Biomedical subjects

Tadahiko Kubo

Publications and source records attributed to Tadahiko Kubo.

15 recordsLinked to original sources

PubMed2006

Conservative surgery for well-differentiated liposarcomas of the extremities adjacent to major neurovascular structures.

BACKGROUND: There is no clear consensus as to the appropriate nomenclature and the best surgical strategy for well-differentiated liposarcomas. A wide surgical excision is recommended over marginal resection for local control of well-differentiated liposarcomas. However, this surgical procedure should be reconsidered for lesions, which come into contact with major neurovascular structures. METHODS: Between 1998 and 2004, 12 well-differentiated liposarcomas of the extremities were treated at our institute. Among them, nine lesions (75%) adjacent to major nerves or blood vessels were marginally resected with careful dissection of these critical structures. The clinical outcomes were reviewed for a mean follow-up time of 4 years. RESULTS: Seven patients continued to be disease-free without any loss of limb function. One patient developed a local recurrence 30 months postoperatively. The other patient with a foot lesion involving the fourth metatarsal bone has experienced slight difficulty in gait-balancing due to the fourth toe amputation, but remains free of disease. The local control rate was 88.9%, even though seven lesions were resected with positive surgical margins. CONCLUSIONS: Our findings suggested that well-differentiated liposarcomas frequently arise in close proximity to major nerves or blood vessels. Marginal resection alone seems to be adequate for these lesions to preserve critical structures.

Adult↗

PubMed2006

Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cells.

Little is known about the biological effects of bisphosphonates on primary malignant bone tumors. The purpose of this study was to investigate the antitumor effects of newly developed minodronate (MIN) on a variety of human malignant bone tumors. We examined the effects of MIN and clinically relevant incadronate (INC) on the proliferation, apoptosis, and cell cycle of two osteosarcoma (Saos-2, MG-63), two chondrosarcoma (SW1353, OUMS27), and two Ewing's sarcoma (RD-ES, SK-ES-1) cell lines. Furthermore, we investigated the anti-invasion effects of MIN on sarcoma cells and the effects of MIN on tumor growth in nude mice. MIN inhibited the viability of all six cell lines in a dose-dependent manner with IC50 values of 2.7 to 5.0 microM, which were significantly lower than those of INC. Importantly, both bisphosphonates affected the viability of normal bone marrow stromal cells much less than sarcoma cells. Both bisphosphonates induced cell cycle perturbation in all sarcoma cells tested and apoptosis in Saos-2 and SW1353 cells, although they failed to induce apoptosis in RD-ES and SK-ES-1 cells. MIN significantly suppressed invasion, even at a low concentration of 1 microM (p < 0.01). Daily injection of 5 microg of MIN inhibited the growth of SK-ES-1 xenograft sarcoma in nude mice without loss of body weight. These findings suggest that MIN may have a beneficial adjuvant role in the treatment of patients with malignant bone tumors.

Animals↗

PubMed2005

Nerve tolerance to high-dose-rate brachytherapy in patients with soft tissue sarcoma: a retrospective study.

BACKGROUND: Brachytherapy, interstitial tumor bed irradiation, following conservative surgery has been shown to provide excellent local control and limb preservation in patients with soft tissue sarcomas (STS), whereas little is known about the tolerance of peripheral nerves to brachytherapy. In particular, nerve tolerance to high-dose-rate (HDR) brachytherapy has never been properly evaluated. In this study, we examined the efficacy and radiation neurotoxicity of HDR brachytherapy in patients with STS in contact with neurovascular structures. METHODS: Between 1995 and 2000, seven patients with STS involving the neurovascular bundle were treated in our institute with limb-preserving surgery, followed by fractionated HDR brachytherapy. Pathological examination demonstrated that 6 patients had high-grade lesions with five cases of negative margins and one case with positive margins, and one patient had a low-grade lesion with a negative margin. Afterloading catheters placed within the tumor bed directly upon the preserved neurovascular structures were postoperatively loaded with Iridium-192 with a total dose of 50 Gy in 6 patients. One patient received 30 Gy of HDR brachytherapy combined with 20 Gy of adjuvant external beam radiation. RESULTS: With a median follow-up of 4 years, the 5-year actuarial overall survival, disease-free survival, and local control rates were 83.3, 68.6, and 83.3%, respectively. None of the 7 patients developed HDR brachytherapy-induced peripheral neuropathy. Of 5 survivors, 3 evaluable patients had values of motor nerve conduction velocity of the preserved peripheral nerve in the normal range. CONCLUSION: In this study, there were no practical and electrophysiological findings of neurotoxicity of HDR brachytherapy. Despite the small number of patients, our encouraging results are valuable for limb-preserving surgery of unmanageable STS involving critical neurovascular structures.

