of CB were positive for H3K36M, while SATB2, RUNX2, p63, and SOX9 were expressed in 30/33 (91%), 33/33 (100%), 29/33 (88%), and 31/32 (97%) CB cases, respectively. Our immunohistochemical results suggest that neoplastic cells in CB frequently express both osteogenic and chondrogenic markers and may have an intermediate feature of osteoblastic and chondroblastic nature..
13. Ryunosuke Oyama, Nokitaka Setsu, Yoshihiro Matsumoto, Makoto Endo, Toshifumi Fujiwara, Keiichiro Iida, Akira Nabeshima, Yasuharu Nakashima, Efficacy and safety of tranexamic acid in patients undergoing surgery for bone and soft tissue tumors: a propensity score matching analysis., Japanese journal of clinical oncology, 10.1093/jjco/hyac078, 2022.05, OBJECTIVE: The aim of this study was to investigate the efficacy and safety of tranexamic acid in patients undergoing surgery for bone and soft tissue tumors. METHODS: Data were retrospectively collected from 454 consecutive patients with bone and soft tissue tumors who underwent open biopsy, marginal resection, curettage or wide resection between January 2017 and December 2018. We performed propensity score matching of patients who received tranexamic acid with those who did not. The primary outcome variables were intra-operative, peri-operative and estimated blood loss (IBL, PBL and EBL, respectively). RESULTS: Tranexamic acid (+) and tranexamic acid (-) groups were defined according to whether patients received tranexamic acid or not. Among the 454 patients, open biopsy was performed in 102, marginal resection in 175, curettage in 54 and wide resection in 123. Intra-operative blood loss was significantly lower in the tranexamic acid (+) group than in the tranexamic acid (-) group for both marginal and wide resection (marginal resection: 17.3 vs. 70.3 g, respectively, P = 0.045; wide resection: 128.8 vs. 273.1 g, respectively, P = 0.023). Peri-operative blood loss and estimated blood loss were also significantly lower in the tranexamic acid (+) group for wide resection (peri-operative blood loss: 341.5 vs. 686.5 g, respectively, P = 0.0039; estimated blood loss: 320.7 vs. 550.6 ml, respectively, P = 0.030). No venous thromboembolism occurred in either group. CONCLUSION: This study suggests that TXA administration safely and effectively reduces blood loss, in particular for wide resection, with no increase in the rate of adverse events..
14. Toshihide Hirai, Hiroshi Kobayashi, Eisuke Kobayashi, Masanori Saito, Toru Akiyama, Kazutaka Kikuta, Takaaki Nakai, Makoto Endo, Shinji Tsukamoto, Michiyuki Hakozaki, Satoshi Takenaka, Shunji Nishimura, Hiroyuki Kawashima, Yoshikazu Tanzawa, Hirotaka Kawano, Sakae Tanaka, Dedifferentiation in low-grade osteosarcoma: a Japanese Musculoskeletal Oncology Group (JMOG) study., International journal of clinical oncology, 10.1007/s10147-022-02223-8, 2022.08, BACKGROUND: Low-grade osteosarcomas, namely parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LGCOS), occasionally dedifferentiate into high-grade malignancy, referred to as dedifferentiation in low-grade osteosarcoma (DLOS). This study aimed to elucidate the clinicopathologic features of DLOS, which are poorly described to date due to the extreme rarity of the disease. METHODS: A total of 33 patients with DLOS were included. Clinical characteristics, including the diagnostic accuracy of tumor biopsy, multimodal treatments, and clinical course, were retrospectively reviewed. Univariate analysis was performed to identify prognostic factors associated with overall survival (OS) and metastasis-free survival (MFS). RESULTS: The tumor subtypes comprised 10 cases (30.3%) of LGCOS and 23 cases (69.7%) of POS. The timing of dedifferentiation was synchronous in 25 (75.8%) and metachronous in 8 (24.2%) patients. The rates of preoperative diagnosis of DLOS were 40.0% and 65.4% for core needle biopsy and incisional biopsy, respectively. All patients underwent surgery and 25 patients received perioperative chemotherapy. Of the 13 patients who received neoadjuvant chemotherapy, 11 exhibited a poor histological response. The 5-year OS and MFS rates were 88.1% and 77.7%, respectively. Univariate analysis revealed that local recurrence was associated with poor OS (P 
15. Shin Ishihara, Takeshi Iwasaki, Kenichi Kohashi, Kengo Kawaguchi, Yu Toda, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Yoshinao Oda, Clinical significance of signal regulatory protein alpha and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain expression in undifferentiated pleomorphic sarcoma., Journal of cancer research and clinical oncology, 10.1007/s00432-022-04078-y, 2022.06, PURPOSE: Undifferentiated pleomorphic sarcoma (UPS) is associated with poor prognosis. Recently, signal regulatory protein alpha (SIRPα), which is the immune checkpoint of macrophages, and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), which is the immune checkpoint of T cells and natural killer cells, have been considered as potential targets for cancer immunotherapy. This study aimed to assess the value of SIRPα and TIGIT as prognostic factors of UPS. MATERIALS AND METHODS: The cBio Cancer Genomics Portal was used to analyze mRNA expression data of 50 UPS cases in the Cancer Genome Atlas. We retrieved 49 UPS cases and performed immunohistochemistry (IHC) to detect programmed death ligand 1 (PD-L1), SIRPα, CD68, CD163, TIGIT, CD155, and CD8. RESULTS: SIRPα was positively associated with CD163 (Pearson's r = 0.51, p = 0.0002) as per open access data and IHC of the cohort (p = 0.002), which revealed that SIRPα-positive macrophage infiltration was higher in UPS cells with ≥ 1% PD-L1 expression than that in UPS cells with 
16. Makoto Endo, Shinya Kawahara, Taishi Sato, Masami Tokunaga, Toshihiko Hara, Taro Mawatari, Tsutomu Kawano, Sadamoto Zenda, Tempei Miyaji, Mototsugu Shimokawa, Sanae Sakamoto, Toshio Takano, Masumi Miyake, Hiroyuki Aono, Yasuharu Nakashima, Protocol for the RETHINK study: a randomised, double-blind, parallel-group, non-inferiority clinical trial comparing acetaminophen and NSAIDs for treatment of chronic pain in elderly patients with osteoarthritis of the hip and knee., BMJ open, 10.1136/bmjopen-2022-068220, 13, 2, e068220, 2023.02, INTRODUCTION: In patients with chronic pain, oral analgesics are essential treatment options to manage pain appropriately, improve activities of daily living abilities and achieve a higher quality of life (QOL). It is desirable to select analgesics for elderly patients based on comparative data on analgesic effect and risk of adverse events; however, there are few comparative studies so far. The purpose of this study is to determine whether the efficacy and safety of acetaminophen are non-inferior to non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of chronic pain associated with osteoarthritis of the hip and knee in elderly patients. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled, double-blind, parallel-group study to compare the analgesic effect and adverse events between acetaminophen or NSAIDs (loxoprofen or celecoxib). A total of 400 elderly patients with osteoarthritis of the hip and knee will be recruited from five institutions in Japan. Patients of 65 years or older with osteoarthritis-related pain will be registered and randomly assigned to acetaminophen, loxoprofen or celecoxib with 2:1:1 allocation. The primary endpoint is change in the Brief Pain Inventory (BPI) item 3 (worst pain) score from baseline to week 8. The secondary endpoints are BPI item 3 score change from baseline to week 4, health-related QOL measured by Short Form-8 Health Survey, and occurrence of adverse events including gastrointestinal disorders and abnormal liver function. Data will be analysed in accordance with a predefined statistical analysis plan. ETHICS AND DISSEMINATION: This study protocol was approved by the Kyushu University Hospital Certified Institutional Review Board for Clinical Trials on 28 January 2021 (KD2020004) and the chief executive of each participating hospital. The results of the study will be submitted to international peer-reviewed journals, and the main findings will be presented at international scientific conferences. TRIAL REGISTRATION NUMBER: jRCTs071200112..
17. Makoto Endo, Tomoko Kataoka, Toshifumi Fujiwara, Satoshi Tsukushi, Masanobu Takahashi, Eisuke Kobayashi, Yoko Yamada, Takaaki Tanaka, Yutaka Nezu, Hiroaki Hiraga, Junji Wasa, Akihito Nagano, Kenji Nakano, Robert Nakayama, Tetsuya Hamada, Masanori Kawano, Tomoaki Torigoe, Akio Sakamoto, Kunihiro Asanuma, Takeshi Morii, Ryunosuke Machida, Yuta Sekino, Haruhiko Fukuda, Yoshinao Oda, Toshifumi Ozaki, Kazuhiro Tanaka, Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib., BMC cancer, 10.1186/s12885-023-10693-w, 23, 1, 219-219, 2023.03, BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019..
18. Kengo Kawaguchi, Kenichi Kohashi, Taro Mori, Hidetaka Yamamoto, Takeshi Iwasaki, Izumi Kinoshita, Yosuke Susuki, Hiroshi Furukawa, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Yoshinao Oda, Prognostic implications of the immunohistochemical expression of perilipin 1 and adipophilin in high-grade liposarcoma., Journal of clinical pathology, 10.1136/jcp-2023-208814, 2023.05, AIMS: Liposarcoma is a malignant soft tissue tumour with adipocytic differentiation. Dedifferentiated liposarcoma (DDLS) and myxoid liposarcoma (MLS) are classified as high-grade liposarcomas. Lipid droplet-associated protein (also known as perilipin 1 (PLIN1)) is the predominant perilipin and has utility as a specific marker of adipogenic differentiation. Adipose differentiation-related protein (also known as adipophilin (ADRP)) is ubiquitously expressed in a range of tissues. High ADRP expression is reportedly a poor prognostic factor in several cancer types. However, no previous studies have examined the association between PLIN1 or ADRP expression and prognosis in sarcoma. This study therefore aimed to evaluate the association between PLIN1 or ADRP expression and prognosis in liposarcoma. METHODS: In total, 97 primary resection specimens (53 MLS and 44 DDLS) were examined in this study. PLIN1 and ADRP expression was evaluated by immunohistochemistry. Survival analyses were performed for MLS and DDLS. RESULTS: Of the 53 MLS specimens, 15 (28.3%) exhibited high PLIN1 expression. PLIN1 expression was not observed in DDLS specimens. High PLIN1 expression was significantly associated with increased disease-free survival (DFS) among patients with MLS (p=0.045). Distinct ADRP expression was observed in 13 of 53 (24.5%) MLS specimens and 5 of 44 (11.4%) DDLS specimens. High ADRP expression was associated with shorter overall survival (OS) in MLS (p=0.042) and DFS and shorter OS in DDLS (p=0.024 and p
19. 骨近傍に発生した高悪性度軟部肉腫の治療成績.
20. 傍脊椎部に発生した悪性神経鞘腫腫瘍の治療成績.
21. 上腕骨悪性腫瘍に対する腫瘍用人工肘関節置換術の治療成績の検討
【はじめに】上腕骨悪性腫瘍に対して腫瘍用人工肘関節を用いた再建術の治療成績について検討した.【対象と方法】2003年4月以降,当科で悪性腫瘍4例に対して広範切除後にHMRS(Stryker社)を用いて再建した.男性2例,女性2例で平均年齢60歳(58～62歳),観察期間は平均1年6ヵ月(11ヵ月～2年11ヵ月)であった.乳癌骨転移,甲状腺癌骨転移に対して上腕骨遠位端置換,脱分化型軟骨肉腫,骨肉腫に対して上腕骨全置換を施行した.術後関節可動域,患肢機能評価(MSTS),合併症,転帰について検討した.【結果】術後の肘関節平均可動域は屈曲109°,伸展-8°であった.MSTSは平均64%であり,合併症として脱分化型軟骨肉腫の1例で深部感染,局所再発を認め肩甲帯離断を行った.【考察】自験例では術後患肢機能は諸家の報告と大きな差はなかった.腫瘍用人工肘関節は局所制御率が高く,良好な上肢機能が得られ有用な再建法の1つである.(著者抄録).
22. 粘液型脂肪肉腫におけるFDG-PETの有用性の検討
【はじめに】粘液型脂肪肉腫は他の軟部肉腫と異なり肺外転移が多いことが知られており,フォローアップに注意を要する.今回,当科における粘液型脂肪肉腫のFDG-PET検査結果および転移巣検索,治療効果判定におけるFDG-PETの有用性を後方視的に検討した.【対象と方法】当院へのPET導入以降,粘液型脂肪肉腫に対して治療前もしくは遠隔転移検索時にFDG-PETを施行した11例14病巣を対象とし,調査を行った.【結果】原発巣,転移巣共に7病巣ずつFDG-PETを施行しており,平均SUVmaxは原発巣が平均2.5±0.5,転移巣が平均2.7±1.6であり有意差は認めなかった(p=0.81).転移巣は脊椎転移の1病巣のみ偽陰性だったが,他はすべて異常集積として検出可能であった.化学療法前後にFDG-PETを撮影したものが2病巣あり,いずれも化学療法後には異常集積が低下し,治療効果ありと判定した.【考察】FDG-PETは,粘液型脂肪肉腫において多くの転移巣を検出可能であるが,脊椎転移では偽陰性の可能性があり注意を要する.また,FDG-PETは治療効果判定において有用となり得る.(著者抄録).
23. パスツール処理骨を用いた再建術の10年以上の長期臨床成績.
24. 原発性悪性脊椎脊髄腫瘍に対する、重粒子線を併用したSeparation surgeryの治療成績.
