Faculty Profiles - OZAKI Toshifumi

Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors. Reviewed International journal

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

Cancer science 115 ( 3 ) 871 - 882 2024.3

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1111/cas.16077

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Prognostic evaluation of the Ki-67 labeling system in histological grading of non-small round cell sarcoma: a supplementary analysis of a randomized controlled trial, JCOG1306 Reviewed

Shintaro Sugita, Kazuhiro Tanaka, Yoshinao Oda, Takayuki Nojima, Naomi Konishi, Ryunosuke Machida, Ryosuke Kita, Haruhiko Fukuda, Toshifumi Ozaki, Tadashi Hasegawa

Japanese Journal of Clinical Oncology 54 ( 6 ) 675 - 680 2024.2

Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Abstract

Background

Soft tissue sarcoma (STS) has various histological types and is rare, making it difficult to evaluate the malignancy of each histological type. Thus, comprehensive histological grading is most important in the pathological examination of STS. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is most commonly used in daily pathological analysis of STS. Among the FNCLCC grading system parameters, mitotic count is a key morphological parameter reflecting the proliferative activity of tumor cells, although its reproducibility may be lacking. Here, we compared the prognostic utility of the conventional and modified FNCLCC grading systems in JCOG1306.

Methods

We analyzed 140 patients with non-small round cell sarcoma. We performed Ki-67 immunostaining using open biopsy specimens before preoperative chemotherapy in all patients. We assessed histological grade in individual cases by conventional FNCLCC grading (tumor differentiation, mitotic count, and necrosis) and modified FNCLCC grading using the Ki-67 labeling index instead of mitotic count. We conducted univariable and multivariable Cox regression analyses to investigate the influence of grade on overall survival.

Results

In univariable analysis, prognosis was worse for patients with conventional FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (hazard ratio [HR] 4.21, 95% confidence interval [CI] 1.47–12.05, P = 0.008). Moreover, prognosis was worse in patients with modified FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (HR 4.90, 95% CI 1.64–14.65, P = 0.004). In multivariable analysis including both conventional and modified FNCLCC grading, the modified grading more strongly affected overall survival (HR 6.70, 95% CI 1.58–28.40, P = 0.010).

Conclusions

The modified FNCLCC grading system was superior to the conventional system in predicting the prognosis of patients with non-small round cell sarcoma according to this supplementary analysis of data from the randomized controlled trial JCOG1306.

DOI： 10.1093/jjco/hyae020

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Superior outcomes of pullout repairs for medial meniscus posterior root tears in partial tear compared to complete radial tear. International journal

Masanori Tamura, Takayuki Furumatsu, Yusuke Yokoyama, Naohiro Higashihara, Koki Kawada, Toshifumi Ozaki

Knee surgery & related research 36 ( 1 ) 8 - 8 2024.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To reveal the outcomes of partial medial meniscus posterior root tears following transtibial pullout repair compared with the outcomes of complete radial meniscus posterior root tears. MATERIALS AND METHODS: We retrospectively evaluated 15 consecutive patients (male/female, 5/10; average age, 64.4 years) who underwent transtibial pullout repair for partial medial meniscus posterior root tears and compared their results with those of 86 consecutive patients who underwent the same surgery for complete medial meniscus posterior root tears. All patients underwent second-look arthroscopy on average 1 year postoperatively, and a semi-quantitative meniscal healing score (anteroposterior width, stability, and synovial coverage, total 10 points) was evaluated. Medial meniscus extrusion was evaluated preoperatively and at second-look arthroscopy. RESULTS: Postoperative clinical scores were not significantly different in the short term. However, second-look arthroscopy revealed a significant difference in repaired meniscal stability (partial tear; 3.3 points, complete tear; 2.3 points, p < 0.001) and total meniscal healing scores (partial tear; 8.3 points, complete tear; 7.1 points, p < 0.001). Medial meniscus extrusion progression was significantly different (partial tear; 0.4 mm, complete tear; 1.0 mm, p < 0.001). CONCLUSION: Partial medial meniscus posterior root tears showed better meniscal healing and less medial meniscus extrusion progression following pullout repair than complete medial meniscus posterior root tears.