Adolescent↗

PubMed2005

Clinical outcomes of 54 pelvic osteosarcomas registered by Japanese musculoskeletal oncology group.

BACKGROUND: To determine the clinical outcomes in patients with pelvic osteosarcoma, we reviewed the experience with 54 pelvic osteosarcoma patients. METHODS: Thirty-five patients underwent surgical treatment with 30 undergoing limb salvage procedures and 5 requiring hemipelvectomies. RESULTS: Oncological outcome was continuously disease free in 12 cases, no evidence of disease in 3, alive with disease in 3, died of disease in 34 and died of other causes in 2. The 5-year survival rate was 29.5%. For the patients who underwent surgery, statistically significant prognostic factors were chemotherapy, surgical margin, tumor location in sacrum, efficacy of chemotherapy, local recurrence, metastasis and treatment for metastases. With univariate analysis, local recurrence, surgical margin and tumors resected from the sacrum were significant prognostic factors for metastasis. Surgical margin, tumor resected from sacrum and metastasis were significant prognostic factors for local recurrence. With regard to postoperative functional mobility, patients with tumors resected from the sacrum exhibited poorer functional mobility when compared with other sites. CONCLUSIONS: Patients with tumors located in the sacrum had worse prognosis, and significant prognostic factor for local recurrence and metastasis. Treatment of pelvic osteosarcoma especially located in the sacrum requires new approaches and further improvements in order to ensure successful outcomes.

Adolescent↗

PubMed2005

Efficiency of magnetic liposomal transforming growth factor-beta 1 in the repair of articular cartilage defects in a rabbit model.

We evaluated the efficacy of a magnetic liposomal delivery system of transforming growth factor (TGF)-beta(1) in the treatment of articular cartilage defects in a rabbit model. Articular cartilage defects were created in the patellar groove of rabbits, and a permanent magnet or a nonmagnetic alloy was implanted in the defect site. Magnetic liposomal drugs, prepared by the conventional film method and sonication, were injected into the defect site 1 week after surgery. First, the efficacy of the magnetic liposomal delivery system was evaluated by using a model compound fluorescence-labeled dextran 40,000 (FD-40). Then, the therapeutic efficiency of magnetic liposomal TGF-beta(1) was evaluated by cartilage histological scoring at 4, 8, and 12 weeks after surgery. The injected magnetic liposomal FD-40 accumulated at the target site where a permanent magnet had been implanted. The histological score showed that the injection of magnetic liposomal TGF-beta(1) under magnetic force was significantly effective in the repair of the defect site over 12 weeks after surgery. Injection of TGF-beta(1) into the cartilage defect was effective as a magnetic liposomal preparation under magnetic force, resulting in acceleration of the cartilage repair, probably because of the desirable accumulation of TGF-beta(1) at the target site.

Animals↗

PubMed2005

Reconstructed patellar tendon length after proximal tibia prosthetic replacement.

