Benign metastasizing leiomyoma in femur and thigh with a history of uterine leiomyoma: A case report and literature review.

Benign metastasizing leiomyoma (BML) is a rare disease that is characterized by well-differentiated smooth muscle tumors occurring extrauterine site in women with a history of uterine leiomyoma. The lung is the most common metastatic site for BML. A 48-year-old woman, who had histories of laparoscopic myomectomy and transabdominal total hysterectomy, visited an orthopedics complaining of a mass in her left thigh and difficulty in walking. Magnetic resonance imaging (MRI) and fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography revealed multiple mass lesions in her both thighs and left femur as well as both lungs. She was referred to our hospital for further examination. We diagnosed her tumors as BML according to histopathological analysis of tumor specimen. The left thigh tumor was resected and the treatment with gonadotropin releasing hormone agonist regressed the size of the residual tumors by approximately 30%. BML should be considered when multiple soft tissue tumors are found in women with a history of leiomyomas.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: a study protocol.

BACKGROUND: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue. Diffuse TGCT (D-TGCT) most commonly develops in the knee, followed by the hip, ankle, elbow, and shoulder. Surgical removal is the only effective treatment option for the patients. However, a local recurrence rate as high as 47% has been reported. Recently, we revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. It plays an important role in the differentiation of adipocytes from precursor cells and exhibits antitumorigenic effects on certain malignancies. Therefore, we are conducting this investigator-initiated clinical trial to evaluate whether zaltoprofen is safe and effective for patients with D-TGCT or unresectable localized TGCT (L-TGCT). METHODS: This study is a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with D-TGCT or L-TGCT. For the treatment group, zaltoprofen 480 mg/day will be administered for 48 weeks; the placebo group will receive similar dosages without zaltoprofen. Twenty participants in each group are needed in this trial (40 participants total). The primary outcome is the progression-free rate at 48 weeks after treatment administration. "Progression" is defined as any serious events (1. Repetitive joint swelling due to hemorrhage, 2. Joint range of motion limitation, 3. Invasion of adjacent cartilage or bone, 4. Severe joint space narrowing, 5. Increase in tumor size) requiring surgical interventions. We hypothesize that the zaltoprofen group will have a higher progression-free rate compared to that of the placebo group at 48 weeks. DISCUSSION: This is the first study to evaluate the efficacy of zaltoprofen in patients with D-TGCT or unresectable L-TGCT. We believe that the results of this trial will validate a novel treatment option, zaltoprofen, to stabilize disease progression for TGCT patients. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( UMIN000025901 ) registered on 4/01/2017.

Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models.

Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor α in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.

Limb saving surgery for Ewing's sarcoma of the distal tibia: a case report.

BACKGROUND: Ewing's sarcoma is a primary malignant tumor of bone occurring mostly in childhood. Few effective reconstruction techniques are available after wide resection of Ewing's sarcoma at the distal end of the tibia. Reconstruction after wide resection is especially difficult in children, as it is necessary to consider the growth and activity of the lower limbs. CASE PRESENTATION: A 12-year-old Japanese boy had presented with right lower leg pain at age 8 years. Imaging examination showed a bone tumor accompanied by a large extra-skeletal mass in the distal part of his tibia. The tumor was histologically diagnosed as Ewing's sarcoma. The patient received chemotherapy, followed by wide resection. Reconstruction consisted of a bone transport method involving external fixation of Taylor Spatial Frame. To prevent infection after surgery, the external fixation pin was coated with iodine. One year after surgery, the patient showed poor consolidation of bone, so iliac bone transplantation was performed on the extended bones and docking site of the distal tibia. After 20 months, tibia formation was good. Three years after surgery, there was no evidence of tumor recurrence or metastases; bone fusion was good, and he was able to run. CONCLUSIONS: The bone transport method is an effective surgical method of reconstruction after wide resection of a bone tumor at the distal end of the tibia, if a pin can be inserted into the distal bone fragment. Coating external fixation pins with iodine may prevent postoperative infection.

Subperiosteal inflammatory pseudotumor mimicking primary malignant bone tumor: A case report.

We report a case of IgG4-positive inflammatory pseudotumor mimicking malignant bone tumor. Biopsy revealed no tumor cells. Surgical excision was performed and an abscess developing beneath the periosteum was observed with Streptococcus constellatus. Preoperative serum IgG4 value of 120 mg/dl normalized postoperatively to 80.6 mg/dl. It was difficult to distinguish inflammatory pseudotumor from sarcoma because it developed under the periosteum. In such cases, it is important to measure blood IgG4 values and perform tissue staining and culturing.

The outcomes of reconstruction using frozen autograft combined with iodine-coated implants for malignant bone tumors: compared with non-coated implants.