25. Yoshihiro Araki, Norio Yamamoto, Yoshikazu Tanzawa, Takahiro Higashi, Aya Kuchiba, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Makoto Endo, Eisuke Kobayashi, Hiroyuki Tsuchiya, Akira Kawai, Family cancer history and smoking habit associated with sarcoma in a Japanese population study., Scientific reports, 10.1038/s41598-022-21500-0, 12, 1, 17129-17129, 2022.10, Sarcoma is a rare cancer, and little is known about the etiology, lifestyle epidemiology, and actual circumstances of treatment in hospitals in Japan. Understanding these issues is essential for the effective prevention and treatment of sarcoma. We therefore investigated the incidence of a personal and family cancer history in a total of 1320 sarcoma patients at the National Cancer Center Hospital. In addition, obesity, hypertension, dyslipidemia, diabetes mellitus, drinking, smoking, age and sex were compared in a descriptive study of 1159 of these sarcoma patients who were ≥ 20 years of age, and 7738 controls derived from the National Health and Nutrition Examination Survey in Japan. A total of 8% of sarcoma patients had a personal history of another cancer, and 30% of soft tissue sarcoma patients had a family cancer history in a first-degree relative (malignant peripheral nerve sheath tumor, 52%; leiomyosarcoma, 46%). A smoking habit was associated with the development of sarcoma (odds ratio [OR], 2.05; 95% confidence interval, 1.78-2.37; p 
26. Takeshi Morii, Ukei Anazawa, Chiaki Sato, Shintaro Iwata, Makoto Nakagawa, Makoto Endo, Tomoki Nakamura, Kunihiro Ikuta, Yoshihiro Nishida, Robert Nakayama, Toru Udaka, Teruya Kawamoto, Munehisa Kito, Kenji Sato, Jungo Imanishi, Toru Akiyama, Hiroshi Kobayashi, Akihito Nagano, Hidetatsu Outani, Shunichi Toki, Toshihiko Nishisho, Keita Sasa, Yoshiyuki Suehara, Hirotaka Kawano, Takafumi Ueda, Hideo Morioka, Dedifferentiated liposarcoma in the extremity and trunk wall: A multi-institutional study of 132 cases by the Japanese Musculoskeletal Oncology Group (JMOG), European Journal of Surgical Oncology, 10.1016/j.ejso.2022.08.024, 2022.09, BACKGROUND: Dedifferentiated liposarcoma occurs predominantly in the retroperitoneum. Given the paucity of cases, information on the clinical characteristics of this entity in the extremities and trunk wall is quite limited. In particular, the significance of preoperative evaluation and principles of intraoperative management of the different components, i.e., well-differentiated and dedifferentiated areas, are still to be defined. METHODS: Clinical characteristics, treatment outcomes, and risk factors for poor oncological outcomes in cases of dedifferentiated liposarcoma in the extremity or trunk wall were analyzed by a retrospective, multicentric study. RESULTS: A total of 132 patients were included. The mean duration from the initial presentation to dedifferentiation was 101 months in dedifferentiation-type cases. The 5-year local recurrence-free survival, metastasis-free survival, and disease-specific survival rates were 71.6%, 75.7%, and 84.7%, respectively. Among 32 patients with metastasis, 15 presented with extrapulmonary metastasis. A percentage of dedifferentiated area over 87.5%, marginal/intralesional margin, and R1/2 resection in the dedifferentiated area were independent risk factors for local recurrence. Dedifferentiated areas over 36 cm2, French Federation of Cancer Centers Sarcoma Group grade III, and intralesional or marginal resection were independent risk factors for metastasis. A dedifferentiated area over 77 cm2 and lung metastasis were independent risk factors for disease-specific mortality. CONCLUSIONS: The typical clinical characteristics of dedifferentiated liposarcoma in the extremity and trunk wall were reconfirmed in the largest cohort ever. The evaluation of the dedifferentiated area in terms of grade, extension, and pathological margin, together with securing adequate surgical margins, was critical in the management of this entity..
27. Yoshinao Oda, Kazuhiro Tanaka, Takanori Hirose, Tadashi Hasegawa, Nobuyuki Hiruta, Masanori Hisaoka, Masato Yoshimoto, Hiroshi Otsuka, Hirofumi Bekki, Takeaki Ishii, Makoto Endo, Toshiyuki Kunisada, Toru Hiruma, Hiroyuki Tsuchiya, Hirohisa Katagiri, Yoshihiro Matsumoto, Akira Kawai, Robert Nakayama, Hiroyuki Kawashima, Satoshi Takenaka, Makoto Emori, Munenori Watanuki, Yukihiro Yoshida, Takeshi Okamoto, Junki Mizusawa, Haruhiko Fukuda, Toshifumi Ozaki, Yukihide Iwamoto, Takayuki Nojima, Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas., BMC cancer, 10.1186/s12885-022-09195-y, 22, 1, 94-94, 2022.01, BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor 
28. Yu Toda, Yuichi Yamada, Kenichi Kohashi, Shin Ishihara, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Daisuke Kiyozawa, Taro Mori, Yusuke Kuboyama, Yuki Tateishi, Hidetaka Yamamoto, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda, Prognostic implication of desmoplastic stroma in synovial sarcoma: a histological review, Pathology - Research and Practice, 10.1016/j.prp.2021.153668, 153668-153668, 2021.10.
29. Shimada E, Endo M, Matsumoto Y, Tsuchihashi K, Ito M, Kusaba H, Nabeshima A, Nawata T, Maekawa A, Matsunobu T, Setsu N, Fujiwara T, Iida K, Nakagawa M, Hirose T, Kanahori M, Oyama R, Isobe T, Ariyama H, Kohashi K, Yamamoto H, Oda Y, Iwamoto Y, Akashi K, Baba E, Nakashima Y, Does the Use of Peripheral Immune-Related Markers Indicate Whether to Administer Pazopanib, Trabectedin, or Eribulin to Advanced Soft Tissue Sarcoma Patients?, Journal of Clinical Medicine, 10.3390/jcm10214972, 10, 21, 4972-4972, 2021.10.
30. Makoto Nakagawa, Masaya Sekimizu, Makoto Endo, Eisuke Kobayashi, Shintaro Iwata, Suguru Fukushima, Akihiko Yoshida, Issay Kitabayashi, Hitoshi Ichikawa, Akira Kawai, Fumihiko Nakatani, Prognostic impact of IDH mutations in chondrosarcoma, Journal of Orthopaedic Science, 10.1016/j.jos.2021.07.024, 2021.09.
31. Eijiro Shimada, Yoshihiro Matsumoto, Makoto Endo, Nokitaka Setsu, Toshifumi Fujiwara, Kenichiro Yahiro, Atsushi Kimura, Yasuharu Nakashima, Clinical benefits of vessel sealing system (LigaSure™) during surgery for soft tissue sarcoma: a propensity score matching analysis, Japanese Journal of Clinical Oncology, 10.1093/jjco/hyab083, 51, 8, 1242-1247, 2021.08, Abstract

Background
Soft tissue sarcomas arise in the deep sites of the buttocks and lower extremities. Since a tourniquet is not applied during surgery for soft tissue sarcomas at such sites, excessive intraoperative blood loss may occur. Various devices, including LigaSure™ (Medtronic, Dublin, Ireland), are used as electrothermal bipolar vessel sealers. However, its clinical relevance in soft tissue sarcomas surgery remains unclear. This study aimed to assess the effectiveness of LigaSure™ in soft tissue sarcomas surgery.




Methods
This study included 168 patients who underwent surgeries for soft tissue sarcomas in the deep sites in the buttocks and lower extremities between January 2004 and March 2018. The primary outcome was intraoperative blood loss, and secondary outcomes were surgery duration, wound complications, perioperative haemoglobin concentrations and intraoperative blood transfusion. To reduce selection biases, propensity score matching was applied. We defined the matched cases wherein LigaSure™ was used as the ‘using group’ and the other matched cases as the ‘non-using group’. Outcomes were compared between both groups.




Results
From each group, 35 cases were selected using propensity score matching. The intraoperative blood loss was significantly smaller statistically in the using group (181.5 ± 240.4 ml vs. 394.7 ± 547.3 ml, respectively; P = 0.041). The duration of operation was longer in the using group (189.9 ± 97.6 min vs. 140.6 ± 75.7 min, respectively; P = 0.007). There were no significant differences in other outcomes.




Conclusion
By using LigaSure™ for soft tissue sarcomas occurring in the buttocks and lower extremities, we observed a trade-off between reduced intraoperative blood loss and longer operative time.


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32. Yoshihiro Ito, Kenichi Kohashi, Makoto Endo, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yosuke Susuki, Kengo Kawaguchi, Hiroshi Furukawa, Yuki Tateishi, Yuichi Yamada, Izumi Kinoshita, Taro Mori, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda, Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation, Virchows Archiv, 10.1007/s00428-021-03189-0, 2021.08.
33. Koichiro Yoshimaru, Tomoaki Taguchi, Tetsuhiro Fujiyoshi, Tomoko Kono, Nway Nway Thin Aung, Mya Thanda Than, Yin Mar Oo, Thandar Oo, Mariko Kakazu, Ko Miyazaki, Yuichi Shibui, Yoshiaki Takahashi, Kenichi Kohashi, Ei Ei Shwe, Kenji Tsuchihashi, Makoto Endo, Toshiharu Matsuura, Yoshinao Oda, Aye Aye, Haruna Yoshioka, Hideto Yoshioka, Surgical Extirpation of a Huge Desmoid Fibromatosis of the Right Buttock: Case Report of a Successful International Collaboration, SN Comprehensive Clinical Medicine, 10.1007/s42399-021-00860-0, 3, 8, 1746-1751, 2021.08.
34. Ishihara, Shin, Iwasaki, Takeshi, Kohashi, Kenichi, Yamada, Yuichi, Toda, Yu, Ito, Yoshihiro, Susuki, Yousuke, Kawaguchi, Kengo, Takamatsu, Dai, Kawatoko, Shinichiro, Kiyozawa, Daisuke, Mori, Taro, Kinoshita, Izumi, Yamamoto, Hidetaka, Fujiwara, Toshifumi, Setsu, Nokitaka, Endo, Makoto, Matsumoto, Yoshihiro, Nakashima, Yasuharu, Oda, Yoshinao, The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma, JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 10.1007/s00432-021-03616-4, 147, 7, 2021.04.
35. Chen, Tom Wei-Wu, Pang, Angela, Puhaindran, Mark E., Maw, Myo Myint, Loong, Herbert H., Sriuranpong, Virote, Chang, Chih-Chi, Mingmalairak, Siyamol, Hirose, Takeshi, Endo, Makoto, Kawai, Akira, Farid, Mohamad, Tan, Sze Huey, Goh, Wei Lin, Quek, Richard, Chan, Jeffrey C. H., Leung, Alex K. C., Ngan, Roger K. C., The treatment landscape of advanced angiosarcoma in Asia-A multi-national collaboration from the Asian Sarcoma Consortium, CANCER SCIENCE, 10.1111/cas.14793, 112, 3, 1095-1104, 2021.03.
36. Takeshi Hirose, Masachika Ikegami, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Hiroyuki Mano, Shinji Kohsaka, Extensive functional evaluation of exon 20 insertion mutations of EGFR, Lung Cancer, 10.1016/j.lungcan.2020.12.023, 152, 135-142, 2021.02.
37. Youngji Kim, Eisuke Kobayashi, Yoshiyuki Suehara, Ayumu Ito, Daisuke Kubota, Yoshikazu Tanzawa, Makoto Endo, Fumihiko Nakatani, Tetsuya Nakatsura, Akira Kawai, Kazuo Kaneko, Shigehisa Kitano, Immunological status of peripheral blood is associated with prognosis in patients with bone and soft-tissue sarcoma, Oncology Letters, 10.3892/ol.2021.12473, 21, 3, 2021.01.
38. Yoshihiro Matsumoto, Hirokazu Saiwai, Keiichiro Iida, Seiji Okada, Makoto Endo, Nokitaka Setsu, Toshifumi Fujiwara, Kenichi Kawaguchi, Yasuharu Nakashima, Shape Factor of the Spinal Cord: A Possible Predictor of Surgical Outcome for Intradural Extramedullary Spinal Tumors in the Thoracic Spine, Global Spine Journal, 10.1177/2192568220982571, 219256822098257-219256822098257, 2021.01, Study Design: Retrospective diagnostic analysis.

Objectives: To establish a new predictor of surgical outcome after surgery for intradural extramedullary spinal tumor (IDEMT) in the thoracic spine, we introduced shape factor (SF), a mathematical description of the morphology of the spinal cord. SF was calculated by dividing object area by the square of perimeter.

Materials and Methods: Forty-three consecutive patients with IDEMT, detected by magnetic resonance imaging at the thoracic level with myelopathic signs, were included. Preoperative transverse cross-sectional area (CSA) and perimeter of the spinal cord (perimeter) at the level of maximal compression were measured. SF was calculated as 4π × CSA/(perimeter)2. The association between clinicoradiological factors and surgical outcome of IDEMT was statistically analyzed.

Results: Mean CSA, perimeter, and SF were 27.8 ± 15.8 mm2, 28.8 ± 6.1 mm, and 0.385 ± 0.14, respectively. A histogram distribution revealed that perimeter and SF, but not CSA, fit the normal distribution. The patients were subdivided into 2 groups according to postoperative modified Japanese Orthopedic Association Score (mJOA). [group F (favorable): n = 32, mJOA ≥ 9; group UF (unfavorable): n = 11, mJOA < 9). Group UF had significantly lower mean CSA and SF. In univariate analysis of possible predictive factors for IDEMT surgery, greater age, lower preoperative mJOA, and lower SF were significantly associated with unfavorable outcome. In multivariate analysis, lower SF was the only significant predictor of postoperative outcome (odds ratio = 2.66, 95% CI 1.10–6.39, p = 0.0115).

Conclusion: Measurements of CSA and perimeter, followed by calculation of SF, may provide valuable quantitative information for the outcome of surgery for IDEMT.