DOI： 10.1186/s43019-023-00206-1

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Longitudinal changes in medial knee joint space narrowing after medial meniscus posterior root repair: A 2-year follow-up study. Reviewed International journal

Koki Kawada, Takayuki Furumatsu, Masanori Tamura, Naohiro Higashihara, Yusuke Yokoyama, Toshifumi Ozaki

The Knee 47 92 - 101 2024.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Despite good clinical results, repair of medial meniscus (MM) posterior root tears (MMPRTs) may not completely prevent knee osteoarthritis progression. This study evaluated changes in the medial joint space (MJS) during the first and second years after repair, compared to narrowing in the contralateral knee, using fixed-flexion view (FFV) radiographs. METHODS: Fifty-four patients who underwent pull-out repair for a unilateral MMPRT were included. FFV radiographs were obtained pre-operatively and at the 1- and 2-year post-repair timepoints to evaluate changes in the MJS and Kellgren-Lawrence grade bilaterally. Clinical outcomes were also evaluated. RESULTS: The change in the MJS was greater in MMPRT knees than in contralateral knees during the first year (0.48 ± 0.80 mm vs. 0.09 ± 0.49 mm, p < 0.001), but this difference lessened in the second year (0.09 ± 0.36 mm vs. 0.07 ± 0.38 mm, p = 0.285). Kellgren-Lawrence grade progression in MMPRT knees was less in the second year. Clinical outcomes significantly improved at both 1 and 2 years post-repair than the pre-operative values (p < 0.001), with continued improvement in clinical outcomes in the second year. There was no significant correlation between patient characteristics and the change in the MJS from preoperatively to 2 years postoperatively. CONCLUSION: Pull-out repair for MMPRTs did not completely prevent MJS narrowing, but the rate of narrowing decreased in the second year (mean, 0.09 mm) compared to that in the first year (mean, 0.48 mm). MJS narrowing in the second year after MM posterior root repair was comparable to that of the contralateral knee. Clinical outcomes further improved over the second year after repair. LEVEL OF EVIDENCE: IV.

DOI： 10.1016/j.knee.2024.01.005

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自宅でできるリハビリテーション(第17回) 股関節唇損傷に対するリハビリテーション Reviewed

山田和希, 山根秀平, 西井彩, 福場美賀夫, 太田晴之, 濱田全紀, 堅山佳美, 鉄永智紀, 尾崎敏文

Loco Cure 10 ( 1 ) 84 - 88 2024.2

遺伝性骨・軟部腫瘍外来における肉腫発生at-risk者への取り組み

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

日本レックリングハウゼン病学会学術大会プログラム・抄録集 15回 25 - 25 2024.2

神経線維腫症1型患者由来ヒトiPS細胞株の樹立

大澤太郎, 中田英二, 岡本真幸, 山田大祐, 二川摩周, 高尾知佳, 平沢晃, 尾崎敏文, 宝田剛志

日本レックリングハウゼン病学会学術大会プログラム・抄録集 15回 24 - 24 2024.2

神経線維腫症1型患者由来ヒトiPS細胞株の樹立

大澤太郎, 中田英二, 岡本真幸, 山田大祐, 二川摩周, 高尾知佳, 平沢晃, 尾崎敏文, 宝田剛志

日本レックリングハウゼン病学会学術大会プログラム・抄録集 15回 24 - 24 2024.2

Assessing the Frequency and Effectiveness of Various Arthroscopic Treatments in the Management of Symptomatic Isolated Medial Meniscus Injuries Including Medial Meniscus Posterior Root Tear: A Retrospective Observational Cohort Study. Reviewed

Masanori Tamura, Takayuki Furumatsu, Yusuke Yokoyama, Keisuke Kintaka, Naohiro Higashihara, Koki Kawada, Toshifumi Ozaki

Acta medica Okayama 78 ( 1 ) 21 - 27 2024.2

Language：English Publishing type：Research paper (scientific journal)

The use of various strategies for arthroscopic meniscal repairs to save the meniscus and prevent the progression of knee osteoarthritis has gradually increased. We investigated the frequency of various arthroscopic treatments and the short-term clinical outcomes of symptomatic isolated medial meniscus (MM) injuries. This retrospective observational study included 193 patients (197 knees) who underwent arthroscopic meniscal treatment for isolated MM injuries between January 2016 and April 2019. Arthroscopic meniscal repairs were divided into two groups: transtibial pullout repairs of MM posterior root tears (MMPRTs) and arthroscopic meniscal repairs for other types of MM injuries. MMPRT pullout repair, other meniscal repairs, and partial meniscectomy were performed in 71.0%, 16.8%, and 12.2% of the knees, respectively. The ratio of women to men and the patient age were higher in the pullout-repair group than the meniscal-repair group. The Preoperative Knee Injury and Osteoarthritis Outcome Score subscale (as an index of daily living activities) was significantly lower in the pullout-repair group than the meniscus-repair group. However, no significant differences were observed in these scores among the two groups postoperatively. Our results suggest that familiarity with the diagnosis and treatment of MMPRTs is necessary for orthopedic surgeons to manage isolated MM injuries.

