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Hiroyuki Tsuchiya - Top 30 Publications

Usefulness of the "grand-piano sign" for determining femoral rotational alignment in total knee arthroplasty.

The "grand-piano sign" is a well-known indicator of proper rotational femoral alignment. We investigated changes in the shape of the femoral anterior cutting plane by changing the rotational alignment, anterior portion depth, and cutting plane flexion angle.

Mid- to long-term clinical outcome of giant cell tumor of bone treated with calcium phosphate cement following thorough curettage and phenolization.

Giant cell tumors of bone (GCTB) are intermediate and locally aggressive bone tumor. Calcium phosphate cement (CPC) is a bone void filler used in orthopaedic surgery. This study investigated the clinical outcome of GCTB treated with thorough curettage, phenolization, and CPC.

Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma.

We have previously established a patient-derived orthotopic xenograft (PDOX) model of undifferentiated spindle cell sarcoma (USCS). Recombinant methioninase (rMETase) has previously demonstrated efficacy in PDOX mouse models of human cancers. In the present study, we determined if rMETase in combination with doxorubicin (DOX) can overcome first-line DOX resistance in a PDOX models of USCS. The USCS PDOX mouse models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, rMETase (100 units/mouse, i.p., daily, for 2 weeks); G4, DOX (3 mg/kg, i.p., weekly, for 2 weeks) combined with rMETase (100 units/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured twice a week. On day 14 after initiation, the USCS PDOX tumor sizes were (G1): 360 ± 85 mm3; DOX (G2): 355 ± 111 mm3, p = .927; rMETase (G3): 182 ± 57 mm3, p = .0003; DOX + rMETase (G4): 134 ± 29 mm3, p = .00001. These results indicate that rMETase can overcome USCS resistance to DOX, which is first line therapy for this disease. The body weight of treated mice was not significantly different in any group. The present results demonstrate the power of the PDOX model to identify effective therapy for recalcitrant cancer and the potential of rMETase to overcome DOX resistance.

The Efficacy of Wide Resection for Musculoskeletal Metastatic Lesions of Renal Cell Carcinoma.

This study evaluated the outcome of wide resection for metastatic renal cell carcinoma (RCC) to the bone or soft tissue.

Aquaporin-1 and -5 are involved in the invasion and proliferation of soft tissue sarcomas.

Recent studies of several carcinomas have reported that aquaporin possesses novel oncogenic properties. The aim of this study was to clarify the involvement of aquaporin-1 and -5 in the proliferation, invasion and metastasis of soft tissue sarcomas.

Current status of immunotherapy for sarcomas.

Although the development of anticancer drugs has improved the outcomes of bone and soft tissue sarcomas, the clinical outcome of patients with relapsed sarcomas remains unsatisfactory due to therapeutic toxicities and resistance to anticancer drugs. Therefore, novel therapeutic modalities are needed to improve the outcome of patients with bone and soft tissue sarcomas. Dendritic cells present tumor antigens and stimulate immune responses, and immune cells, such as cytotoxic T lymphocytes, kill tumor cells by recognizing tumor antigens. However, immune-suppressive conditions by immune regulator PD-1, CTLA-4 and regulatory T cells help tumor growth and progression. In this report, current immunotherapies including cellular immunotherapy and checkpoint inhibitors are introduced, and the advantages and disadvantages of the treatments are discussed.

Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase.

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.

Risk factors for postoperative deep infection in bone tumors.

Postoperative deep infection after bone tumor surgery remains a serious complication. Although there are numerous reports about risk factors for postoperative deep infection in general surgery, there is only a small number of reports about those for bone tumor surgery. This retrospective study aimed to identify risk factors for postoperative deep infection after bone tumor resection.

Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and recalcitrant, highly-malignant mesenchymal tumor in need of improved therapeutic strategies. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). We previously described the development of a PDOX model of adult pleomorphic RMS where the tumor behaved similar to the patient donor. A high-grade pleomorphic rhabdomyosarcoma from a striated muscle was previously grown orthotopically in the right biceps-femoris muscle of nude mice to establish the PDOX model. In the present study, the PDOX models were randomized into the following treatment groups when tumor volume reached 100 mm3: G1, control without treatment; G2, cyclophosphamide (CPA) 140 mg/kg, intraperitoneal (i.p.) injection, weekly, for 3 weeks; G3, temozolomide (TEM), 25 mg/kg, per oral (p.o.), daily, for 21 days; G4, temozolomide (TEM) 25 mg/kg, p.o., daily, for 21 days combined with irinotecan (IRN), 4 mg/kg, i.p., daily for 21 days. After 3 weeks, treatment of PDOX with TEM combined with IRN was so powerful that it resulted in tumor regression and the smallest tumor volume compared to other groups. The RMS PDOX model should be of use to design the treatment program for the patient and for drug discovery and evaluation for this recalcitrant tumor type.

Mesenchymal chondrosarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study on 57 patients.

This study aimed to elucidate the clinical features and prognostic factors of mesenchymal chondrosarcoma (MCS) and investigate optimal treatment strategies.

Differences in range of motion with the same combined anteversion after total hip arthroplasty.

We investigated the various impingement angles (including both bony and prosthetic impingement) and impingement types that can occur after THA, even when the same combined anteversion parameter is used. We also investigated the relationship between impingement angle and acetabular morphology or femoral anteversion.

The accuracy of the "projected surgical transepicondylar axis" relative to the "true surgical transepicondylar axis" in total knee arthroplasty.

In TKA, we have used the "projected SEA", which is obtained by projecting the "true SEA" on the distal femoral cutting plane in clinical practice to determine the femoral component rotation. There are no reports examining the accuracy of the "projected SEA". In this study, we investigated the difference between the "true SEA" and "projected SEA".

A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology.

In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance, respectively, twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm3; CDDP (G2): 608.6±126.9 mm3; TRAB (G3): 286.6±133.0 mm3; TEM (G4): 182.9±69.1 mm3. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while accurately maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology.

A novel anionic-phosphate-platinum complex effectively targets an undifferentiated pleomorphic sarcoma better than cisplatinum and doxorubicin in a patient-derived orthotopic xenograft (PDOX).

A patient high-grade undifferentiated pleomorphic soft-tissue sarcoma (UPS) from a striated muscle was previously orthotopically implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) nude-mouse model. In the present study, two weeks after orthotopic transplantation of the UPS, mice were treated intraperitoneally with cisplatinum (CDDP), doxorubicin (DOX) or a novel anionic-phosphate-platinum compound 3Pt. Treatments were repeated weekly for a total of 3 times. Six weeks after transplantation, all mice were sacrificed and evaluated. After two weeks treatment, tumor sizes were as follows: control (G1): 2208.3 mm3; CDDP (G2): 841.8±3 mm3, p=0.0001; DOX (G3): 693.1±3 mm3, p=6.56E-7; 3Pt (G4): 333.7±1 mm3, p=4.8E-8. 3Pt showed significantly more efficacy compared to other therapy drugs tested: CDDP (p=0.0002), DOX (p=0.001). There were no animal deaths in any of the four groups. The present results suggest 3Pt is a promising new candidate for UPS since it was demonstrated to be effective in a PDOX model.

Effectiveness and Safety of Needle Medial Collateral Ligament Pie-Crusting in Total Knee Arthroplasty: A Cadaveric Study.

Effective Metabolic Targeting of Human Osteosarcoma Cells In Vitro and in Orthotopic Nude-mouse Models with Recombinant Methioninase.

Methionine dependence may be the only known general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC]) (recombinant methioninase [rMETase]), which was subsequently tested in mouse models of various types of human tumors. The present study aimed to investigate the efficacy of rMETase on human osteosarcoma cells in vitro and in vivo.

Two-dimensional motion analysis of dynamic knee valgus identifies female high school athletes at risk of non-contact anterior cruciate ligament injury.