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39. Tsuchihashi, Kenji, Kusaba, Hitoshi, Yoshihiro, Tomoyasu, Fujiwara, Toshifumi, Setsu, Nokitaka, Endo, Makoto, Matsumoto, Yoshihiro, Imajima, Takashi, Shinohara, Yudai, Ito, Mamoru, Yamaga, Satoru, Tanoue, Kenro, Arimizu, Kohei, Ohmura, Hirofumi, Hanamura, Fumiyasu, Yamaguchi, Kyoko, Isobe, Taichi, Ariyama, Hiroshi, Nakashima, Yasuharu, Akashi, Koichi, Baba, Eishi, Eribulin as a first-line treatment for soft tissue sarcoma patients with contraindications for doxorubicin, SCIENTIFIC REPORTS, 10.1038/s41598-020-77898-y, 10, 1, 2020.12.
40. Nakayama, Robert, Hayakawa, Keiko, Kobayashi, Eisuke, Endo, Makoto, Asano, Naofumi, Yonemoto, Tsukasa, Kawashima, Hiroyuki, Hamada, Kenichiro, Watanabe, Itsuo, Futani, Hiroyuki, Goto, Takahiro, Nishida, Yoshihiro, Ozaki, Toshifumi, What Factors Are Associated with Treatment Outcomes of Japanese Patients with Clear Cell Chondrosarcoma?, CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, 10.1097/CORR.0000000000001266, 478, 11, 2537-2547, 2020.11.
41. Outani, Hidetatsu, Kobayashi, Eisuke, Wasa, Junji, Saito, Masato, Takenaka, Satoshi, Hayakawa, Keiko, Endo, Makoto, Takeuchi, Akihiko, Kobayashi, Hiroshi, Kito, Munehisa, Morii, Takeshi, Imanishi, Jungo, Ueda, Takafumi, Clinical Outcomes of Patients with Metastatic Solitary Fibrous Tumors: A Japanese Musculoskeletal Oncology Group (JMOG) Multiinstitutional Study, ANNALS OF SURGICAL ONCOLOGY, 10.1245/s10434-020-09306-8, 28, 7, 2020.11.
42. Fujiwara, Toshifumi, Ebihara, Toshihiro, Kitade, Kazuki, Setsu, Nokitaka, Endo, Makoto, Iida, Keiichiro, Matsumoto, Yoshihiro, Matsunobu, Tomoya, Oda, Yoshinao, Iwamoto, Yukihide, Nakashima, Yasuharu, Risk Factors of Periprosthetic Infection in Patients with Tumor Prostheses Following Resection for Musculoskeletal Tumor of the Lower Limb, JOURNAL OF CLINICAL MEDICINE, 10.3390/jcm9103133, 9, 10, 2020.10.
43. Ichigatani A, Hanada M, Kadota H, Yoshida S, Setsu N, Makoto Endo, Matsumoto Y, Nakashima Y, Appropriate Wound Closure after Malignant Soft Tissue Tumor Excision: Need for Flap Surgery in Recurrent Tumors, Fukuoka Acta Medica, 111, 2, 86-91, 2020.06.
44. Kenta Nio, Kenji Tsuchihashi, Keisuke Taguchi, Tomoyasu Yoshihiro, Kyoko Yamaguchi, Mamoru Ito, Shohei Moriyama, Mitsuhiro Fukata, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Takahiro Wakasaki, Ryuji Yasumatsu, Hiroshi Ariyama, Hitoshi Kusaba, Junji Kishimoto, Koichi Akashi, Eishi Baba, Exploratory retrospective study of risk factors for thromboembolism treated with multi-kinase inhibitor pazopanib or lenvatinib, International Journal of Surgery: Oncology, 10.1097/ij9.0000000000000089, 5, 4, 89-89, 2020.06.
45. Kenichiro Yahiro, Yoshihiro Matsumoto, Hisakata Yamada, Makoto Endo, Nokitaka Setsu, Toshifumi Fujiwara, Makoto Nakagawa, Atsushi Kimura, Eijiro Shimada, Seiji Okada, Yoshinao Oda, Yasuharu Nakashima, Activation of TLR4 signaling inhibits progression of osteosarcoma by stimulating CD8-positive cytotoxic lymphocytes, Cancer Immunology, Immunotherapy, 10.1007/s00262-020-02508-9, 69, 5, 745-758, 2020.05, Background: Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis of advanced cases is still poor. Recently, there have been several reports suggesting the relationship between innate immunity and OS, but the detailed mechanism is unknown. We demonstrate the relationship between OS and Toll-like receptor 4 (TLR4) which is one of the most important factors in innate immunity. Methods: We established a syngenic mouse tumor model using C3H/HeN, C3H/HeJ mouse and a highly metastatic OS cell line, LM8. TLR4 activation with lipopolysaccharide (LPS) was performed on both mice and its influence on the progression of OS was evaluated. We also performed CD8 + cells depletion to examine the influence on TLR4 activation effects. Results: Tumor volume of C3H/HeN mice was significantly smaller and overall survival of C3H/HeN mice was significantly longer than C3H/HeJ mice. We found more CD8+ cells infiltrating in lung metastases of C3H/HeN mice and depletion of CD8+ cells canceled the antitumor effects of LPS. Conclusion: TLR4 activation by LPS increased CD8+ cells infiltrating into lung metastases and suppressed OS progression in the mouse model. TLR4 activation may suppress the progression of OS via stimulating CD8+ cells and can be expected as a novel treatment for OS..
46. Fumiko Kito, Rieko Oyama, Rei Noguchi, Emi Hattori, Marimu Sakumoto, Makoto Endo, Eisuke Kobayashi, Akihiko Yoshida, Akira Kawai, Tadashi Kondo, Establishment and characterization of novel patient-derived extraskeletal osteosarcoma cell line NCC-ESOS1-C1., Human cell, 10.1007/s13577-019-00291-z, 33, 1, 283-290, 2020.01, Extraskeletal osteosarcoma (ESOS) is a rare mesenchymal malignancy producing osteoid and bone in soft tissue without skeletal attachment. ESOS exhibits chemoresistance and poor prognosis, and is distinct from osseous osteosarcoma. The biological characteristics of ESOS are not fully understood, and patient-derived cell lines of ESOS are not available from public cell banks. Here, we established a novel cell line of ESOS and characterized its genetic and biological characteristics as well as examined its response to anti-cancer reagents. The cell line was established using tumor tissue from a 58-year-old female patient with ESOS, and named as NCC-ESOS1-C1. Phenotypes relevant to malignancy such as proliferation and invasion were examined in vitro, and genetic features were evaluated using the NCC Oncopanel assay. The response to inhibitors was monitored by screening of an anti-cancer reagent library. The cells constantly proliferated, showing spheroid formation and invasion capabilities. The NCC Oncopanel revealed the presence of actionable mutations in PIK3CA. Library screening revealed the presence of anti-cancer reagents with significant anti-proliferative effects on NCC-ESOS1-C1 at a low concentration. In conclusion, we established and characterized a novel ESOS cell line, NCC-ESOS1-C1. This cell line will be a useful resource for basic research and preclinical studies..
47. Makoto Endo, Shunji Takahashi, Nobuhito Araki, Hideshi Sugiura, Takafumi Ueda, Tsukasa Yonemoto, Mitsuru Takahashi, Hideo Morioka, Hiroaki Hiraga, Toru Hiruma, Toshiyuki Kunisada, Akihiko Matsumine, Kazato Goda, Akira Kawai, Time lapse analysis of tumor response in patients with soft tissue sarcoma treated with trabectedin A pooled analysis of two phase II clinical trials, Cancer Medicine, 10.1002/cam4.2991, 2020.01, The time course of the response to each drug is important to avoid inappropriate termination of treatment by misjudging tumor progression; however, little is known about soft tissue sarcoma (STS) regarding this matter. This study aimed to perform a time-lapse analysis of tumor response in patients with STS treated with trabectedin from 2 phase II clinical trials. We examined 66 patients with translocation-related sarcoma registered in 2 Japanese phase II clinical trials. All patients previously received standard therapy before the administration of trabectedin at 1.2 mg/m2 every 3 weeks. Imaging evaluation was performed according to the study protocol. The sum of the maximum diameters of the target lesions was calculated and analyzed over time. Among the 66 patients, 9 (13.6%) showed partial response (PR) to trabectedin. Histological diagnoses of these 9 responders comprised 6 myxoid liposarcoma, 2 synovial sarcoma, and a mesenchymal chondrosarcoma. The median period from treatment initiation to the first PR was 123 (range, 34-328) days. The pattern of tumor response to trabectedin showed an increasing tendency in size in the initial stage, usually followed by a size decrease with repeated administration. STS response to trabectedin was characterized as delayed and potentially persistent. Clinicians treating STS with trabectedin should know the features of the response pattern to avoid interrupting the treatment before maximal efficacy is achieved..
48. Robert Nakayama, Tomoaki Mori, Yusuke Okita, Yutaka Shiraishi, Makoto Endo, A multidisciplinary approach to soft-tissue sarcoma of the extremities, Expert Review of Anticancer Therapy, 10.1080/14737140.2020.1814150, 2020, Introduction: Soft-tissue sarcoma (STS) denotes a group of rare and highly heterogeneous malignant tumors of mesenchymal origin. Accurate histological diagnosis is critical for selecting appropriate treatment. Complete tumor resection is the primary treatment for STS, and the efficacies of radiotherapy and chemotherapy have been tested in the adjuvant setting to improve oncological outcomes. Because most STS lesions arise in the extremities, preserving limb function and managing limb impairment after radical local treatment represent significant challenges. Areas covered: This article reviews the current front-line treatments for patients with extremity STS and discusses the multidisciplinary team-based efforts needed to improve oncological outcomes and survivorship. Expert opinion: Given the rarity, variety, and complexity of STS, a multidisciplinary approach involving experts in various disciplines is vital for improving outcomes in patients ranging from diagnosis to survivorship. A major challenge is building a sustainable system in each region permitting all patients with extremity STS to be treated at high-volume centers with multidisciplinary teams dedicated to this rare and complex disease..
49. Yoshihiro Matsumoto, Akira Matsunobu, Kenichi Kawaguchi, Mistumasa Hayashida, Keiichiro Iida, Hirokazu Saiwai, Seiji Okada, Makoto Endo, Nokitaka Setsu, Toshifumi Fujiwara, Shingo Baba, Satoshi Nomoto, Yasuharu Nakashima, Clinical results of carbon-ion radiotherapy with separation surgery for primary spine/paraspinal sarcomas, International Journal of Clinical Oncology, 10.1007/s10147-019-01505-y, 24, 11, 1490-1497, 2019.11, Purpose: To evaluate the clinical outcome of combination of carbon-ion radiotherapy with separation surgery (CIRT-SS) in patients with primary spinal/paraspinal sarcoma (PSPS) and epidural spinal cord compression (ESCC). Methods: CIRT-SS was performed in 11 consecutive patients. Patients treated in the primary and salvage settings were categorized into Group A (n = 8) and Group B (n = 3), respectively. Clinical results and imaging findings were collected, with a particular focus on ESCC grade, treatment-associated adverse events (AEs), and the locoregional control (LRC) rate and overall survival (OS). Results: The median follow-up period from the start of CIRT-SS was 25 months (7–57 months). ESCC was improved by SS in all cases. No patients exhibited radiation-induced myelopathy (RIM), but three developed Grade 3 vertebral compression fracture (VCF) during follow-up. Locoregional recurrences were observed in four patients [Group A: 1 (12.5%), Group B: 3 (100%)]. Over the entire follow-up period, three patients developed distant metastases and two patients died. The 2-year LRC rate and OS were 70% and 80%, respectively. Conclusion: CIRT-SS in the primary setting achieved acceptable LRC and OS without RIM in patients with PSPS and with ESCC. VCF was the most frequent AE associated with CIRT-SS..
50. Eisuke Kobayashi, Yoichi Naito, Naofumi Asano, Aiko Maejima, Makoto Endo, Shunji Takahashi, Yasunori Megumi, Akira Kawai, Interim results of a real-world observational study of eribulin in soft tissue sarcoma including rare subtypes, Japanese journal of clinical oncology, 10.1093/jjco/hyz096, 49, 10, 938-946, 2019.11, Background: Although eribulin is used to treat soft tissue sarcomas (STSs), treatment data for rare subtypes are limited. We conducted a post-marketing surveillance study to assess safety and efficacy of eribulin in STS patients stratified by subtype. Methods: Japanese patients (n = 256) with advanced or metastatic STS receiving eribulin treatment were monitored for treatment status, adverse events, diagnostic imaging, and clinical outcomes at 3 months and 1 year. Interim analysis was performed. Patients will be monitored up to 2 years. Results: Interim analysis included 3-month (n = 255), imaging (n = 226), and 1-year (n = 105) data. STS subtype distribution was normal. Median number of eribulin cycles was 3.0 (range: 1-17 cycles). Among patients with imaging data, best overall tumor response (12 weeks) was partial response, 7.5% (n = 17); stable disease, 34.5% (n = 78); and stable disease ≥11 weeks, 10.2% (n = 23). Overall response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) for all patients were 7.5%, 42.0% and 17.7%, respectively. ORR, DCR, and CBR were 10.3%, 32.0% and 16.5%, respectively, for patients with STS subtypes other than liposarcoma and leiomyosarcoma and included responses from patients with rare STS subtypes. Adverse drug reactions (ADRs) occurred in 211 (82.7%) patients (42 [16.5%] patients had serious ADRs), and none led to death. ADRs leading to drug withdrawal and dose reduction occurred in 27 (10.6%) and 55 (21.6%) patients, respectively. Conclusion: Eribulin was generally well tolerated and showed antitumor activity against STSs, including rare subtypes that currently have few treatment options. Clinical trial number: NCT03058406 (ClinicalTrials.gov)..