DOI： 10.18926/AMO/66667

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High Fracture Rate of AVANTA Silicone Implant Following Arthroplasty of the Thumb MCP Joint of Rheumatoid Arthritis Patients with Boutonniere Deformities. Reviewed

Daisuke Kaneda, Keiichiro Nishida, Yoshihisa Nasu, Ryuichi Nakahara, Ryozo Harada, Yoshifumi Hotta, Shuichi Naniwa, Toshifumi Ozaki

Acta medica Okayama 78 ( 1 ) 71 - 78 2024.2

Language：English Publishing type：Research paper (scientific journal)

We retrospectively investigated the mid-term outcomes of arthroplasty using the AVANTA silicone implant for thumb metacarpophalangeal (MCP) joints with boutonniere deformity in patients with rheumatoid arthritis (RA). This study involved 36 thumbs of 33 RA patients with a mean follow-up period of 5.1 years (range, 2.0-13.3). Postoperatively, the mean extension was significantly increased and the mean flexion was significantly decreased (p<0.001, p<0.001, respectively), resulting in the mean arc of range of motion (ROM) shifting in the direction of extension after surgery. Implant fracture was observed in 10 thumbs (28%), and 4 of these (11%) underwent revision surgery. The survivorship with implant fracture and revision surgery as endpoints were 73.4% and 91.8% at 5 years, respectively. The preoperative arc of ROM and the postoperative flexion range of the implant-fracture group were significantly greater than those in the no-implant-fracture group (p=0.039, 0.034, respectively). These results suggest the importance of patient education and careful rehabilitation to prevent excessive flexion. Overall, the AVANTA silicone implant showed a relatively high rate of implant fracture at our institute.

DOI： 10.18926/AMO/66673

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

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

International journal of molecular sciences 25 ( 3 ) 2024.1

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3390/ijms25031443

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Initial tension at suture fixation affects the suture breakage following medial meniscus posterior root repair: a retrospective cohort study. International journal

Masanori Tamura, Takayuki Furumatsu, Yusuke Yokoyama, Naohiro Higashihara, Koki Kawada, Toshifumi Ozaki

Journal of ISAKOS : joint disorders & orthopaedic sports medicine 2024.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: This study aimed to investigate whether the initial suture tension when pullout sutures are fixed affects postoperative clinical outcomes following medial meniscus posterior root repair. METHODS: The data of 48 patients who underwent transtibial pullout repair using two simple stitches (outer and inner sutures) with an additional all-inside posteromedial pullout were retrospectively investigated. The patients were sequentially divided into two groups to compare the clinical efficacy of the initial pullout tension when pullout sutures were fixed: the 30N Group (April 2019 to September 2019, 24 patients) and the 15N group (October 2019 to February 2020, 24 patients). The rate of suture breakage (suture cutout or rupture) at the second-look arthroscopy at 1 year postoperatively and clinical outcomes at 2 years postoperatively were compared between the two groups. RESULTS: In both groups, each clinical score significantly improved at 2 years postoperatively. At the second-look arthroscopy, the rate of posteromedial suture breakage was significantly higher in the 30 N Group (19 patients, 79%) than in the 15 N Group (10 patients, 42%); the rate of outer suture breakage was also higher in the 30 N group (five patients, 21%) than in the 15 N group (no patients). On comparing 2 years of preoperative clinical scores between the groups categorized according to posteromedial suture breakage, the pain score was significantly higher in the suture breakage group. CONCLUSION: The initial tension of pullout repair of the medial meniscus posterior root tear is related to suture breakages. To prevent suture breakage, 15 N is a more initially suitable condition than 30 N. LEVEL OF EVIDENCE: Level III.

DOI： 10.1016/j.jisako.2024.01.004

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Papers - OZAKI Toshifumi