Faculty Profiles - NISHIDA, Yoshihiro

Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression via BMP signaling Reviewed Open Access

Mori, N; Esaki, N; Shimoyama, Y; Shiraki, Y; Asai, N; Sakai, T; Nishida, Y; Takahashi, M; Enomoto, A; Mii, S

PATHOLOGY RESEARCH AND PRACTICE Vol. 245 page： 154443 2023.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Pathology Research and Practice

Osteosarcoma, the most common primary malignant bone tumor, is defined by the formation of neoplastic osteoid and/or bone. This sarcoma is a highly heterogeneous disease with a wide range of patient outcomes. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in various types of malignant tumors. We previously reported that CD109 is expressed in osteoblasts and osteoclasts in normal human tissues and plays a role in bone metabolism in vivo. While CD109 has been shown to promote various carcinomas through the downregulation of TGF-β signaling, the role and mechanism of CD109 in sarcomas remain largely unknown. In this study, we investigated the molecular function of CD109 in sarcomas using osteosarcoma cell lines and tissue. Semi-quantitative immunohistochemical analysis using human osteosarcoma tissue revealed a significantly worse prognosis in the CD109-high group compared with the CD109-low group. We found no association between CD109 expression and TGF-β signaling in osteosarcoma cells. However, enhancement of SMAD1/5/9 phosphorylation was observed in CD109 knockdown cells under bone morphogenetic protein-2 (BMP-2) stimulation. We also performed immunohistochemical analysis for phospho-SMAD1/5/9 using human osteosarcoma tissue and found a negative correlation between CD109 expression and SMAD1/5/9 phosphorylation. In vitro wound healing assay showed that osteosarcoma cell migration was significantly attenuated in CD109-knockdown cells compared with control cells in the presence of BMP. These results suggest that CD109 is a poor prognostic factor in osteosarcoma and affects tumor cell migration via BMP signaling.

DOI： 10.1016/j.prp.2023.154443

Investigation of inpatient convalescent rehabilitation outcomes in branch atheromatous disease Reviewed

Clinical results of active surveillance for extra-abdominal desmoid-type fibromatosis Reviewed Open Access

Sakai, T; Nishida, Y; Ito, K; Ikuta, K; Urakawa, H; Koike, H; Imagama, S

CANCER MEDICINE Vol. 12 ( 5 ) page： 5245 - 5254 2023.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Cancer Medicine

Background: The treatment of choice for desmoid-type fibromatosis (DF) has been changed to active surveillance (AS). However, few studies have reported clinical outcomes of AS modality in Asian countries. This study aimed to clarify the significance of AS as a DF treatment modality. Methods: A total of 168 lesions from 162 patients with extra-abdominal DF were included. The mean age at diagnosis was 39 years (1–88 years), and the median maximum tumor diameter at the first visit was 64.1 mm (13.2–255.8 mm). The clinical outcomes of AS and the risk factors requiring active treatment (AT) (defined as an event) from AS modality were investigated. Results: Of the 168 lesions, 94 (56%) were able to continue AS, with a 5-year event-free survival of 54.8%. Of the 68 lesions with PD, 21 (30.9%) lesions were able to continue AS. Neck location (p = 0.043) and CTNNB1 S45F mutation (p = 0.003) were significantly associated with the transition to AT, and S45F mutation was a significant factor associated with the transition to AT by multivariate analysis (hazard ratio: 1.96, p = 0.048). AT outcomes after AS were evaluable in 65 lesions, and 49 (75%) lesions did not require a transition to a second AT. Conclusions: AS was revealed as an effective treatment modality. The transition to AT needs to be considered for neck location and CTNNB1 S45F mutation DF. Good results can be obtained by selecting a treatment method that considers the tumor location even in cases that require intervention.