51. Makoto Nakagawa, Fumihiko Nakatani, Hironori Matsunaga, Takahiko Seki, Makoto Endo, Yoko Ogawara, Yukino Machida, Takuo Katsumoto, Kazutsune Yamagata, Ayuna Hattori, Shuhei Fujita, Yukiko Aikawa, Takamasa Ishikawa, Tomoyoshi Soga, Akira Kawai, Hirokazu Chuman, Nobuhiko Yokoyama, Suguru Fukushima, Kenichiro Yahiro, Atsushi Kimura, Eijiro Shimada, Takeshi Hirose, Toshifumi Fujiwara, Nokitaka Setsu, Yoshihiro Matsumoto, Yukihide Iwamoto, Yasuharu Nakashima, Issay Kitabayashi, Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma, Oncogene, 10.1038/s41388-019-0929-9, 38, 42, 6835-6849, 2019.10, Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma..
52. Makoto Endo, Nokitaka Setsu, Toshifumi Fujiwara, Takeaki Ishii, Makoto Nakagawa, Kenichiro Yahiro, Atsushi Kimura, Eijiro Shimada, Yasuharu Nakashima, Yoshihiro Matsumoto, Diagnosis and Management of Subcutaneous Soft Tissue Sarcoma, Current Treatment Options in Oncology, 10.1007/s11864-019-0656-z, 20, 7, 2019.07, The proper diagnosis and treatment planning for subcutaneous soft tissue sarcoma is very important. Soft tissue tumors can occur anywhere in the body, but if they occur subcutaneously, patients can easily notice a subcutaneous soft tissue mass. Therefore, it is possible to determine through recording, the growth speed of the mass, which is often difficult to obtain with deep-situated soft tissue masses. Palpation can also provide information about the firmness and mobility of the mass. Thus, history taking and physical examinations are informative for subcutaneous soft tissue tumors, compared to tumors that occur deeply. Because subcutaneous soft tissue tumors are easily recognized, they are often resected, without sufficient imaging analyses or thorough treatment planning. An operation performed based on such an inadequate preoperative plan is called a “whoops surgery.” In the case of “whoops surgeries,” subsequent radical surgery is required to remove additional areas, including hematomas that result from the initial surgery, that require a wider range of resection and soft tissue reconstruction. Therefore, as with deep-seated soft tissue tumors, it is important to conduct careful imaging examinations and make appropriate preoperative plans for subcutaneous soft tissue tumors. Subcutaneous soft tissue sarcomas often show an invasive pattern, and such tumors require a more careful assessment to prevent local recurrence after surgery. During surgery, it is necessary to remove the entire infiltration area along the fascia. Sometimes, an adequately wide excision is necessary, which is considered the minimum necessary procedure to eradicate the lesion. As noted above, clinicians who see patients with subcutaneous soft tissue tumors are encouraged to have sufficient knowledge and experience regarding the diagnosis and treatment. This article is intended for all doctors who deal with subcutaneous soft tissue tumors and focuses on essential points regarding their diagnosis and management..
53. Koichi Ogura, Kosuke Uehara, Toru Akiyama, Yusuke Shinoda, Shintaro Iwata, Satoshi Tsukushi, Eisuke Kobayashi, Takeshi Hirose, Tsukasa Yonemoto, Makoto Endo, Yoshikazu Tanzawa, Fumihiko Nakatani, Hirotaka Kawano, Sakae Tanaka, Akira Kawai, Development of a patient-oriented disease specific outcome measure of health-related quality of life (HRQOL) for musculoskeletal oncology patients, Journal of Orthopaedic Science, 10.1016/j.jos.2018.10.020, 24, 3, 539-547, 2019.05, Background: According to improved functional outcome and life expectancy in orthopaedic oncology patients, there has been a growing interest in not only oncologic and functional outcomes but also health-related quality of life (HRQOL), including body image, mental status, or social activities, after surgery. However, there has been a lack of disease-specific measures focusing on the ability of orthopaedic oncology patients to evaluate their HRQOL comprehensively. Therefore, our aims in the present study were 1) to develop a patient-oriented disease-specific outcome measure of HRQOL for musculoskeletal oncology patients (COMMON-LE), and 2) to examine the practical applicability, reliability and validity of the COMMON-LE for patients with musculoskeletal tumors in the lower extremity. Methods: The COMMON-LE was developed by expert committee of orthopaedic oncology and rehabilitation. A total of 101 patients were surveyed using the COMMON-LE, as well as the TESS, the MSTS score, and the SF-36, to assess their psychometric characteristics, including reliability, validity, and responsiveness. Results: The COMMON-LE showed no marked floor and ceiling effects. Test-retest reliability and internal consistency determined using the intraclass correlation coefficient (0.928) and Cronbach's alpha (0.948–0.968), respectively, were excellent. Each domain of the COMMON-LE (pain, ADL, socioemotional condition and general health) was well correlated with the scores of the standard measures (SF-36, TESS, MSTS score). Factor analysis and the AIC network showed the questionnaire items of the COMMON-LE were clearly separable into three clusters according to their content, corresponding to each domain of the questionnaire. Conclusions: We have successfully developed and validated a disease-specific measure, the COMMON-LE, to evaluate not only physical function, but also various aspects of HRQOL in patients with musculoskeletal tumors. The COMMON-LE has sufficient reliability and internal consistency, and good validity, and appears to be practically applicable to this group of patients..
54. Nikita Patel, Juehong Wang, Kumiko Shiozawa, Kevin B. Jones, Yanfeng Zhang, Jeremy W. Prokop, George G. Davenport, Naoe T. Nihira, Zhenyue Hao, Derek Wong, Laurel Brandsmeier, Sarah K. Meadows, Arthur V. Sampaio, Ryan Vander Werff, Makoto Endo, Mario R. Capecchi, Kelly M. McNagny, Tak W. Mak, Torsten O. Nielsen, T. Michael Underhill, Richard M. Myers, Tadashi Kondo, Le Su, HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression, iScience, 10.1016/j.isci.2019.02.008, 13, 43-54, 2019.03, Histone deacetylases (HDACs)are promising targets for cancer therapy, although their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in the regulation of MDM2 acetylation at previously uncharacterized lysines. Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 ubiquitin ligase E3 (MULE). This mechanism further reveals a therapeutic connection between the MULE ubiquitin ligase function and tumor suppression. Specifically, we show that HDAC inhibitor treatment promotes the accumulation of MULE, which diminishes the t(X; 18)translocation-associated synovial sarcomagenesis by directly targeting the fusion product SS18-SSX for degradation. These results uncover a new HDAC2-dependent pathway that integrates reversible acetylation signaling to the anticancer ubiquitin response..
55. Akihiko Takeuchi, Akihiro Nomura, Norio Yamamoto, Katsuhiro Hayashi, Kentaro Igarashi, Susumu Tandai, Akira Kawai, Akihiko Matsumine, Shinji Miwa, Yoshihiro Nishida, Tomoki Nakamura, Ryu Terauchi, Manabu Hoshi, Toshiyuki Kunisada, Makoto Endo, Kenichi Yoshimura, Toshinori Murayama, Hiroyuki Tsuchiya, Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors A study protocol, BMC Musculoskeletal Disorders, 10.1186/s12891-019-2453-z, 20, 1, 2019.02, Background: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue. Diffuse TGCT (D-TGCT) most commonly develops in the knee, followed by the hip, ankle, elbow, and shoulder. Surgical removal is the only effective treatment option for the patients. However, a local recurrence rate as high as 47% has been reported. Recently, we revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. It plays an important role in the differentiation of adipocytes from precursor cells and exhibits antitumorigenic effects on certain malignancies. Therefore, we are conducting this investigator-initiated clinical trial to evaluate whether zaltoprofen is safe and effective for patients with D-TGCT or unresectable localized TGCT (L-TGCT). Methods: This study is a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with D-TGCT or L-TGCT. For the treatment group, zaltoprofen 480 mg/day will be administered for 48 weeks; the placebo group will receive similar dosages without zaltoprofen. Twenty participants in each group are needed in this trial (40 participants total). The primary outcome is the progression-free rate at 48 weeks after treatment administration. "Progression" is defined as any serious events (1. Repetitive joint swelling due to hemorrhage, 2. Joint range of motion limitation, 3. Invasion of adjacent cartilage or bone, 4. Severe joint space narrowing, 5. Increase in tumor size) requiring surgical interventions. We hypothesize that the zaltoprofen group will have a higher progression-free rate compared to that of the placebo group at 48 weeks. Discussion: This is the first study to evaluate the efficacy of zaltoprofen in patients with D-TGCT or unresectable L-TGCT. We believe that the results of this trial will validate a novel treatment option, zaltoprofen, to stabilize disease progression for TGCT patients. Trial registration: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000025901) registered on 4/01/2017..
56. Koichi Ogura, Kosuke Uehara, Toru Akiyama, Yusuke Shinoda, Shintaro Iwata, Satoshi Tsukushi, Eisuke Kobayashi, Takeshi Hirose, Tsukasa Yonemoto, Makoto Endo, Yoshikazu Tanzawa, Fumihiko Nakatani, Hirotaka Kawano, Sakae Tanaka, Akira Kawai, Minimal clinically important differences in Toronto Extremity Salvage Score for patients with lower extremity sarcoma, Journal of Orthopaedic Science, 10.1016/j.jos.2019.03.022, 2019.01, Background: The Toronto Extremity Salvage Score (TESS) is the most widely used patient-reported outcome measure for orthopaedic oncology patients. However, minimal clinically important differences (MCIDs) in the TESS have not been analyzed. The aim of this study was to define the MCIDs of TESS in patients with lower extremity sarcoma. Methods: A total of 85 patients were investigated to calculate the MCIDs for TESS. Three different methods were used: 1) distribution-based methods based on one-half of the standard deviation and standard error of measurement (SEM) at the baseline, 2) anchor-based and receiver operating characteristic (ROC) analysis, and 3) anchor-based using Akaike's Information Criterion (AIC) analysis. Results: The MCIDs at 6 months were 4.9–7.8 by distribution-based methods and 4.3–4.4 by anchor-based methods. The MCIDs at 12 months were 4.0–6.9 by distribution-based methods and 10.6–11.6 by anchor-based methods. Conclusions: We calculated MCID values for the TESS based on distribution- and anchor-based approaches. Our results seem reasonable since MCIDs calculated by the different approaches had similar values. This knowledge will enable clinicians to identify meaningful functional improvements in sarcoma patients..
57. Makoto Endo, Patrick P. Lin, Surgical margins in the management of extremity soft tissue sarcoma, Chinese Clinical Oncology, 10.21037/cco.2018.08.10, 7, 4, 2018.08, Standard treatment of localized soft tissue sarcoma should include surgical resection, which can be performed alone or in combination with perioperative radiotherapy and/or chemotherapy. The purpose of surgical intervention is to excise the tumor completely and to prevent disease relapse. Surgeons should remove the tumor with a sufficiently wide margin of the surrounding normal tissue; however, it is also necessary to pay attention to maximizing postoperative physical function. In order to balance the two competing goals, surgeons have been working to establish better methods for determining surgical margins and better guidelines for achieving adequate margins. At the present time, limb-sparing surgery is the mainstay of surgical treatment for soft tissue sarcomas of the extremities. In this article, we review the fundamentals of surgical margins as they pertain to soft tissue sarcomas and make recommendations for surgical treatment based upon current literature..
58. Rieko Oyama, Mami Takahashi, Fusako Kito, Marimu Sakumoto, Kumiko Shiozawa, Zhiwei Qiao, Akihiko Yoshida, Makoto Endo, Akira Kawai, Tadashi Kondo, Establishment and characterization of patient-derived xenograft and its cell line of primary leiomyosarcoma of bone, In Vitro Cellular and Developmental Biology - Animal, 10.1007/s11626-018-0258-2, 54, 6, 458-467, 2018.06, Primary leiomyosarcoma (LMS) of bone is a rare and aggressive mesenchymal malignancy that differentiates toward smooth muscle. Complete resection is the only curable treatment, and novel therapeutic approaches for primary LMS of bone have long been desired. Patient-derived xenografts (PDXs) and cell lines are invaluable tools for preclinical studies. Here, we established PDXs from a patient with primary LMS of bone and a cell line from an established PDX. Bone primary LMS tissue was subcutaneously implanted into highly immune-deficient mice. After two passages, a piece of the tumor was subjected to tissue culturing, and a morphological evaluation and proteomic analysis were performed on the PDX and the established cell line. Moreover, the responses of the established cell line to anti-cancer drugs were examined. Microscopic observations revealed that the PDX tumors retained their original histology. The cell line was established from the third-generation PDX and named NCC-LMS1-X3-C1. The cells were maintained for over 18 mo and 40 passages. The cells exhibited a spindle shape and aggressive growth. Mass spectrometric protein identification revealed that the original tumor tissue, PDX tumor tissue, and NCC-LMS1-X3-C1 cells had similar but distinct protein expression profiles. We previously established the cell line, NCC-LMS1-C1, from the tumor tissue of same patient. We found that the response to drug treatments was different between NCC-LMS1-X3-C1 and NCC-LMS1-C1, suggesting the heterogeneous traits of tumor cells in the identical tumor tissue. This set of PDXs and stable cell line will be a useful resource for bone LMS research..
59. Rieko Oyama, Fusako Kito, Marimu Sakumoto, Kumiko Shiozawa, Shunichi Toki, Makoto Endo, Akihiko Yoshida, Akira Kawai, Tadashi Kondo, Establishment and proteomic characterization of a novel synovial sarcoma cell line, NCC-SS2-C1, In Vitro Cellular and Developmental Biology - Animal, 10.1007/s11626-018-0237-7, 1-8, 2018.04, Synovial sarcoma is an aggressive mesenchymal tumor, characterized by the presence of unique transfusion gene, SS18–SSX. Cell lines enable researchers to investigate the molecular backgrounds of disease and the significance of SS18–SSX in relevant cellular contexts. We report the establishment and proteomic characterization of a novel synovial sarcoma cell line. Primary tissue culture was performed using tumor tissue of synovial sarcoma. The established cell line was authenticated by assessing its DNA microsatellite short tandem repeat analysis and characterized by in vitro assay. Proteomic study was achieved by mass spectrometry, and the results were analyzed by treemap. The cell line NCC-SS2-C1 was established from a primary tumor tissue of a synovial sarcoma patient. The cell line has grown well for 11 mo and has been subcultured more than 15 times. The established cells were authenticated by assessing their short tandem repeat pattern comparing with that of original tumor tissue. The cells showed polygonal in shape and formed spheroid when seeded on the low-attachment dish. Proteomic analysis revealed the molecular pathways which are unique to the original tumor tissue or the established cell line. In conclusion, a novel synovial sarcoma cell line NCC-SS2-C1 was successfully established from the primary tumor tissue. The cell line has characteristic transfusion SS18–SSX and poses aggressive in vitro growth and capability of spheroid formation. Thus, NCC-SS2-C1 cell line will be a useful tool for investigation of the mechanisms of disease and the biological role of fusion gene..