A common problem after proximal tibia prosthetic reconstruction is insufficient extensor mechanism or extensor lag. Maintaining the reconstructed patellar tendon length is an important way to minimize extensor lag. We measured the patellar tendon length and extensor lag serially. From 1994-2003, seven consecutive patients with malignant bone tumors of the proximal tibia had prosthetic reconstruction. The extensor mechanism was reconstructed by reattachment of the patellar tendon to the prosthesis with a synthetic material and augmented by a gastrocnemius flap. The patellar tendon length was measured according to the Insall-Salvati ratio. The ratios at 30 degrees knee flexion decreased immediately postoperatively, and reverted to almost the same preoperative values within 18 months. The mean ratios at 60 degrees knee flexion are significantly greater than 30 degrees at 6 months postoperatively. These findings indicate that the patellar tendon stretched, whereas the extensor lag improved continuously for 12 months postoperatively. In the revision at 22 months postoperatively, although the patellar tendon was not reattached to the replaced prosthesis, the ratio and the extensor lag had not worsened. These results show that providing strong continuity of the patellar tendon, gastrocnemius flap, and leg extensors can decrease the extensor lag, although the patellar tendon stretches.

Adolescent↗

PubMed2004

Evaluation of systemic chemotherapy with magnetic liposomal doxorubicin and a dipole external electromagnet.

The development of an active drug delivery system is an attractive approach to increase the targetability of anticancer agents. In the present study, we examined the efficiency of systemic chemotherapy with small magnetic liposomes containing doxorubicin (magnetic DOX liposomes) and an externally applied electromagnetic force in osteosarcoma-bearing hamsters. Syrian male hamsters inoculated with osteosarcoma, OS515, in the limb were studied 7 days after inoculation. The efficiency of this system was evaluated by measuring the tissue distribution and tumor-suppressing effects of DOX on primary tumor growth and lung metastases. A DC dipole electromagnet was used, and the hamster's tumor-bearing limb was placed between 2 poles after the i.v. administration of liposomes. The dose of DOX and the magnetic field strength were fixed at 5 mg/kg and 0.4 T, respectively. Administration of magnetic DOX liposomes followed by 60 min application of magnetic field produced a 3- to 4-fold higher maximum DOX concentration in the tumor. This newly designed systemic chemotherapy significantly suppressed primary tumor growth for at least 2 weeks, though other DOX treatments also suppressed compared to control. Histologic examination confirmed a greater antitumor effect of this systemic chemotherapy compared to standard methods. In addition, this approach significantly suppressed lung metastases measured at 3 weeks posttreatment. These results suggest that this systemic chemotherapy can effectively reduce primary tumor growth and suppress lung metastasis due to increased targeting of DOX. Such targeted drug delivery for anticancer agents would provide clinical advantages compared to current methods.

Animals↗

PubMed2004

Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway.

Osteosarcoma (OS) is a primary malignancy of bone with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, approximately 30% of patients still develop distant metastasis. Our previous work using clinical OS samples suggested that expression of the Wnt receptor LRP5 might be associated with tumor metastasis. In the present study, we used a Dickkopf (Dkk) family member and a dominant-negative LRP5 receptor construct to modulate Wnt signaling in OS cells. Saos-2 cells, which ectopically express Dkk-3, do not undergo apoptosis and exhibit enhanced resistance to serum starvation and chemotherapy-induced cytotoxicity. Transfection of Dkk-3 and dominant-negative LRP5 into Saos-2 cells significantly reduces invasion capacity and cell motility. This blockade is associated with changes in cell morphology consistent with a less invasive phenotype. In addition, Dkk-3 and dominant-negative LRP5 also induce changes in beta-catenin localization consistent with an increase in cell-cell adhesion. Taken together, these results support a possible role for Wnt signaling in the pathobiology and progression of human OS.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma.