DOI： 10.1002/cam4.5329

Senda, J; Ito, K; Kotake, T; Mizuno, M; Kishimoto, H; Yasui, K; Katsuno, M; Nishida, Y; Sobue, G

JOURNAL OF STROKE & CEREBROVASCULAR DISEASES Vol. 32 ( 3 ) page： 106937 2023.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Stroke and Cerebrovascular Diseases

Purpose: We investigated inpatient convalescent rehabilitation outcomes of Branch atheromatous disease (BAD). Subjects and methods: The subjects were 116 patients with lenticulostriate artery territory - BAD (LSA-BAD) and 29 with paramedian pontine artery territory - BAD (PPA-BAD). For all patients, the National Institutes of Health Stroke Scale (NIHSS), Functional Independence Measure (FIM) scores, and Brunnstrom recovery stages (BRS) of the upper limb, fingers, and lower limb were measured on admission and at discharge. Results: There were no significant differences in clinical characteristics on admission between the LSA-BAD and PPA-BAD groups. The neurological severity of PPA-BAD, as measured by the NIHSS, was significantly milder compared with that of LSA-BAD upon admission (p = 0.015) and at discharge (p = 0.001). Patients with LSA-BAD had significantly less improvement in the BRS of the upper limb (p = 0.001), fingers (p < 0.001), and lower limb (p = 0.007) at discharge. Furthermore, they had significantly smaller changes in BRS between admission and discharge for the upper limb (p = 0.033) and fingers (p = 0.014) compared with patients with PPA-BAD. The improvement in BRS for patients with LSA-BAD tended to be limited to two stages; however, both patients with LSA-BAD and PPA-BAD saw sufficient gains in FIM at discharge. Conclusion: Rehabilitation outcomes following BAD in the convalescent period should be assessed in terms of improvements in pure-motor hemiparesis and activities of daily living. Furthermore, the disturbance patterns in the corticospinal tract by ischemic stroke lesions may be different between LSA-BAD and PPA-BAD.

DOI： 10.1016/j.jstrokecerebrovasdis.2022.106937

Which modality is better to diagnose high-grade transformation in retroperitoneal liposarcoma? Comparison of computed tomography, positron emission tomography, and magnetic resonance imaging Reviewed Open Access

Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA Reviewed Open Access

Cortes-Ciriano, I; Steele, CD; Piculell, K; Al-Ibraheemi, A; Eulo, V; Bui, MM; Chatzipli, A; Dickson, BC; Borcherding, DC; Feber, A; Galor, A; Hart, J; Jones, KB; Jordan, JT; Kim, RH; Lindsay, D; Miller, C; Nishida, Y; Proszek, PZ; Serrano, J; Sundby, T; Szymanski, JJ; Ullrich, NJ; Viskochil, D; Wang, X; Snuderl, M; Park, PJ; Flanagan, AM; Hirbe, AC; Pillay, N; Miller, DT

CANCER DISCOVERY Vol. 13 ( 3 ) page： 654 - 671 2023.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Cancer Discovery

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis.

DOI： 10.1158/2159-8290.CD-22-0786

Nakashima, Y; Yokoyama, Y; Ogawa, H; Sakakibara, A; Sunagawa, M; Nishida, Y; Mizuno, T; Yamaguchi, J; Onoe, S; Watanabe, N; Kawakatsu, S; Igami, T; Ebata, T

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY Vol. 28 ( 3 ) page： 482 - 490 2023.3

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Clinical Oncology

Background: Survival in patients with retroperitoneal liposarcoma (RPLS) depends on the surgical management of the dedifferentiated foci. The present study investigated the diagnostic yield of contrast-enhanced CT, 18F-fluorodeoxyglucose positron emission tomography (PET), and diffusion-weighted MRI in terms of dedifferentiated foci within the RPLS. Methods: Patients treated with primary or recurrent RPLS who underwent the above imaging between January 2010 and December 2021 were retrospectively reviewed. The diagnostic accuracy of the three modalities for histologic subtype of dedifferentiated liposarcoma (DDLS) and French Federation of Cancer Center (FNCLCC) grade 2/3 were compared using receiver operating characteristic curves and areas under the curves (AUCs). Results: The cohort involved 32 patients with 53 tumors; 30 of which exhibited DDLS and 31 of which did FNCLCC grades 2/3. The optimal thresholds for predicting DDLS were mean CT value of 31 Hounsfield Unit (HU) (AUC = 0.880, 95% CI 0.775–0.984; p < 0.001), maximum standardized uptake value (SUVmax) of 2.9 (AUC = 0.865 95% CI 0.792–0.980; p < 0.001), while MRI failed to differentiate DDLS. The cutoff values for distinguishing FNCLCC grades 1 and 2/3 were a mean CT value of 24 HU (AUC = 0.858, 95% CI 0.731–0.985; p < 0.001) and SUVmax of 2.9 (AUC = 0.885, 95% CI 0.792–0.978; p < 0.001). MRI had no sufficient power to separate these grades. Conclusions: Contrast-enhanced CT and PET were useful for predicting DDLS and FNCLCC grade 2/3, while MRI was inferior to these two modalities.