60. Marimu Sakumoto, Rieko Oyama, Mami Takahashi, Yoko Takai, Fusako Kito, Kumiko Shiozawa, Zhiwei Qiao, Makoto Endo, Akihiko Yoshida, Akira Kawai, Tadashi Kondo, Establishment and proteomic characterization of patient-derived clear cell sarcoma xenografts and cell lines, In Vitro Cellular and Developmental Biology - Animal, 10.1007/s11626-017-0207-5, 54, 2, 163-176, 2018.02, Clear cell sarcoma (CCS) is an aggressive mesenchymal malignancy characterized by the unique chimeric EWS-ATF1 fusion gene. Patient-derived cancer models are essential tools for the understanding of tumorigenesis and the development of anti-cancer drugs; however, only a limited number of CCS cell lines exist. The objective of this study was to establish patient-derived CCS models. We established patient-derived CCS models from a 43-yr-old female patient. We prepared the patient-derived xenografts (PDXs) from tumor tissues obtained through biopsy or surgery and isolated stable cell lines from PDXs and the original tumor tissue. The presence of gene fusions was examined by RT-PCR, and Sanger sequencing. The established cell lines were characterized by short tandem repeat, viability, colony and spheroid formation, and invasion analyses. Differences in gene enrichment between the primary tumor and cell lines were examined by mass spectrometry and KEGG pathway analysis. The cell lines were maintained for more than 80 passages, and had tumorigenic characteristics such as colony and spheroid formation and invasion. Mass spectrometric proteome analysis demonstrated that the cell lines were enriched for similar but distinct molecular pathways, compared to those in the xenografts and original tumor tissue. Next, tyrosine kinase inhibitors were screened for their suppressive effects on viability. We found that ponatinib, vandetanib, and doxorubicin suppressed the growth of cell lines, and had equivalent IC50 values. Further in-depth investigation and understanding of drug-sensitivity mechanisms will be important for the clinical applications of our cell lines..
61. Kenichiro Yahiro, Yoshihiro Matsumoto, Jun-Ichi Fukushi, Kenichi Kawaguchi, Makoto Endo, Nokitaka Setsu, Keiichiro Iida, Suguru Fukushima, Makoto Nakagawa, Atsushi Kimura, Yoshinao Oda, Yasuharu Nakashima, Class III β-Tubulin Overexpression Induces Chemoresistance to Eribulin in a Leiomyosarcoma Cell Line, Analytical cellular pathology (Amsterdam), 10.1155/2018/8987568, 2018, 2018.01, Eribulin is a new drug to treat soft tissue sarcoma (STS) that exerts antitumor activity by binding to microtubules. The prognosis of STS is poor, and eribulin is expected to improve the treatment outcome. We observed several cases that exhibited resistance to eribulin and developed an eribulin-resistant leiomyosarcoma cell line to investigate the mechanism of resistance. The IC50 of eribulin was 125 times higher in the resistant cell line than in the parental cell line, and eribulin did not induce G2/M arrest in resistant cells. The resistant cell line showed increased expression of MDR1 transcript, but protein levels and functional analysis results were similar to the parental cell line. We found that class III β-tubulin (TUBB3) was overexpressed in the resistant cell line, and siRNA knockdown of TUBB3 partially recovered sensitivity to eribulin. TUBB3 expression in clinical samples varied, suggesting that TUBB3 has the potential to be a biomarker for selection of anticancer drugs and may be a target for overcoming resistance to eribulin..
62. Yoshihiro Matsumoto, Kenichi Kawaguchi, Jun ichi Fukushi, Makoto Endo, Nokitaka Setsu, Keiichiro Iida, Satoshi Baba, Hirokazu Saiwai, Akinobu Matsushita, Mitsumasa Hayashida, Seiji Okada, Yasuharu Nakashima, Clinical outcome and prognostic factors of malignant spinal dumbbell tumors, Spine Surgery and Related Research, 10.22603/ssrr.2018-0004, 2, 4, 317-323, 2018.01, Introduction: To investigate the clinical outcome and prognostic factors of malignant spinal dumbbell tumors (m-SDTs). Methods: We retrospectively reviewed the clinical outcome of 22 consecutive cases of m-SDTs and analyzed the prognostic factors associated with worse outcome. Results: Nineteen of the 22 cases were managed with surgery (86%), and gross total resection (GTR) was achieved in four cases (21%). The duration of overall survival (OS) ranged from 3 to 140 months, with a median survival time of 15.3 months. The 5 year OS rate was 55.6%. In multivariate analysis, histological subtype (high-grade malignant peripheral nerve sheath tumor) (hazard ratio [HR] 14.9, p = 0.0191), GTR (HR 0.07, p = 0.0343), and presence of local recurrences (HR 11.2, p = 0.0479) were significant and independent predictors of OS. Conclusions: On the basis of clinical data, we propose that GTR and prevention of local recurrence may improve the clinical outcome of m-SDTs..
63. Yoshihiro Araki, Akihiko Yoshida, Yoshikazu Tanzawa, Makoto Endo, Eisuke Kobayashi, Akira Kawai, Reconstruction of the Shoulder Joint with a Custom-Made Ceramic Implant After a Total Scapulectomy A Case Report, JBJS case connector, 10.2106/JBJS.CC.17.00061, 8, 1, e12, 2018.01, CASE: We describe a 22-year-old woman who underwent total scapulectomy and shoulder joint reconstruction with use of a custom-made ceramic implant composed of hydroxyapatite and beta-tricalcium phosphate (β-TCP) for a recurrent atypical perineurioma that had arisen from the scapula. CONCLUSION: To our knowledge, there have been no previous reports of shoulder joint reconstruction with use of a custom-made ceramic implant after a total scapulectomy. The patient showed excellent function of the new shoulder joint and good range of motion without pain or dislocation at 18 months postsurgery. This new method of reconstructing the shoulder joint after a total scapulectomy appears useful and promising..
64. Marimu Sakumoto, Mami Takahashi, Rieko Oyama, Yoko Takai, Fusako Kito, Kumiko Shiozawa, Zhiwei Qiao, Akihiko Yoshida, Makoto Endo, Akira Kawai, Tadashi Kondo, Establishment and proteomic characterization of NCC-LMS1-C1, a novel cell line of primary leiomyosarcoma of the bone, Japanese Journal of Clinical Oncology, 10.1093/jjco/hyx096, 47, 10, 954-961, 2017.10, Background: Leiomyosarcoma (LMS) is one of most aggressive mesenchymal malignancies that differentiate towards smooth muscle. The clinical outcome of LMS patients is poor; as such, there is an urgent need for novel therapeutic approaches. Experimental models such as patient-derived cell lines are invaluable tools for pre-clinical studies. In the present study, we established a stable cell line from the tumor tissue of a patient with a primary LMS of the bone. Despite the urgent need for novel therapeutic strategies in LMS, there are only a few LMS cell lines available in public cell banks, none of which are primary to the bone. Methods: Bone primary LMS tumor tissues were sampled to establish cell lines. Morphological and proteomic analyses were performed and sensitivity to pazopanib was evaluated. Results: NCC-LMS1-C1 cells were maintained for over 100 passages. The cells exhibited a spindle shape and aggressive growth; they also expressed smooth muscle actin, reflecting the original LMS tissue (i.e. smooth muscle cells). The cells also showed tumor characteristics such as colony formation on soft agar and sensitivity to pazopanib, doxorubicin and cisplatin, with half-maximal inhibitory concentrations of 4.5, 0.11 and 20 μM, respectively. Proteomic analyses by mass spectrometry and antibody array revealed some differences in the protein expression profiles of these cells as compared to the original tumor tissue. Conclusions: Our results indicate that the NCC-LMS1-C1 cell lines will be useful for LMS research..
65. Yuka Hiraki-Hotokebuchi, Yuichi Yamada, Kenichi Kouhashi, Hidetaka Yamamoto, Makoto Endo, Nokitaka Setsu, Kuma Yuki, Takamichi Ito, Yukihide Iwamoto, Masutaka Furue, Yoshinao Oda, Alteration of PDGFRβ-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans, Human Pathology, 10.1016/j.humpath.2017.07.001, 67, 60-68, 2017.09, Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumor of intermediate malignancy and fibroblastic/myofibroblastic differentiation. Fibrosarcomatous (FS) component is a high-grade component of DFSP. The detailed oncogenic difference between DFSP and FS components is not clear. We thus investigated the Akt-mTOR pathway in both components. We used 65 tumor samples obtained from 65 patients. The phosphorylation of Akt-mTOR pathway proteins (Akt, mTOR, 4EBP1, and S6RP) and PDGFRα/β was assessed by immunohistochemical staining, the results of which were confirmed by Western blotting. The immunohistochemical results were as follows: in ordinary DFSP components, p-PDGFRα–positive tumors were 41.9% (18/43 cases), p-PDGFRβ 55.8% (24/43 cases), p-Akt 51.2% (22/43 cases), p-mTOR 39.5% (17/43 cases), p-4EBP1 46.5% (20/43 cases), and p-S6RP 41.8% (18/43 cases); in DFSP components of FS-DFSP, 52.6% (10/19 cases), 47.4% (9/19 cases), 52.6% (10/19 cases), 36.8% (7/19 cases), 52.6% (10/19 cases), and 52.6% (10/19 cases); and in FS components, 45.5% (10/22 cases), 36.4% (8/22 cases), 72.7% (16/22 cases), 54.5% (12/22 cases), 72.7% (16/22 cases), and 68.2% (15/22 cases), respectively. There were significant positive correlations of the phosphorylation of most of the Akt-mTOR pathway proteins (p-Akt, p-mTOR, p-4EBP1, and p-S6RP) with each other (P <.05 phospho-pdgfr was well correlated with the phosphorylation of akt-mtor pathway proteins in dfsp components ordinary and fs-dfsps but these correlations were weaker fs components. this study suggested association activation pdgfr progression to fs. is thus a potential therapeutic target imatinib-resistant id="gencho_ronbuns10034984" class="qir_handle_link">
66. Yoshihiro Araki, Akihiko Yoshida, Hirokazu Chuman, Yoshikazu Tanzawa, Makoto Endo, Akira Kawai, Eisuke Kobayashi, Angioleiomyoma mimicking pes anserinus bursitis: A case report., The Journal of dermatology, 10.1111/1346-8138.13876, 44, 8, e194-e195, 2017.08.
67. Rieko Oyama, Mami Takahashi, Akihiko Yoshida, Marimu Sakumoto, Yoko Takai, Fusako Kito, Kumiko Shiozawa, Zhiwei Qiao, Yasuhito Arai, Tatsuhiro Shibata, Yoshihiro Araki, Makoto Endo, Akira Kawai, Tadashi Kondo, Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines, Scientific Reports, 10.1038/s41598-017-04967-0, 7, 1, 4712, 2017.07, CIC-DUX4 sarcoma (CDS) is a group of rare, mesenchymal, small round cell tumours that harbour the unique CIC-DUX4 translocation, which causes aberrant gene expression. CDS exhibits an aggressive course and poor clinical outcome, thus novel therapeutic approaches are needed for CDS treatment. Although patient-derived cancer models are an essential modality to develop novel therapies, none currently exist for CDS. Thus, the present study successfully established CDS patient-derived xenografts and subsequently generated two CDS cell lines from the grafted tumours. Notably, xenografts were histologically similar to the original patient tumour, and the expression of typical biomarkers was confirmed in the xenografts and cell lines. Moreover, the xenograft tumours and cell lines displayed high Src kinase activities, as assessed by peptide-based tyrosine kinase array. Upon screening 119 FDA-approved anti-cancer drugs, we found that only actinomycine D and doxorubicin were effectively suppress the proliferation among the drugs for standard therapy for Ewing sarcoma. However, we identified molecular targeting reagents, such as bortezomib and crizotinib that markedly suppressed the growth of CDS cells. Our models will be useful modalities to develop novel therapeutic strategies against CDS..
68. Nobuhiko Yokoyama, Tomoya Matsunobu, Yoshihiro Matsumoto, Jun-Ichi Fukushi, Makoto Endo, Mihoko Hatano, Akira Nabeshima, Suguru Fukushima, Seiji Okada, Yukihide Iwamoto, Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells, Scientific Reports, 10.1038/srep45332, 7, 2017.03, Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS..
69. Takashi Hatano, Masanobu Ohishi, Goichi Yoshimoto, Moriyasu Yamauchi, Akira Maekawa, Hidetaka Yamamoto, Yoshinao Oda, Makoto Endo, Hirofumi Bekki, Tomoya Matsunobu, Yasuharu Nakashima, Ken Okazaki, Jun-Ichi Fukushi, Akiko Oyamada, Yukihide Iwamoto, Methotrexate-related lymphoproliferative disorder presenting with severe swelling of the elbow joint, JBJS Case Connector, 10.2106/JBJS.CC.17.00002, 7, 3, 2017.01, Case: A patient with rheumatoid arthritis (RA) who was being treated with methotrexate (MTX) therapy presented with severe swelling of the left elbow. Magnetic resonance imaging showed a tumor-like lesion around the elbow joint. Fluorodeoxyglucose positron emission tomography indicated multiple lesions in the lung and the lymph nodes. An open biopsy of a cervical lymph node was performed, and MTX-related lymphoproliferative disorder (MTX-LPD) was diagnosed. After cessation of the MTX therapy, the elbow swelling regressed, and the patient was in remission of MTX-LPD. Conclusion: MTX-LPD should be considered in the differential diagnosis when a patient with RA develops severe joint swelling while on MTX therapy..