Female athletes are at greater risk of non-contact ACL injury. Three-dimensional kinematic analyses have shown that at-risk female athletes have a greater knee valgus angle during drop jumping. The purpose of this study was to evaluate the relationship between knee valgus angle and non-contact ACL injury in young female athletes using coronal-plane two-dimensional (2D) kinematic analyses of single-leg landing.

Spontaneous shrinkage of solitary osteochondromas.

Osteochondromas are the most common benign bone tumors, and thus far, their spontaneous shrinkage is considered a rare phenomenon. This study was designed to investigate the exact ratio of remission to progressive or stable cases and analyze the mechanism of tumor regression on the basis of existing theories.

Non-tuberculous Mycobacterium or Fungus Induced Chronic Tenosynovitis with Rice Body of the Hand.

Chronic tenosynovitis of the wrist and hand is commonly seen by orthopedists, especially hand surgeons. However, cases with rice body formation are comparatively rare. Thus, we retrospectively reviewed the cases of chronic tenosynovitis in our department and evaluated the necessity of antibiotic therapy in the early post-surgical stage.

New methods for the evaluation of bone quality. Bone anabolic agents and bone quality.

Teriparatide(TPTD)products that can be used clinically in Japan include a daily subcutaneous injection form produced by genetic engineering and a weekly subcutaneous injectable TPTD acetate form produced by chemical synthesis. Published reports indicate that both forms exhibit excellent antifracture efficacy, and as the only anabolic agents that promote osteogenesis, TPTD products now occupy a prominent position. However, the two forms differ considerably, not only in frequency of administration, but also in mechanism of action. The daily form stimulates osteogenesis and accompanying resorption through more radical high bone turnover, and early in the course of treatment, intracortical porosity and apatite crystallization decrease, while immature collagen crosslinking increases. However, because daily formulations also produce an increase in cortical surface area or cortical thickness, the effects are counterbalanced, and bone strength is maintained. In contrast, the weekly form prioritizes osteogenesis, and by concurrently lowering turnover below pretreatment levels, improves trabecular bone mass and structure, and enhances strength without leading to cortical porosity and other undesirable phenomena. Abaloparatide, a PTHrP(1-34)analog that is homologous with the biologically active site of PTH drugs, is currently under development, and we eagerly anticipate further clarification of the mechanism of action of each formulation on bone.

Efficacy In Vitro of Caffeine and Valproic Acid on Patient-Derived Undifferentiated Pleomorphic Sarcoma and Rhabdomyosarcoma Cell Lines.

We have previously reported that caffeine (CAF) can enhance chemotherapy efficacy of bone and soft-tissue sarcoma established cell lines via cell-cycle perturbation. We subsequently tested the combination of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with caffeine on established human osteosarcoma cells in vitro. Both VPA and CAF caused concentration-dependent cell death of the osteosarcoma cell lines in vitro, and their combination was synergistic. We subsequently established patient-derived cell lines from undifferentiated pleomorphic sarcoma (UPS) and rhabdomyosarcoma (RMS), both of which are recalcitrant cancers. These cell lines are termed AC-UPS01 and AC-RMS01, respectively.

Incidental durotomy during total en bloc spondylectomy.

The incidence of incidental durotomy (ID) during total en bloc spondylectomy (TES) tends to be higher than that during other spinal surgeries because of the peculiarities of TES, including its highly invasive nature, epidural tumor extension, and use in patients who often have complicated medical backgrounds. However, there have been no detailed reports on ID associated with TES.

Knee joint preservation surgery in osteosarcoma using tumour-bearing bone treated with liquid nitrogen.

To preserve the joint structure in order to maintain good limb function in patients with osteosarcoma, we perform epiphyseal or metaphyseal osteotomy and reconstruction using frozen autografts that contain a tumour treated with liquid nitrogen. There are two methods of using liquid nitrogen-treated autografts: the free-freezing method and the pedicle-freezing method. The purpose of this study was to evaluate the results of intentional joint-preserving reconstruction using the free-freezing method and the pedicle-freezing method in patients with osteosarcoma.

Reliability of radiographic evaluations of the stage of osteoarthritis of the hip joint and an approach to improve the staging criteria.