BACKGROUND: We have developed magnetite cationic liposomes (MCLs) and applied them to local hyperthermia as a mediator. MCLs have a positive charge and generate heat under an alternating magnetic field (AMF) by hysteresis loss. In this study, the effect of hyperthermia using MCLs was examined in an in vivo study of hamster osteosarcoma. METHOD: MCLs were injected into the osteosarcoma and then subjected to an AMF. RESULTS: The tumor was heated at over 42 degrees C, but other normal tissues were not heated as much. Complete regression was observed in 100% of the treated group hamsters, whereas no regression was observed in the control group hamsters. At day 12, the average tumor volume of the treated hamsters was about 1/1000 of that of the control hamsters. In the treated hamsters, no regrowth of osteosarcomas was observed over a period of 3 months after the complete regression. CONCLUSION: These results suggest that this treatment is effective for osteosarcoma.

Journal Article↗

PubMed2004

Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma.

The Wingless-type (Wnt) family of proteins and its coreceptor LRP5 have recently been implicated in human skeletal development. Wnt pathway modulates cell fate and cell proliferation during embryonic development and carcinogenesis through activation of receptor-mediated signaling. Osteosarcoma (OS) is a bone-forming tumor of mesenchymal origin whose growth control has been linked to autocrine or paracrine stimulation by several growth factor families. We examined 4 OS cell lines for WNT1, WNT4, WNT5A, WNT7A, WNT11, FZD1-10 and LRP5 expression by reverse transcription polymerase chain reaction (RT-PCR). In addition, RT-PCR for LRP5 expression was performed in 44 OS patient samples and the findings were correlated with clinical data. Expression profiling of Wnts and their receptors revealed the presence of several isoforms in OS cell lines. Overall, 22/44 (50%) of OS patient samples showed evidence of LRP5 expression. Presence of LRP5 correlated significantly with tumor metastasis (p = 0.005) and the chondroblastic subtype of OS (p = 0.045). In addition, patients whose tumors were positive for LRP5 showed a trend toward decreased event-free survival (p = 0.066). No significant association was found between LRP5 expression and age, gender, site of disease, site of metastasis or degree of chemotherapy-induced tumor necrosis. Sequencing of exon 3 of LRP5 in 10 OS patient-derived cell cultures showed no activating mutation of LRP5. These results showed that expression of LRP5 is a common event in OS and strongly suggest a role for LRP and Wnt signaling in the pathobiology and progression of this disease.

Adolescent↗

PubMed2003

Injectable magnetic liposomes as a novel carrier of recombinant human BMP-2 for bone formation in a rat bone-defect model.

Small-sized magnetic liposomes with incorporated recombinant human bone morphogenetic protein-2 (rhBMP-2) were prepared, and the efficiency for bone formation after topical injection was evaluated in a rat bone-defect model. A critical-sized segmental bone defect was created in the mid-part of the femoral shaft, and a permanent magnet was attached. Topical injection onto the defects was performed with different liposomal preparations (nonmagnetic and magnetic liposomes) using different treatment modalities (different doses and different treatment timing of rhBMP-2). Weekly evaluations were made radiographically and microcomputed tomographically, histologically, and/or by mechanical testing at 9 weeks after surgery. A single topical application of magnetic liposomes with an appropriate amount of rhBMP-2 (approximately 3 microg) incorporated under magnetic induction immediately after surgery was effective for new bone formation. The combined treatment of topical magnetic rhBMP-2 liposomes and magnetic implantation at the injury site was effective for the treatment of bone defects. This injectable carrier for BMP is expected to have many advantages over solid carriers because it can be prepared easily and can be less invasively applied to the injured site at any time after surgery.

Animals↗

PubMed2003

Targeted gene delivery to human osteosarcoma cells with magnetic cationic liposomes under a magnetic field.

