Faculty Profiles - NISHIDA, Yoshihiro

A phase III study comparing methotrexate (M), adriamycin (A) and cisplatin (P) with MAP plus ifosfamide (MAP plus IF) for the treatment of osteosarcoma: JCOG0905 Reviewed

Hiraga, H; Machida, R; Kawai, A; Matsumoto, Y; Yonemoto, T; Nishida, Y; Nagano, A; Ae, K; Yoshida, S; Asanuma, K; Toguchida, J; Huruta, D; Nakayama, R; Akisue, T; Hiruma, T; Morii, T; Tanaka, K; Kataoka, T; Fukuda, H; Ozaki, T

ANNALS OF ONCOLOGY Vol. 33 ( 7 ) page： S1225 - S1225 2022.9

Short-term clinical outcomes of Kyocera Modular Limb Salvage System designed cementless stems for the endoprosthetic reconstruction of lower extremities: a Japanese Musculoskeletal Oncology Group multi-institutional study Reviewed Open Access

Tsukushi, S; Nishida, Y; Hirose, T; Nakata, E; Nakagawa, R; Nakamura, T; Imanishi, J; Nagano, A; Tamiya, H; Ueda, T

BMC CANCER Vol. 22 ( 1 ) page： 781 2022.7

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

Background: The high rate of aseptic loosening of cemented stems has led to their frequent use in endoprosthetic reconstruction. However, problems, such as stem breakage and stress shielding at the insertion site, remain. The Japanese Musculoskeletal Oncology Group (JMOG) has developed Kyocera Modular Limb Salvage System (KMLS) cementless stems with a unique tapered press-fit and short fixation design. This study aimed to clarify the short-term postoperative outcomes of this prosthesis and validate the stem design. Methods: One hundred cases of KMLS cementless stems (51 male patients; median age, 49 years; mean follow-up period, 35 months), with a minimum follow-up of 2 years, for the proximal femur (PF), distal femur (DF), and proximal tibia were prospectively registered for use. Prosthesis survival, complication rates, postoperative functional, and radiographical evaluation were analyzed. Complications or failures after insertion of the KMLS endoprostheses were classified into five types and functional results were analyzed according to the MSTS scoring system at postoperative 1 year. The diaphyseal interface and anchorage were graded by the ISOLS system at postoperative 2 years. Results: The overall prosthesis survival rates at 2 and 4 years were 88.2 and 79.6%, respectively. The prosthesis-specific survival rate excluding infection and tumor recurrence was 90.2 and 87.9%, respectively. Younger age (p = 0.045) and primary tumor (p = 0.057) were associated with poor prognosis of prosthesis-specific survival excluding infection and tumor recurrence. Complications were observed in 31 patients, 13 patients underwent revision surgery. The mean MSTS functional score at 1 year postoperatively was 68%. Early implant loosening was significantly more common in the DF (p = 0.006) and PF/DF straight stem (p = 0.038). The ISOLS radiographic evaluation at 2 years after surgery revealed good bone remodeling and anchorage in most cases (bone remodeling: 90% / excellent and good, anchorage: 97% / excellent and good). Conclusions: Tumor endoprosthesis long-term fixation to the diaphysis of the lower extremity remains challenging. The KMLS cementless stem with a unique tapered press fit design showed good short-term results in maintaining bone stock. To prevent early loosening, a curved stem should be used in PF and DF, but long-term follow-up is necessary.

DOI： 10.1186/s12885-022-09873-x

Efficacy of auranofin as an inhibitor of desmoid progression Reviewed Open Access

Ito, K; Nishida, Y; Hamada, S; Shimizu, K; Sakai, T; Ohkawara, B; Alman, BA; Enomoto, A; Ikuta, K; Koike, H; Zhang, JR; Ohno, K; Imagama, S

SCIENTIFIC REPORTS Vol. 12 ( 1 ) page： 11918 2022.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Anticancer drugs and molecular targeted therapies are used for refractory desmoid-type fibromatosis (DF), but occasionally cause severe side effects. The purpose of this study was to identify an effective drug with fewer side effects against DF by drug repositioning, and evaluate its efficacy. FDA-approved drugs that inhibit the proliferation of DF cells harboring S45F mutations of CTNNB1 were screened. An identified drug was subjected to the investigation of apoptotic effects on DF cells with analysis of Caspase 3/7 activity. Expression of β-catenin was evaluated with western blot analysis, and immunofluorescence staining. Effects of the identified drug on in vivo DF were analyzed using Apc1638N mice. Auranofin was identified as a drug that effectively inhibits the proliferation of DF cells. Auranofin did not affect Caspase 3/7 activity compared to control. The expression level of β-catenin protein was not changed regardless of auranofin concentration. Auranofin effectively inhibited the development of tumorous tissues by both oral and intraperitoneal administration, particularly in male mice. Auranofin, an anti-rheumatic drug, was identified to have repositioning effects on DF. Since auranofin has been used for many years as an FDA-approved drug, it could be a promising drug with fewer side effects for DF.