DOI： 10.1007/s10147-022-02287-6

An Effective Therapy that Antibody-Drug Conjugates Targeting Meflin (+) Cells for Osteosarcoma Reviewed

誌説 Competitionとcooperation Reviewed

西田佳弘

整形外科 Vol. 74 ( 2 ) page： 106 - 106 2023.2

Sakoda, T; Esaki, N; Ando, R; Miyai, Y; Iida, T; Matsuyama, M; Shiraki, Y; Mii, S; Nishida, Y; Takahashi, M; Enomoto, A

CANCER SCIENCE Vol. 114 page： 760 - 760 2023.2

Dedifferentiated liposarcoma in the extremity and trunk wall: A multi-institutional study of 132 cases by the Japanese Musculoskeletal Oncology Group (JMOG) Reviewed

Morii, T; Anazawa, U; Sato, C; Iwata, S; Nakagawa, M; Endo, M; Nakamura, T; Ikuta, K; Nishida, Y; Nakayama, R; Udaka, T; Kawamoto, T; Kito, M; Sato, K; Imanishi, J; Akiyama, T; Kobayashi, H; Nagano, A; Outani, H; Toki, S; Nishisho, T; Sasa, K; Suehara, Y; Kawano, H; Ueda, T; Morioka, H

EJSO Vol. 49 ( 2 ) page： 353 - 361 2023.2

Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Surgical Oncology

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.

DOI： 10.1016/j.ejso.2022.08.024

Hyaluronan in articular cartilage: Analysis of hip osteoarthritis and osteonecrosis of femoral head Reviewed Open Access

Zhang, JR; Nishida, Y; Koike, H; Ito, K; Zhuo, LS; Nishida, K; Kimata, K; Ikuta, K; Sakai, T; Urakawa, H; Seki, T; Imagama, S

JOURNAL OF ORTHOPAEDIC RESEARCH Vol. 41 ( 2 ) page： 307 - 315 2023.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Orthopaedic Research

Hyaluronan (HA) plays crucial roles in the maintenance of high-quality cartilage extracellular matrix. Several studies have reported the HA in synovial fluid in patients with osteoarthritis (OA), but few have described the changes of HA in articular cartilage of OA or idiopathic osteonecrosis of the femoral head (ONFH). KIAA1199 was recently reported to have strong hyaluronidase activity. The aim of this study was to clarify the HA metabolism in OA and ONFH, particularly the involvement of KIAA1199. Immunohistochemical analysis of KIAA1199 and HA deposition was performed for human OA (n = 10), ONFH (n = 10), and control cartilage (n = 7). The concentration and molecular weight (MW) of HA were determined by competitive HA ELISA and Chromatography, respectively. Regarding HA metabolism-related molecules, HAS1, HAS2, HAS3, HYAL1, HYAL2, and KIAA1199 gene expression was assessed by reverse transcriptase polymerase chain reaction. Histological analysis showed the overexpression of KIAA1199 in OA cartilage, which was accompanied by decreased hyaluronic acid binding protein (HABP) staining compared with ONFH and control. Little KIAA1199 expression was observed in cartilage at the collapsed area of ONFH, which was accompanied by a slight decrease in HABP staining. The messenger RNA (mRNA) expression of HAS2 and KIAA1199 was upregulated in OA cartilage, while the mRNA expression of genes related to HA catabolism in ONFH cartilage showed mostly a downward trend. The MW of HA in OA cartilage increased while that in ONFH cartilage decreased. HA metabolism in ONFH is suggested to be generally indolent, and is activated in OA including high expression of KIAA1199. Interestingly, MW of HA in OA cartilage was not reduced.

DOI： 10.1002/jor.25364