70. Yoshihiro Matsumoto, Makoto Shinoto, Makoto Endo, Nokitaka Setsu, Keiichiro Iida, Jun-Ichi Fukushi, Kenichi Kawaguchi, Seiji Okada, Hirofumi Bekki, Reiko Imai, Tadashi Kamada, Yoshiyuki Shioyama, Yasuharu Nakashima, Evaluation of risk factors for vertebral compression fracture after carbon-ion radiotherapy for primary spinal and paraspinal sarcoma, BioMed Research International, 10.1155/2017/9467402, 2017, 2017, Background and Purpose. Carbon-ion radiotherapy (C-ion RT) was effective therapy for inoperable spinal and paraspinal sarcomas. However, a significant adverse event following radiotherapies is vertebral compression fractures (VCFs). In this study, we investigated the incidence of and risk factors for post-C-ion RT VCFs in patients with spinal or paraspinal sarcomas. Material and Methods. Thirty consecutive patients with spinal or paraspinal sarcomas treated with C-ion RT were retrospectively reviewed. Various clinical parameters and the Spinal Instability Neoplastic Score (SINS) were used to evaluate the risk factors for post-C-ion RT VCFs. Results. The overall incidence of VCFs was 23% (median time: 7 months). Patients with VCFs showed a markedly higher SINS score (median value, 9 points) than those without VCF (5 points). The area under the receiver operating characteristic curve for the SINS score was 0.88, and the optimum SINS cut-off score was 8 points. The cumulative incidence of VCFs at 1 year was 9% for patients with a SINS score under 8 points, versus 80% for those with a SINS score of 8 points or higher (p
71. Suguru Fukushima, Makoto Endo, Yoshihiro Matsumoto, Jun-Ichi Fukushi, Tomoya Matsunobu, Ken-Ichi Kawaguchi, Nokitaka Setsu, Keiichiro Iida, Nobuhiko Yokoyama, Makoto Nakagawa, Kenichiro Yahiro, Yoshinao Oda, Yukihide Iwamoto, Yasuharu Nakashima, Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor, PLoS One, 10.1371/journal.pone.0178064, 12, 5, e0178064, 2017, BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear.
METHODS: The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α-specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α.
RESULTS: The nuclear expression of HIF-1α was positive in 75.6% of MPNST samples (62/82 cases). Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P ≤ 0.0001) analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis.
CONCLUSION: Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs..
72. Yoshihiro Matsumoto, Shingo Baba, Makoto Endo, Nokitaka Setsu, Keiichiro Iida, Jun-Ichi Fukushi, Kenichi Kawaguchi, Seiji Okada, Hirofumi Bekki, Takuro Isoda, Yoshiyuki Kitamura, Hiroshi Honda, Yasuharu Nakashima, Metabolic Tumor Volume by (18)F-FDG PET/CT Can Predict the Clinical Outcome of Primary Malignant Spine/Spinal Tumors, BioMed Research International, 10.1155/2017/8132676, 2017, 8132676, 2017, BACKGROUND AND PURPOSE: Primary malignant spine/spinal tumors (PMSTs) are rare and life-threatening diseases. In this study, we demonstrated the advantage of volume-based (18)F-FDG PET/CT metabolic parameter, metabolic tumor volume (MTV), for assessing the aggressiveness of PMSTs.
MATERIALS AND METHODS: We retrospectively reviewed 27 patients with PMSTs and calculated SUVmax, MTV, and total lesion glycolysis (TLG) to compare their accuracy in predicting progression-free survival (PFS) and overall survival (OS) by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were used to compare the reliability of the metabolic parameters and various clinical factors.
RESULTS: MTV exhibited greater accuracy than SUVmax or TLG. The cut-off values for PFS and OS derived from the AUC data were MTV 45 ml and 83 ml and TLG 250 SUV⁎ml and 257 SUV⁎ml, respectively. MTV above cut-off value, but not TLG, was identified as significant prognostic factor for PFS by log-lank test (p = 0.04). In addition, MTV was the only significant predictive factors for PFS and OS in the multivariate analysis.
CONCLUSIONS: MTV was a more accurate predictor of PFS and OS in PMSTs compared to TLG or SUVmax and helped decision-making for guiding rational treatment options..
73. Tomoaki Mori, Robert Nakayama, Makoto Endo, Hiroaki Hiraga, Masato Tomita, Naomasa Fukase, Eisuke Kobayashi, Akira Kawai, Takafumi Ueda, Hideo Morioka, Forty-eight cases of leiomyosarcoma of bone in Japan A multicenter study from the Japanese musculoskeletal oncology group, Journal of Surgical Oncology, 10.1002/jso.24322, 114, 4, 495-500, 2016.09, Background: Leiomyosarcoma of bone (LMSoB) is a rare malignant bone tumor. This multicenter retrospective study was conducted to investigate the diagnosis and the clinical outcome of primary LMSoB in Japan. Methods: Forty-eight patients (average age: 52 years [range 14–88 years]) with primary LMSoB who were treated at registered institutes in Japan between 1991 and 2014 were recruited. The median follow-up period was 44 months (range: 2–273). Results: The 5-year overall survival rates and disease-free survival rates were 78.3% and 44.9%, respectively. Surgical treatment was performed in 42 patients, and R0 resection was achieved in 31 patients. Neoadjuvant chemotherapy was administered in 18 patients. The most common regimen (cisplatin-based chemotherapy) was administered in 15 patients, however, no patient achieved a good response in both radiological and histological evaluations. The presence of metastasis at the first visit and a lack of definitive surgery were significantly correlated with poor overall survival, and the surgical margin was a significant prognostic factor for disease-free survival. Conclusions: This study is the largest LMSoB case series ever reported. Surgical treatment with wide margins was the only treatment that proved to be effective, whereas adjuvant chemotherapy in the present setting did not improve the overall survival. J. Surg. Oncol. 2016;114:495–500..
74. Hirofumi Bekki, Jun-ichi Fukushi, Hideki Mizu-uchi, Makoto Endo, Yoshinao Oda, Yukihide Iwamoto, Fibromatosis of the soleus muscle presenting as pes equinus: A case report, Foot & Ankle Online Journal, 9, 3, 4, 2016.08.
75. Akira Maekawa, Kenichi Kouhashi, Masaaki Kuda, Kunio Iura, Takeaki Ishii, Makoto Endo, Tetsuya Nakatsura, Yukihide Iwamoto, Yoshinao Oda, Prognostic significance of FOXM1 expression and antitumor effect of FOXM1 inhibition in synovial sarcomas, BMC Cancer, 10.1186/s12885-016-2542-4, 16, 1, 2016.07, Background: Synovial sarcoma (SS) is a soft tissue sarcoma of unknown histogenesis. Most metastatic or unresectable cases are incurable. Novel antitumor agents and precise prognostication are needed for SS patients. The protein forkhead box M1 (FOXM1), which belongs to the FOX family of transcription factors, is considered to be an independent predictor of poor survival in many cancers and sarcomas, but the prognostic implications and oncogenic roles of FOXM1 in SS are poorly understood. Here we examined the correlation between FOXM1 expression and clinicopathologic and prognostic factors, and we investigated the efficacy of FOXM1 target therapy in SS cases. Methods: Immunohistochemical study of 106 tumor specimens was conducted to evaluate their immunohistochemical expression of FOXM1. An in vitro study examined the antitumor effect of the FOXM1 inhibitor thiostrepton and small interference RNA (siRNA) on two SS cell lines. We also assessed the efficacy of the combined use of doxorubicin (DOX) and thiostrepton. Results: Univariate and multivariate analyses revealed that FOXM1 expression was associated with poor prognosis in SS. The cDNA microarray analysis using clinical samples revealed that the expression of cell cycle-associated genes was correlated with FOXM1 expression. FOXM1 inhibition by thiostrepton showed significant antitumor activity on the SS cell lines in vitro. FOXM1 interruption by siRNA increased the chemosensitivity for DOX in both SS cell lines. Conclusion: FOXM1 expression is a novel biomarker, and its inhibition is a potential treatment option for SS..
76. K. Tahara, K. Yamashita, A. Hiwatashi, O. Togao, K. Kikuchi, M. Endo, H. Otsuka, Y. Oda, H. Honda, MR Imaging Findings of a Leiomyosarcoma of the Thoracic Spine: A Case Report, Clinical Neuroradiology, 10.1007/s00062-015-0420-0, 26, 2, 229-233, 2016.06, We report a case of leiomyosarcoma of the thoracic spine. Primary leiomyosarcoma is a malignant connective tissue tumor originating from smooth muscle cells. Leiomyosarcoma frequently occurs in the uterus, retroperitoneal space, gastrointestinal tract, and deep soft tissues; primary leiomyosarcoma of the bone is rare. The MR imaging including intravoxel incoherent motion (IVIM) imaging findings of the current case indicated a low diffusion coefficient and high blood flow, which were in concurrence with high cell density on histology and increased vascularity by angiography. Although some benign tumors such as osteoblastoma and giant cell tumor would show similar findings on IVIM imaging, these additional imaging features may narrow the differential diagnosis of spinal tumors..
77. Makoto Endo, III. An update on drug therapy for chordoma, Japanese Journal of Cancer and Chemotherapy, 43, 3, 317-321, 2016.03.
78. Matsunobu T, Bekki H, Harimaya K, Matsumoto Y, Endo M, Yoshitake K, Oda Y, Iwamoto Y, Osteosarcoma of the middle and distal phalanges of the little toe with a cancerous ulcer, Int J Case Rep Images, 10.5348/ijcri-201632-CR-10619, 7, 3, 185-189, 2016.03.
79. Yoshihiro Matsumoto, Makoto Endo, Katsumi Harimaya, Mitsumasa Hayashida, Toshio Doi, Yukihide Iwamoto, Malignant peripheral nerve sheath tumors presenting as spinal dumbbell tumors clinical outcomes and characteristic imaging features, European Spine Journal, 10.1007/s00586-014-3467-8, 24, 10, 2119-2125, 2015.10, Purpose: To investigate the clinical outcomes and imaging features of malignant peripheral nerve sheath tumors (MPNSTs) presenting as spinal dumbbell tumors. Methods: We retrospectively reviewed the clinical outcomes and imaging features of consecutive cases of spinal dumbbell MPNSTs (n = 8) and schwannomas (n = 15). Results: A maximal diameter >5 cm was more frequently seen in MPNSTs (88 %) than in schwannomas (14 %). Irregularly lobulated margins occurred frequently in MPNSTs (75 %), but not in schwannomas (21 %). Indistinguishable boundaries were observed in 63 % of MPNSTs, but only 7 % of schwannomas. Osteolytic bone destruction was found exclusively in MPNSTs (50 % of MPNSTs vs. 0 % of schwannomas). Conclusions: There is little clinical information relating to spinal dumbbell MPNSTs. We propose that the following imaging features are suggestive of spinal dumbbell MPNSTs: maximal diameter >5 cm, irregularly lobulated shape, boundary indistinguishable from surrounding tissues, and osteolytic bone destruction..
80. Ali Salanti, Thomas M. Clausen, Mette O. Agerbæk, Nader Al Nakouzi, Madeleine Dahlbäck, Htoo Z. Oo, Sherry Lee, Tobias Gustavsson, Jamie R. Rich, Bradley J. Hedberg, Yang Mao, Line Barington, Marina A. Pereira, Janine LoBello, Makoto Endo, Ladan Fazli, Jo Soden, Chris K. Wang, Adam F. Sander, Robert Dagil, Susan Thrane, Peter J. Holst, Le Meng, Francesco Favero, Glen J. Weiss, Morten A. Nielsen, Jim Freeth, Torsten O. Nielsen, Joseph Zaia, Nhan L. Tran, Jeff Trent, John S. Babcook, Thor G. Theander, Poul H. Sorensen, Mads Daugaard, Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein, Cancer Cell, 10.1016/j.ccell.2015.09.003, 28, 4, 500-514, 2015.10, Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification..
81. M. R. Whitehouse, Makoto Endo, S. Zachara, T. O. Nielsen, N. V. Greidanus, B. A. Masri, D. S. Garbuz, C. P. Duncan, Adverse local tissue reactions in metal-onpolyethylene total hip arthroplasty due to trunnion corrosion The risk of misdiagnosis, Bone and Joint Journal, 10.1302/0301-620X.97B8.34682, 97-B, 8, 1024-1030, 2015.08, Adverse reaction to wear and corrosion debris is a cause for concern in total hip arthroplasty (THA). Modular junctions are a potential source of such wear products and are associated with secondary pseudotumour formation. We present a consecutive series of 17 patients treated at our unit for this complication following metal-on-highly cross-linked polyethylene (MoP) THA. We emphasise the risk of misdiagnosis as infection, and present the aggregate laboratory results and pathological findings in this series. The clinical presentation was pain, swelling or instability. Solid, cystic and mixed softtissue lesions were noted on imaging and confirmed intra-operatively. Corrosion at the head-neck junction was noted in all cases. No bacteria were isolated on multiple pre- and intra-operative samples yet the mean erythrocyte sedimentation rate was 49 (9 to 100) and C-reactive protein 32 (0.6 to 106) and stromal polymorphonuclear cell counts were noted in nine cases. Adverse soft-tissue reactions can occur in MoP THA owing to corrosion products released from the head-neck junction. The diagnosis should be carefully considered when investigating pain after THA. This may avoid the misdiagnosis of periprosthetic infection with an unidentified organism and mitigate the unnecessary management of these cases with complete single- or two-stage exchange..