DOI： 10.1038/s41598-022-15756-9

Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi-institutional study Reviewed Open Access

Kozawa, E; Nishida, Y; Kawai, A; Hayakawa, K; Setsu, N; Kawashima, H; Iwata, S; Tsuchiya, H; Tsukushi, S; Takenaka, S; Imanishi, J; Baba, I; Nagano, A; Morii, T; Shirai, T; Shimizu, K; Kawano, H

CANCER SCIENCE Vol. 113 ( 7 ) page： 2397 - 2408 2022.7

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

Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease-specific survival (DSS) and disease-free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5-year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5-year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high-grade chondrosarcoma, particularly for those with DDCS.

DOI： 10.1111/cas.15382

Recurrent genomic patterns of MPNST evolution correlate with clinical outcome Reviewed

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

CANCER RESEARCH Vol. 82 ( 12 ) 2022.6

S100-negative epithelioid malignant peripheral nerve sheath tumor with possible perineurial differentiation Reviewed

Yamashita, K; Funauchi, Y; Hayakawa, K; Ae, K; Matsumoto, S; Ikuta, K; Nishida, Y; Ueno, T; Shimoyama, Y; Hiruta, N; Machinami, R; Kawachi, H; Takeuchi, K

VIRCHOWS ARCHIV Vol. 480 ( 6 ) page： 1269 - 1275 2022.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Virchows Archiv

Epithelioid malignant peripheral nerve sheath tumor (MPNST) is a rare subtype of MPNST composed of epithelioid cells with abundant cytoplasm. Currently, strong and diffuse immunostaining for S100 protein and SOX10 is generally regarded as a characteristic feature of epithelioid MPNST. However, malignant tumors with epithelioid morphology that arise from a peripheral nerve or a pre-existing benign nerve sheath tumor should be regarded as epithelioid MPNSTs when they do not show characteristic features that definitively lead to other specific diagnoses. Here, we describe 3 cases of epithelioid MPNST in the peripheral nerve or schwannoma that was negative for S100 protein and SOX10 expression. Instead, these tumors were positive for EMA, GLUT1, claudin 1, and cytokeratin to varying degrees, while all of them retained SMARCB1 and H3K27me3 by immunohistochemistry. EMA, GLUT1, and claudin 1 are known markers of perineurial cell differentiation; thus, they could possibly represent epithelioid MPNST with perineurial cell differentiation.

DOI： 10.1007/s00428-021-03218-y

Surgical treatment for extremity rhabdomyosarcoma: longitudinal national questionnaire survey in Japan Reviewed

Nishida, Y; Kawai, A

JAPANESE JOURNAL OF CLINICAL ONCOLOGY Vol. 52 ( 4 ) page： 362 - 369 2022.4

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

Background: Extremity rhabdomyosarcoma differs from other soft tissue sarcomas, being highly sensitive to chemotherapy and radiotherapy and having a high rate of metastasis to lymph nodes. Therefore, the treatment modality differs from that of other soft tissue sarcomas. The purpose of this study was to conduct a longitudinal questionnaire survey of orthopedic oncologists in charge of surgical treatment for extremity rhabdomyosarcoma in Japan to determine whether the treatment modality chosen here is in line with the international and national treatment ones. Methods: Questionnaire surveys were conducted in 2012 and 2019 to orthopedic oncologists of Japanese Orthopaedic Association and Japanese Musculoskeletal Oncology Group. Results: Responses were obtained from 80 facilities and 76 facilities, respectively. Fewer than 50% of the facilities treated one or more patients a year in both years. Many facilities first performed diagnostic biopsy, but most did not perform pretreatment re-excision. The number of facilities that provided radiotherapy in addition to surgery increased significantly from 2012 to 2019 (P = 0.028), but it was still 21% in 2019. The number of facilities performing excision and lymph node dissection was 19% in both 2012 and 2019, which was a very low result without improvement. The departments responsible for follow-up have been changed to pediatrics and orthopedic oncology in tandem (P = 0.0004). Conclusions: Radiotherapy and pathological evaluation of lymph nodes are important for improving the prognosis of patients with extremity rhabdomyosarcoma. It is necessary to continue and develop more efficient educational activities on the appropriate medical treatment modalities for extremity RMS.