Gene delivery using cationic liposomes results in relatively low transfection, especially under in vivo conditions. This system, however, can overcome some of the problems associated with viral delivery systems. The present study was carried out in order to improve the transfection efficiency of cationic liposomes by preparing magnetic cationic liposomes (MCL). Small MCL approximately 40 nm in diameter and incorporating one or two magnetite particles were prepared with phosphatidylethanolamine and 3beta-[N-(N', N'-dimethylaminoethane)-carbamoyl] cholesterol. The efficiency of MCL in gene delivery was evaluated by using plasmid DNA containing a luciferase reporter gene and human osteosarcoma Saos-2 cells. Without a magnetic field, maximum luciferase activity was observed when DNA was mixed with MCL at a 1:5 ratio and incubated with cells for 6 h. Under a magnetic field, maximum luciferase activity was achieved by 30-min magnetic induction. This improvement in transfection efficiency by magnetic induction was approximately 3.5-fold. The feasibility of this active transgenic system was further shown by measuring apoptosis rates after transfection of the p53 gene to Saos-2 cells. Apoptosis rates increased to 18.9% from 2.4% by magnetic induction. In conclusion, a gene delivery system including MCL and magnetic induction was found to achieve rapid and enhanced gene delivery in vitro. Such a gene delivery system may be applicable under in vivo conditions, and is expected to offer numerous clinical advantages.

Bone Neoplasms↗

PubMedDate not supplied

Acetabular osteosarcoma treated by irradiation-vascularized hybrid bone graft.

BACKGROUND: Periacetabular reconstruction after malignant bone tumor resection to preserve limb function is extremely challenging. The optimal reconstruction method has not yet received consensus and the functional outcomes still remain unsatisfactory. CASE REPORT: A thirteen-year-old girl who was suffering from acetabular osteosarcoma was treated with wide excision of the tumor, followed by periacetabular reconstruction with an autogenous extracorporeal irradiated osteoarticular graft combined with a vascularized fibula graft. Incorporation of the irradiated pelvic bone was achieved despite infection and limb function turned out to be acceptable. CONCLUSION: This is the first report on an irradiation-vascularized hybrid autograft to reconstruct massive bone loss in primary limb-sparing surgery.

Acetabulum↗

PubMedDate not supplied

Histological findings in a human autogenous pasteurized bone graft.

BACKGROUND: Autogenous bone graft after pasteurization is one of the most valuable procedures for reconstruction of large bone defects following excision of malignant musculoskeletal tumors. To date, there have been no documented histological reports on pasteurized bone grafts, apart from short-term histological results. CASE REPORT: We treated a 27-year-old male with a periosteal chondrosarcoma of the tibia by wide excision and reimplantation of the large pasteurized bone. Biopsy specimens harvested from the pasteurized bone over 3 years after reimplantation were evaluated histologically. The graft cortices remained totally necrotic with empty osseous lacuna, whereas the architecture of the acellular cortical bones was still maintained without microfractures. Deposited seams of woven bone existed focally on the surface of the acellular trabeculae. CONCLUSION: Our medium-term histological outcome suggests the limitations of incorporating a pasteurized hone graft, but also advocates its role as a useful temporary material for the reconstruction of massive bone defects.

Adult↗

PubMedDate not supplied

Postradiation malignant fibrous histiocytoma and osteosarcoma of a patient with high telomerase activities.

BACKGROUND: An extremely rare case of postradiation malignant fibrous histiocytoma (MFH) and osteosarcoma (OS) secondary to radiation therapy for leukemia-related osteolytic lesions is presented. In addition, the telomere biology of these tumors was investigated. CASE REPORT: A 14-year-old boy was diagnosed with acute lymphocytic leukemia. The right tibia was irradiated at a total dose of 60 Gy, and the left tibia was irradiated at a total dose of 40 Gy. The left tibia developed MFH and the right tibia developed OS. RESULTS: Telomere reduction (MFH 70.2, OS 70.0%) and high telomerase activities (MFH 12.1, OS 17.7 TPG) were observed. These results reflect an aggressive feature of postradiation sarcomas. CONCLUSION: Prognosis for patients diagnosed with postradiation sarcoma is poor due to its aggressiveness. However, even if sarcoma occurs after irradiation in more than two fields in a single patient, improvements in prognosis are anticipated with appropriate chemotherapies and wide resection.

Adolescent↗