82. Mihoko Hatano, Yoshihiro Matsumoto, Jun-Ichi Fukushi, Tomoya Matsunobu, Makoto Endo, Seiji Okada, Kunio Iura, Satoshi Kamura, Toshifumi Fujiwara, Keiichiro Iida, Yuko Fujiwara, Akira Nabeshima, Nobuhiko Yokoyama, Suguru Fukushima, Yoshinao Oda, Yukihide Iwamoto, Cadherin-11 regulates the metastasis of Ewing sarcoma cells to bone, Clinical and Experimental Metastasis, 10.1007/s10585-015-9729-y, 32, 6, 579-591, 2015.08, Ewing sarcoma (ES) is a small round-cell tumor of the bones and soft tissues. ES frequently causes distant metastases, particularly in the lung and bone, which worsens patient prognosis. Cadherin-11 (Cad-11) is an adhesion molecule that is highly expressed in osteoblasts. Its expression is associated with bone metastases in prostate and breast cancer patients, and is known to occur in ES. Here we investigated the effects of Cad-11 on bone metastases of ES. Human ES cell lines RD-ES, SK-ES-1, SK-N-MC, and TC-71 cells were transduced with lentivirus containing Cad-11 shRNA or control shRNA (ES/Cad-11 and ES/Ctr). RD-ES and TC-71 were infected with a lentivirus luciferase vector. Adhesion assays were performed using these cells and recombinant Cad-11-Fc chimera or mouse osteoblast cell line MC3T3-E1. Cell motility was investigated via wound-healing assay. Intracardiac injection of RD-ES/Cad-11 and RD-ES/Ctr was used to create a mouse model of experimental bone metastasis. The association between Cad-11 expression and bone metastases and clinical prognosis in ES patients was analyzed by immunohistochemistry. We found knockdown of Cad-11 in ES cells resulted in reduced attachment ability and cell motility. In a mouse model of metastasis, RD-ES/Cad-11 cells caused fewer metastases than RD-ES/Ctr cells. The expression of Cad-11 in ES patients was significantly related to bone metastases (P 
83. Quincy S.C. Chu, T. O. Nielsen, T. Alcindor, A. Gupta, Makoto Endo, A. Goytain, H. Xu, S. Verma, R. Tozer, M. Knowling, V. B. Bramwell, J. Powers, L. K. Seymour, E. A. Eisenhauer, A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocationassociated recurrent/metastatic sarcomas-NCIC-CTG IND 200, Annals of Oncology, 10.1093/annonc/mdv033, 26, 5, 973-981, 2015.05, Background: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. Patients and methods: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. Results: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score
84. A. Nabeshima, Yoshihiro Matsumoto, Jun-Ichi Fukushi, K. Iura, T. Matsunobu, Makoto Endo, Toshifumi Fujiwara, Keiichiro Iida, Y. Fujiwara, M. Hatano, N. Yokoyama, S. Fukushima, Yoshinao Oda, Y. Iwamoto, Tumour-associated macrophages correlate with poor prognosis in myxoid liposarcoma and promote cell motility and invasion via the HB-EGF-EGFR-PI3K/Akt pathways, British Journal of Cancer, 10.1038/bjc.2014.637, 112, 3, 547-555, 2015.02, Background:Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, and metastasis occurs in up to one-third of cases. However, the mechanisms of invasion and metastasis remain unclear. Tumour-associated macrophages (TAMs) have important roles in tumour invasion, metastasis, and/or poor prognosis. The aim of this study was to investigate the relationship between TAMs and MLS.Methods:Using 78 primary MLS samples, the association between clinical prognosis and macrophage infiltration was evaluated by immunochemistry. The effects of macrophages on cell growth, cell motility, and invasion of MLS cell lines were investigated in vitro. In addition, clinicopathological factors were analysed to assess their prognostic implications in MLS.Results:Higher levels of CD68-positive macrophages were associated with poorer overall survival in MLS samples. Macrophage-conditioned medium enhanced MLS cell motility and invasion by activating epidermal growth factor receptor (EGFR), with the key ligand suggested to be heparin-binding EGF-like growth factor (HB-EGF). The phosphoinositide 3-kinase/Akt pathway was mostly involved in HB-EGF-induced cell motility and invasion of MLS. The expression of phosphorylated EGFR in MLS clinical samples was associated with macrophage infiltration. In addition, more significant macrophage infiltration was associated with poor prognosis even in multivariate analysis.Conclusions:Macrophage infiltration in MLS predicts poor prognosis, and the relationship between TAMs and MLS may be a new candidate for therapeutic targets of MLS..
85. Makoto Endo, Marieke A. De Graaff, Davis R. Ingram, Simin Lim, Dina C. Lev, Inge H. Briaire-De Bruijn, Neeta Somaiah, Judith V.M.G. Bovée, Alexander J. Lazar, Torsten O. Nielsen, NY-ESO-1 (CTAG1B) expression in mesenchymal tumors, Modern Pathology, 10.1038/modpathol.2014.155, 28, 4, 587-595, 2015.01, New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1..
86. Yusuke Takahashi, Kenichi Kohashi, Yuichi Yamada, Makoto Endo, Nokitaka Setsu, Takeaki Ishii, Hidetaka Yamamoto, Yukihide Iwamoto, Yoshinao Oda, Activation of the Akt/mammalian target of rapamycin pathway in myxofibrosarcomas, Human Pathology, 10.1016/j.humpath.2013.12.012, 45, 5, 984-993, 2014.05.
87. Yuichi Yamada, Kenichi Kohashi, Fumiyoshi Fushimi, Yusuke Takahashi, Nokitaka Setsu, Makoto Endo, Hidetaka Yamamoto, Shoji Tokunaga, Yukihide Iwamoto, Yoshinao Oda, Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors, Cancer, 10.1002/cncr.28506, 120, 6, 864-876, 2014.03.
88. Makoto Endo, Le Su, Torsten O. Nielsen, Activating transcription factor 2 in mesenchymal tumors, Human Pathology, 10.1016/j.humpath.2013.09.003, 45, 2, 276-284, 2014.02.
89. Yoshihiro Matsumoto, Yusuke Takahashi, Akihisa Haraguchi, Tatsuro Okamoto, Katsumi Harimaya, Tomoya Matsunobu, Makoto Endo, Yoshinao Oda, Yukihide Iwamoto, Intraosseous hemangioma arising in the clavicle, Skeletal Radiology, 10.1007/s00256-013-1715-3, 43, 1, 89-93, 2014.01.
90. Makoto Endo, Hidetaka Yamamoto, Katsumi Harimaya, Kenichi Kouhashi, Takeaki Ishii, Nokitaka Setsu, Yukihide Iwamoto, Yoshinao Oda, Conventional spindle cell-type malignant peripheral nerve sheath tumor arising in a sporadic schwannoma, Human Pathology, 10.1016/j.humpath.2013.05.021, 44, 12, 2845-2848, 2013.12, Malignant peripheral nerve sheath tumor is a malignant tumor showing nerve sheath differentiation. Approximately one-half of malignant peripheral nerve sheath tumors arise from a benign peripheral nerve sheath tumor, which is commonly a neurofibroma in patients with neurofibromatosis type 1. Malignant peripheral nerve sheath tumor arising in a sporadic schwannoma of soft tissue is extremely rare. In this condition, malignant cells usually show epithelioid morphology, meeting the diagnostic criteria for epithelioid malignant peripheral nerve sheath tumor. Here, we present an extraordinary case of spindle cell-type malignant peripheral nerve sheath tumor arising in a schwannoma on the back of a 58-year-old woman without neurofibromatosis. The malignant component showed hypercellular spindle cell proliferation with high mitotic activities; in contrast, the benign component showed hypocellular spindle cell proliferation in a palisading pattern and with Verocay bodies. Immunohistochemical S-100 protein staining showed a clear contrast between the malignant (negative) and benign (positive) components, which was useful for differentiating cellular schwannoma. Recognizing this rare condition is helpful in the pathologic diagnosis of schwannoma showing cellular proliferation in part..
91. Michael R. Whitehouse, Makoto Endo, Bassam A. Masri, Adverse Local Tissue Reaction Associated With a Modular Hip Hemiarthroplasty, Clinical Orthopaedics & Related Research, 10.1007/s11999-013-3133-1, 471, 12, 4082-4086, 2013.12.
92. Makoto Endo, Kenichi Kohashi, Hidetaka Yamamoto, Takeaki Ishii, Tatsuya Yoshida, Tomoya Matsunobu, Yukihide Iwamoto, Yoshinao Oda, Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion gene, Human Pathology, 10.1016/j.humpath.2013.04.003, 44, 11, 2603-2608, 2013.11.
93. Nokitaka Setsu, Kenichi Kohashi, Fumiyoshi Fushimi, Makoto Endo, Hidetaka Yamamoto, Yusuke Takahashi, Yuichi Yamada, Takeaki Ishii, Koichirou Yokoyama, Yukihide Iwamoto, Yoshinao Oda, Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma, Cancer, 10.1002/cncr.28255, 119, 19, 3504-3513, 2013.10.
94. Makoto Endo, Tatsuya Yoshida, Hidetaka Yamamoto, Takeaki Ishii, Nokitaka Setsu, Kenichi Kohashi, Tomoya Matsunobu, Yukihide Iwamoto, Yoshinao Oda, Low-grade central osteosarcoma arising from bone infarct, Human Pathology, 10.1016/j.humpath.2012.11.011, 44, 6, 1184-1189, 2013.06.
95. Yusuke Takahashi, Yoshinao Oda, Hidetaka Yamamoto, Takeaki Ishii, Nokitaka Setsu, Makoto Endo, Shuichi Matsuda, Yukihide Iwamoto, Fibrocartilaginous mesenchymoma arising in the pubic bone: A case report, Pathology International, 10.1111/pin.12052, 63, 4, 226-229, 2013.04.
96. Suguru Matsuura, Takeaki Ishii, Makoto Endo, Yusuke Takahashi, Nokitaka Setsu, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Yoshinao Oda, Epithelial and cartilaginous differentiation in clear cell chondrosarcoma, Human Pathology, 10.1016/j.humpath.2012.05.012, 44, 2, 237-243, 2013.02.
97. Makoto Endo, Hidetaka Yamamoto, Nokitaka Setsu, Kenichi Kohashi, Yusuke Takahashi, Takeaki Ishii, Kei-ichiro Iida, Yoshihiro Matsumoto, Michiyuki Hakozaki, Mikiko Aoki, Hiroshi Iwasaki, Yoh Dobashi, Kenichi Nishiyama, Yukihide Iwamoto, Yoshinao Oda, Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors, Clinical Cancer Research, 10.1158/1078-0432.CCR-12-1067, 19, 2, 450-461, 2013.01, PURPOSE:
Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.
EXPERIMENTAL DESIGN:
Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.
RESULTS:
Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro.
CONCLUSION:
mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs..
98. Nokitaka Setsu, Kenichi Kohashi, Makoto Endo, Hidetaka Yamamoto, Sadafumi Tamiya, Yusuke Takahashi, Yuichi Yamada, Takeaki Ishii, Shuichi Matsuda, Ryohei Yokoyama, Yukihide Iwamoto, Yoshinao Oda, Phosphorylation of signal transducer and activator of transcription 3 in soft tissue leiomyosarcoma is associated with a better prognosis, International Journal of Cancer, 10.1002/ijc.27655, 132, 1, 109-115, 2013.01.
99. Makoto Endo, Torsten O. Nielsen, Pazopanib for metastatic soft-tissue sarcoma, The Lancet, 380, 9844, 801, 2012.09.
100. Nokitaka Setsu, Kenichi Kohashi, Makoto Endo, Hidetaka Yamamoto, Yoshihiro Ohishi, Kazunobu Sueyoshi, Yukihide Iwamoto, Masazumi Tsuneyoshi, Toru Motoi, Arisa Kumagai, Yoshinao Oda, Inhibin-α and synaptophysin immunoreactivity in synovial sarcoma with granular cell features, Human Pathology, 10.1016/j.humpath.2011.07.012, 43, 6, 850-857, 2012.06.
101. Ai Anami, Kotaro Fukushima, Yasuyuki Fujita, Shoji Satoh, Emi Matsumoto, Makoto Endo, Yoshinao Oda, Norio Wake, Antenatally diagnosed congenital orbital teratoma in which rupture was associated with intrauterine fetal death, Journal of Obstetrics and Gynaecology Research, 10.1111/j.1447-0756.2011.01738.x, 38, 3, 578-581, 2012.03.
102. Nokitaka Setsu, Hidetaka Yamamoto, Kenichi Kohashi, Makoto Endo, Shuichi Matsuda, Ryohei Yokoyama, Kenichi Nishiyama, Yukihide Iwamoto, Yoh Dobashi, Yoshinao Oda, The Akt/mammalian target of rapamycin pathway is activated and associated with adverse prognosis in soft tissue leiomyosarcomas, Cancer, 10.1002/cncr.26448, 118, 6, 1637-1648, 2012.03.
103. Makoto Endo, Chikashi Kobayashi, Nokitaka Setsu, Yusuke Takahashi, Kenichi Kohashi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi, Yoshinao Oda, Prognostic Significance of p14(ARF), p15(INK4b), and p16(INK4a) Inactivation in Malignant Peripheral Nerve Sheath Tumors, Clinical Cancer Research, 10.1158/1078-0432.CCR-10-2393, 17, 11, 3771-3782, 2011.06, PURPOSE:
p14(ARF), p15(INK4b), and p16(INK4a) are tumor suppressor genes that are located closely at 9p21 and are often coinactivated by genetic or epigenetic alterations. Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with poor prognosis. However, the prognostic implications of inactivation of p14(ARF), p15(INK4b), and p16(INK4a) in MPNSTs have not been adequately investigated. Here we carried out a genetic, epigenetic, and expression analysis of p14(ARF), p15(INK4b), and p16(INK4a), and clarified the prognostic significance of their inactivation in MPNSTs.