DOI： 10.1093/jjco/hyab206

Effects of Neuromuscular Electrical Stimulation on Lower Limb Muscle Strength After Living Donor Liver Transplant: A Case-Control Study Reviewed

Hattori, K; Mizuno, Y; Ogura, Y; Inoue, T; Nagaya, M; Jobara, K; Kurata, N; Nishida, Y

TRANSPLANTATION PROCEEDINGS Vol. 54 ( 3 ) page： 749 - 754 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Transplantation Proceedings

Background: Early mobilization after liver transplant (LT) plays an important role in postoperative recovery and complication prevention; however, patients undergoing LT cannot achieve early mobilization because of mechanical ventilation and poor preoperative physical performance. We investigated the effect of neuromuscular electrical stimulation (NMES) on lower limb muscle strength after living donor liver transplant (LDLT). Methods: Adult patients who underwent LDLT between December 2016 and January 2019 at a university hospital were recruited. A consecutive series of patients who underwent LDLT without NMES therapy before the clinical trial (April 2014-May 2016) were enrolled as the non-NMES (control) group. Patients in the NMES group received NMES on the quadriceps muscles starting 1 day post LDLT for 4 weeks. The study was conducted in accordance with the Declaration of Helsinki, and all patients provided informed consent. Results: Twenty-four patients in the NMES group and 16 patients in the non-NMES group were analyzed. There was no significant difference between groups regarding changes in any outcome. Conclusions: The application of NMES in patients with LDLT did not yield greater improvement of muscle strength, functional capacity, activities of daily living, or length of hospital stay 4 weeks postoperatively compared with the control group. However, developing a novel NMES device and confirming whether additional NMES is effective for other body areas may yield different results.

DOI： 10.1016/j.transproceed.2022.01.028

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

Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase Reviewed Open Access

Koike, H; Nishida, Y; Shinomura, T; Ohkawara, B; Ohno, K; Zhuo, LS; Kimata, K; Ushida, T; Imagama, S

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol. 23 ( 8 ) 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences

KIAA1199 has a strong hyaluronidase activity in inflammatory arthritis. This study aimed to identify a drug that could reduce KIAA1199 activity and clarify its effects on inflammatory arthritis. Rat chondrosarcoma (RCS) cells were strongly stained with Alcian blue (AB). Its stainability was reduced in RCS cells, which were over-expressed with the KIAA1199 gene (RCS-KIAA). We screened the drugs that restore the AB stainability in RCS-KIAA. The effects of the drug were evaluated by particle exclusion assay, HA ELISA, RT-PCR, and Western blotting. We further evaluated the HA accumulation and the MMP1 and three expressions in fibroblast-like synoviocytes (FLS). In vivo, the effects of the drug on symptoms and serum concentration of HA in a collagen-induced arthritis mouse were evaluated. Ipriflavone was identified to restore AB stainability at 23%. Extracellular matrix formation was significantly increased in a dose-dependent manner (p = 0.006). Ipriflavone increased the HA accumulation and suppressed the MMP1 and MMP3 expression on TNF-α stimulated FLS. In vivo, Ipriflavone significantly improved the symptoms and reduced the serum concentrations of HA. Conclusions: We identified Ipriflavone, which has inhibitory effects on KIAA1199 activity. Ipriflavone may be a therapeutic candidate based on its reduction of KIAA1199 activity in inflammatory arthritis.

DOI： 10.3390/ijms23084089

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

Cancers Vol. 14 ( 4 ) page： 1 - 11 2022.2

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

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

CiNii Research

Clinical outcome in patients who underwent amputation due to extremity soft tissue sarcoma: Tokai Musculoskeletal Oncology Consortium study Reviewed

Hagi, T; Nakamura, T; Nagano, A; Koike, H; Yamada, K; Aiba, H; Fujihara, N; Wasa, J; Asanuma, K; Kozawa, E; Ishimura, D; Kawanami, K; Izubuchi, Y; Shido, Y; Sudo, A; Nishida, Y

JAPANESE JOURNAL OF CLINICAL ONCOLOGY Vol. 52 ( 2 ) page： 157 - 162 2022.2

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

Background: Soft tissue sarcomas are a diverse group of rare malignant tumours, mostly occurring in the lower extremities. Amputations are necessary for achieving local control when the soft tissue sarcomas are too large and/or have neurovascular involvement. Patients who require amputation have a poorer prognosis than those who undergo limb-salvage surgery. Patients and Methods: We investigated the tumour characteristics and the clinical outcomes in 55 patients with primary soft tissue sarcomas, who underwent amputation. We excluded patients with amputation performed distal to the wrist or ankle joints and those with recurrent soft tissue sarcomas. Results: The mean tumour size was 11.1 cm. Hip disarticulation was performed in 6 patients, 20 underwent above the knee amputation, 8 underwent knee disarticulation and 12 underwent below the knee amputation. Shoulder disarticulation was performed in three patients, five underwent above the elbow amputation, and one underwent below the elbow amputation. The 5-year disease-specific survival rate was 52.8%. The 5-year recurrence-free survival rate and 5-year metastasis-free survival rates were 90.1% and 38.5%, respectively. Larger tumour size, age and the distant metastases at first presentation were predictors of poor prognosis for survival in multivariate analysis. Twenty-eight patients could walk using artificial limbs. The level of amputation (above versus below the knee) showed a significant difference in achieving independent gait. Conclusion: Amputation is a useful treatment option for achieving local control in patients with large soft tissue sarcomas. Patients had an opportunity of walking, especially for those who underwent below the knee amputation.

DOI： 10.1093/jjco/hyab184