A few reports have shown that the reliability of the Japanese Orthopaedic Association stage classification of hip osteoarthritis was not high. The objective of this study was to assess the reliability of the stage classification of coxarthrosis, and to evaluate whether a modification of the classification improves reliability.

Contribution of methylglyoxal to delayed healing of bone injury in diabetes.

Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end‑products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/kg) for 5 days. A bone defect (1.0‑mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0‑400 µM) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493±14.1 mg/dl and 8.0±0.05%, respectively. Compared with non‑diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO‑derived AGEs, Nε‑(carboxymethyl)‑lysine and Nδ‑(5‑hydro‑5‑methyl‑4‑imidazolone‑2‑yl)‑ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose‑dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.

An unusual case of proximal humeral simple bone cyst in an adult from secondary cystic change.

Simple bone cysts (SBC) have been documented to occur in adults with closed physeal plates, most commonly affecting the calcaneus in this patient subset. Although most authors theorize an association to trauma, etiology of simple bone cysts remains an enigma up to now.

Galeazzi-equivalent Fractures: Report of Two Cases and Literature Review.

The Galeazzi-equivalent fracture is a rare injury that occurs in children. The most important issue is the distal ulnar epiphyseal injury. Although there have been some case reports, most of them performed only short term follow-up. This article describes two cases of this fracture with long term follow-up until epiphyseal closure. First case is a 12-year-old girl who sustained a Galeazziequivalent fracture of her right forearm and underwent emergency surgery. At follow-up of 5 years and 10 months postsurgery, radiographs show ulnar growth arrest of one mm and she has mild pain. Second case is a 15-year-old boy who sustained an open Galeazzi-equivalent fracture of his left forearm and underwent emergency surgery. At follow-up of 3 years and 3 months postsurgery, radiographs show no growth arrest of the distal ulna. He has no residual complaint. Long term follow-up is absolutely necessary to monitor ulnar growth.

Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model.

Previously, a patient-derived orthotopic xenograft (PDOX) model was established with a lung metastasis from an osteosarcoma patient which developed after adjuvant cisplatinum (CDDP) treatment. In this model, we previously demonstrated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared with CDDP. In the present report, osteosarcoma tissue was implanted orthotopically in the distal femur of mice which were randomized into the following groups when tumor volume reached approximately 100 mm3; On day 14 after initiation of treatment, all but CDDP significantly inhibited tumor volume growth compared with untreated controls. Control (G1): 793.7 ± 215.0 mm3; CDDP (G2): 588.1 ± 176.9 mm3; Salmonella typhimurium A1-R (S. typhimurium A1-R) intravenous (i.v.) (G3): 269.7 ± 72.7 mm3; S. typhimurium A1-R intra-arterial (i.a.) (G4): 70.2 ± 18.9 mm3 (CDDP: p = 0.056; S. typhimurium A1-R i.v.: p = 0.0001; S. typhimurium A1-R i.a.: p = 0.00003, all vs. untreated controls). i.a. administration of S. typhimurium A1-R was significantly more effective than either CDDP (p = 0.00007), or i.v. administration of S. typhimurium A1-R (p = 0.00007) and significantly regressed the tumor volume compared with day 0 (p = 0.001). The new model of i.a. administration of S. typhimurium A1-R has great promise for the treatment of recalcitrant osteosarcoma.

Giant cell tumor of the thoracic spine completely removed by total spondylectomy after neoadjuvant denosumab therapy.

Denosumab, a novel monoclonal antibody that targets the receptor activator of nuclear factor-κB (RANK) ligand (RANKL), has recently been used to treat patients with giant cell tumor of bone (GCTB). However, few reports have described the clinical results of denosumab therapy for spinal GCTB and evaluated treatment efficacy with respect to the entirety of the resected vertebra after denosumab therapy.

Inhibition of biofilm formation on iodine-supported titanium implants.

We have developed iodine-supported titanium implants that suppress microbial activities and conducted in vivo and in vitro studies to determine their antimicrobial properties.