EXPERIMENTAL DESIGN:
p14(ARF), p15(INK4b), and p16(INK4a) protein expressions were assessed by immunohistochemistry in 129 formalin-fixed samples of MPNST including 85 primary tumors. Thirty-nine samples, for which frozen material was available, were also investigated by Western blotting and quantitative reverse transcription PCR (RT-PCR) to detect p14(ARF), p15(INK4b), and p16(INK4a) protein and mRNA expression, and by multiplex real-time PCR, PCR single strand conformation polymorphism and methylation-specific PCR to detect p14(ARF), p15(INK4b), and p16(INK4a) gene alterations.
RESULTS:
Immunohistochemically decreased expressions of p14(ARF), p15(INK4b), and p16(INK4a) were observed in 48%, 54%, and 49% of primary MPNSTs, respectively, and were significantly correlated with their concordant mRNA levels. As for gene alterations, homozygous deletion of CDKN2A was detected in one third of the cases. Inactivation of p14(ARF) and p16(INK4a) was associated with poor prognosis by both univariate and multivariate analyses. Furthermore, cases with inactivation of all p14(ARF), p15(INK4b), and p16(INK4a) genes showed the worst prognosis in a combined prognostic assessment.
CONCLUSION:
A comprehensive analysis of p14(ARF), p15(INK4b), and p16(INK4a) inactivation status provides useful prognostic information in MPNSTs..
104. Xiaofeng Yan, Masakazu Takahara, Long Dugu, Lining Xie, Chisato Gondo, Makoto Endo, Yoshinao Oda, Takeshi Nakahara, Hiroshi Uchi, Satoshi Takeuchi, Yating Tu, Yoichi Moroi, Masutaka Furue, Expression of cathepsin K in neurofibromatosis 1-associated cutaneous malignant peripheral nerve sheath tumors and neurofibromas, Journal of Dermatological Science, 10.1016/j.jdermsci.2010.04.005, 58, 3, 227-229, 2010.06.
105. Makoto Endo, Musculoskeletal tumor. III. Chemotherapy of liposarcoma--the current status of chemotherapy and new findings in clinical trials of novel drugs, Japanese Journal of Cancer and Chemotherapy, 37, 3, 434-438, 2010.03.
106. Makoto Endo, Yoshinao Oda, Katsumi Harimaya, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kohashi, Shuichi Kurihara, Nokitaka Setsu, Suguru Matsuura, Hiroshi Matono, Shuichi Matsuda, Yukihide Iwamoto, Masazumi Tsuneyoshi, Low-grade dedifferentiated liposarcoma of the neck: magnetic resonance imaging and pathological correlation, Journal of Orthopaedic Science, 10.1007/s00776-009-1407-y, 15, 1, 148-152, 2010.01.
107. Eisuke Kobayashi, Akira Kawai, Makoto Endo, Yoshiyuki Suehara, Ken Takeda, Fumihiko Nakatani, Takayuki Asano, Minoru Sakuraba, Hirokazu Chuman, Kunihiko Seki, Yasuo Beppu, Myxoinflammatory fibroblastic sarcoma, Journal of Orthopaedic Science, 10.1007/s00776-008-1274-y, 13, 6, 566-571, 2008.
108. Makoto Endo, Ukihide Tateishi, Kunihiko Seki, Umio Yamaguchi, Fumihiko Nakatani, Akira Kawai, Hirokazu Chuman, Yasuo Beppu, Prognostic implications of glucose transporter protein-1 (Glut-1) overexpression in bone and soft-tissue sarcomas, Japanese Journal of Clinical Oncology, 10.1093/jjco/hym125, 37, 12, 955-960, 2007.12, Background: The glucose transporter protein 1 (Glut-1) overexpression is associated with poor overall survival (OS) in various malignant tumors. The aim of this study was to investigate prognostic significance of Glut-1 overexpression in patients with bone and soft-tissue sarcomas. Methods: A total of 67 patients (mean age, 43 years; range, 8-79 years) with bone and soft tissue sarcomas were analyzed. Pathologic confirmation was observed from surgical specimens in all patients. Pathologic variables including tumor differentiation, necrosis, mitotic index, MIB-1 (Ki-67) grade and Glut-1 expression were assessed. Clinical characteristics and pathologic variables were determined by Kaplan-Meyer curve of OS after treatment. Results: Glut-1 overexpression was found in 56 patients (83%). The patients with Glut-1 overexpression showed significantly poor OS compared with those without Glut-1 overexpression (P = 0.029). The presence of metastasis, treatment without surgical resection, tumor differentiation, necrosis, mitotic index and MIB-1 grade were also significantly negative prognostic factors. The presence of metastasis was independently associated with poor OS (P = 0.031). Conclusions: Assessment of Glut-1 expression prior to treatment has a predictive potential effect in patients with bone and soft-tissue sarcomas..
109. Makoto Endo, Akira Kawai, Eisuke Kobayashi, Yuki Morimoto, Umio Yamaguchi, Fumihiko Nakatani, Hirokazu Chuman, Kunihiko Seki, Yasuo Beppu, Solitary intramuscular myxoma with monostotic fibrous dysplasia as a rare variant of Mazabraud's syndrome, Skeletal Radiology, 10.1007/s00256-006-0234-x, 36, 6, 523-529, 2007.06, The rare coexistence of intramuscular myxoma (IM) and fibrous dysplasia (FD) is known as Mazabraud's syndrome. IM tends to occur multifocally and is associated most frequently with polyostotic FD in Mazabraud's syndrome. We present an extremely rare combination of a solitary IM and monostotic FD as a variant of Mazabraud's syndrome, and discuss the importance of recognizing this rare coexistence for appropriate management of the patient..
110. Ako Hosono, Umio Yamaguchi, Atsushi Makimoto, Makoto Endo, Atsuko Watanabe, Tadakazu Shimoda, Mitsunori Kaya, Tadaki Matsumura, Hiroshi Sonobe, Tomomi Kusumi, Takehiko Yamaguchi, Tadashi Hasegawa, Utility of immunohistochemical analysis for cyclo-oxygenase 2 in the differential diagnosis of osteoblastoma and osteosarcoma, Journal of Clinical Pathology - Clinical Molecular Pathology, 10.1136/jcp.2006.038828, 60, 4, 410-414, 2007.04, Aims: To study the immunoexpression of cyclo-oxygenase (COX) 2 in osteoblastomas (OBs) and osteosarcomas (OSs), and to assess the utility of immunohistochemical analysis for COX 2 in the differential diagnosis of the two tumour forms. Methods: The immunohistochemical features of COX 2 were studied in 11 OBs and 30 OSs, including 26 high-grade OSs (16 osteoblastic, 7 chondroblastic, and 3 fibroblastic) and 4 low-grade OSs. Results: Tumour cells from all 11 OBs unequivocally showed diffuse, intense and cytoplasmic immunoreactivity for COX 2. Strong cytoplasmic expression of COX 2 was observed in 5 of 26 (19%) high-grade OSs, all chondroblastic. In one osteoblastic-type OS, COX 2 was expressed in the chondroblastic component, but this tumour was considered to be COX 2 negative. No COX 2 expression was noted in atypical osteoblastic cells. Staining in the four low-grade OSs was negative. Conclusion: The results of immunohistochemical analysis of COX 2 suggest that in addition to the routine histopathological evaluation, COX 2 is a valuable diagnostic marker in the distinction between OB and OS..
111. K. Okada, T. Hasegawa, U. Tateishi, Makoto Endo, E. Itoi, Dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features, Journal of Clinical Pathology - Clinical Molecular Pathology, 10.1136/jcp.2005.029629, 59, 11, 1200-1202, 2006.11, A 35-year-old Japanese man was admitted to the National Cancer Center, Tokyo, Japan, in December 2000, with a 2-month history of pain around the left thigh. Radiographs showed a poorly demarcated osteolytic lesion with focal mineralisation and endosteal scalloping in the left proximal femur. Biopsy showed a proliferation of highly anaplastic cells without any cartilaginous component. A wide excision of the left proximal femur with a replacement by endoprosthesis was carried out in February 2001 after treatment with methotrexate and 20 Gy radiation therapy. Pathological examination of the surgical specimen showed a focus of low-grade chondrosarcoma and the coexistence of telangiectatic osteosarcoma-like features. The patient was diagnosed with dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features. Lung metastasis appeared in July 2001 despite an adjuvant chemotherapy including methotrexate, cis-platinum and doxorubicin. The latest follow-up study in June 2004 showed multiple lung metastases. Establishing a definitive diagnosis of dedifferentiated chondrosarcoma may be difficult with limited small biopsy specimens. Dedifferentiated chondrosarcoma should be included in the differential diagnosis of osteolytic tumours with focal calcification and endosteal scalloping even if an extraosseous tumour component is not identified..
112. Makoto Endo, Tadaki Matsumura, Takehiko Yamaguchi, Umio Yamaguchi, Yuki Morimoto, Fumihiko Nakatani, Akira Kawai, Hirokazu Chuman, Yasuo Beppu, Tadakazu Shimoda, Tadashi Hasegawa, Cyclooxygenase-2 overexpression associated with a poor prognosis in chondrosarcomas, Human Pathology, 10.1016/j.humpath.2005.12.001, 37, 4, 471-476, 2006.04, Recent studies have shown increased levels of cyclooxygenase (COX)-2 in various human malignancies, including some bone and soft tissue tumors, but little is known about the presence of COX-2 in chondrosarcomas. We performed immunohistochemical staining for COX-2 in 74 chondrosarcomas and compared the staining results with the characteristics and outcome of the patients. Thirty-seven men and 37 women between the ages of 14 and 81 years (median, 50 years) participated in the study. The tumors were located in the axial skeleton in 47 cases and in the long bones in 27 cases. The largest diameters of the tumors ranged from 2.7 to 32 cm (median, 8.0 cm). The immunohistochemistry findings revealed the overexpression of COX-2 in 16 (22%) of the 74 patients. Thirteen (41%) of 32 grade 2 and 2 (67%) of 3 grade 3 chondrosarcomas showed overexpression for COX-2, whereas only 1 (3%) of 39 grade 1 chondrosarcomas showed overexpression. Overexpression of COX-2 was significantly associated with histologic grade (P
113. Umio Yamaguchi, Tadashi Hasegawa, Yuki Morimoto, Ukihide Tateishi, Makoto Endo, Fumihiko Nakatani, Akira Kawai, Hirokazu Chuman, Yasuo Beppu, M. Endo, H. Kurotaki, K. Furuta, A practical approach to the clinical diagnosis of Ewing's sarcoma/primitive neuroectodermal tumour and other small round cell tumours sharing EWS rearrangement using new fluorescence in situ hybridisation probes for EWSR1 on formalin fixed, paraffin wax embedded tissue, Journal of Clinical Pathology - Clinical Molecular Pathology, 10.1136/jcp.2004.025502, 58, 10, 1051-1056, 2005.10, Background: Over 90% of Ewing's sarcoma/primitive neuroectodermal tumour (ES/PNET) cases have the t(11;22) chromosomal rearrangement, which is also found in other small round cell tumours, including desmoplastic small round cell tumour (DSRCT) and clear cell sarcoma (CCS). Although this rearrangement can be analysed by fluorescence in situ hybridisation (FISH) using routinely formalin fixed, paraffin wax embedded (FFPE) tissues when fresh or frozen tissues are not available, a sensitive and convenient detection method is needed for routine clinical diagnosis. Aims: To investigate the usefulness of newly developed probes for detecting EWS rearrangement resulting from chromosomal translocations using FISH and FFPE tissue in the clinical diagnosis of ES/PNET, DSRCT, and CCS. Methods: Sixteen ES/PNETs, six DSRCTs, and six CCSs were studied. Three poorly differentiated synovial sarcomas, three alveolar rhabdomyosarcomas, and three neuroblastomas served as negative controls. Interphase FISH analysis was performed on FFPE tissue sections with a commercially available EWSR1 (22q12) dual colour, breakapart rearrangement probe. Results: One fused signal and one split signal of orange and green, demonstrating rearrangement of the EWS gene, was detected in 14 of 16 ES/PNETs, all six DRSCTs, and five of six CCSs, but not in the negative controls. Conclusions: Interphase FISH using this newly developed probe is sensitive and specific for detecting the EWS gene on FFPE tissues and is of value in the routine clinical diagnosis of ES/PNET, DSRCT, and CCS..
114. Makoto Endo, Tadashi Hasegawa, Takashi Tashiro, Umio Yamaguchi, Yuki Morimoto, Fumihiko Nakatani, Tadakazu Shimoda, Bizarre parosteal osteochondromatous proliferation with a t(1;17) translocation, Virchows Archiv, 10.1007/s00428-005-1266-7, 447, 1, 99-102, 2005.07, Bizarre parosteal osteochondromatous proliferation (BPOP) is a benign lesion that tends to recur repeatedly. Histologically, BPOP contains three components (cartilage, bone, and spindle cells) in differing amounts. The histological findings of BPOP are similar to those of florid reactive periostitis (FRP) and subungual (Dupuytren's) exostosis. Some authors have postulated that all of these conditions are reactive proliferative lesions representing different phases of reactive processes. Whether BPOP is a reactive proliferative lesion or a neoplastic lesion, however, remains controversial. Recently, a t(1;17)(q32;q21) translocation in BPOP was detected using chromosome banding and fluorescence in situ hybridization (FISH) analyses. Here, we describe a 39-year-old Japanese female with BPOP arising in the proximal phalanx of her third toe. A cytogenetic analysis revealed a t(1;17)(q42;q23) translocation. The breakpoints in this case are located close to those of previously reported cases. These results suggest that t(1;17) is a distinct translocation of BPOP and that BPOP is a neoplastic lesion, rather than a reactive proliferative process..


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