OBJECTIVE: We perform reconstruction using frozen tumor bone treated by liquid nitrogen after excision of malignant bone tumors. To prevent post-operative infection, we use iodine-coated implants that we developed. The purpose of this study is to compare the outcome of reconstruction using frozen autograft with non-coated implants (group N) and iodine-coated implants (group I). METHODS: Sixty-two patients were included in group N. The mean age was 31.9 ± 2.3 years. A total of 20 patients died and two were lost to follow-up, averaging 20.0 ± 2.9 months post-operatively, leaving 40 patients available for an assessment at a mean of 79.1 ± 5.8 months post-operatively. There were 38 patients in group I. The mean age was 29.8 ± 3.9 years. The mean follow-up period was 32.1 ± 3.0 months. All patients were alive at the latest follow-up. Survival of frozen bone was determined by Kaplan-Meier analysis. RESULTS: In group N, survival of frozen bone was 80.7 ± 6.0% and 57.4 ± 10.2% at 5 and 10 years, respectively. Complications were encountered in 31 of 62 patients (50.0%), including deep infection in 10 (16.1%), fracture in 11 (17.7%), local soft-tissue recurrence in 6 (9.7%) and bone absorption in 4 (6.5%). In group I, survival of frozen bone was 86.7 ± 6.3% at 5 years. Complications were encountered in 8 of 38 patients (21.1%), including deep infection in one (2.6%), fracture in four (10.5%), local soft-tissue recurrence in two (5.3%) and bone absorption in one (2.6%). There was a significantly lower infection rate in group I (P = 0.032). CONCLUSION: Reconstruction using frozen autograft combined with iodine-coated implants for patients with malignant bone tumor is very useful method in which good limb function can be gained with minimized risk of infection.

Magnetic resonance angiography evaluation of the bone tunnel and graft following ACL reconstruction with a hamstring tendon autograft.

PURPOSE: In this study, magnetic resonance angiography (MRA) was performed in the early phase after anterior cruciate ligament (ACL) reconstruction to analyse the changes in nutrient blood vessels and blood flow to the femoral and tibial tunnels and the intraosseous tendon grafts. METHODS: The subjects were 30 patients who underwent single-bundle ACL reconstruction with an autogenous hamstring tendon. MRA was performed at 2, 3, and 6 months postoperatively (n = 10 at each time point). The mean overall signal-to-noise ratios (SNRs) in the tunnel regions and in the region of the tendon graft were compared in each femur and tibia. RESULTS: Blood vessels from arteries reached the femoral and tibial tunnels 2 months postoperatively. The tunnel walls showed high signal intensity, while the intraosseous tendon grafts had lower intensity. SNRs showed significant differences between the femoral and tibial tunnels overall and the intraosseous tendon grafts. At 3 and 6 months postoperatively, the signal intensity of the tunnel walls was decreased significantly, while that of the intraosseous tendon grafts was also decreased, but not significantly. At these times, the SNRs of the femoral and tibial tunnels did not differ significantly, both overall and in the region of the intraosseous tendon grafts. CONCLUSION: Revascularization around the femoral and tibial tunnels occurred at 2 months postoperatively, with blood flow subsequently decreasing over time until 6 months. This revascularization may be involved in bone tendon healing and maturation of the tendon graft within the bone tunnels. Evaluations of revascularization by MRA may show the maturation stage of the graft and guide medical rehabilitation. LEVEL OF EVIDENCE: IV.

Quantitative evaluation of revascularization at bone tunnels and grafts with contrast-enhanced magnetic resonance angiography after anterior cruciate ligament reconstruction.

PURPOSE: Quantitative evaluation of vascular ingrowth to the bone tunnel walls and tendon graft after anterior cruciate ligament reconstruction for up to two years post-surgery using magnetic resonance angiography (MRA). METHODS: The study population consists of 100 patients that underwent reconstruction with multi-stranded semitendinosus tendons. The patients were retrospectively divided into those that underwent MRA two, three, four to six, and ≥ seven months after surgery (46, 17, 16, and 21 patients, respectively). Digital imaging and communication in medicine (DICOM) MRA images were imported into image processing software (OsiriX®), and the mean signal-to-noise ratio (SNR) of the bone tunnel walls in the femur and tibia and tendon graft parenchyma in the bone tunnels were measured. RESULTS: On MRA, the signal intensities of the bone tunnel walls in the femur and tibia (12.6 ± 3.41 and 10.7 ± 3.04) were greater than that in the tendon graft (2.65 ± 1.94 and 2.50 ± 2.02, respectively) at two months after surgery. At three months after surgery, the intensities of the tendon grafts (6.25 ± 2.18 and 5.77 ± 1.57, respectively) were greater than those of the bone tunnel wall (2.56 ± 1.29 and 2.50 ± 1.11, respectively). At four to six months, the intensities in the bone tunnel wall were 1.76 ± 0.73 and 1.62 ± 0.72, respectively, and those in the tendon graft were 5.01 ± 2.11 and 4.01 ± 2.35, respectively. At ≥ seven months after surgery, the intensities in the bone tunnel wall were 1.36 ± 0.63 and 1.21 ± 0.87, respectively, and those in the tendon graft were 4.25 ± 1.87 and 3.44 ± 1.99, respectively. CONCLUSION: Blood flow was seen around the bone tunnel on the femoral and tibial sides two months after ACL reconstruction and in the tendon graft parenchyma three months after surgery. The remodeling process continued after seven months.

Metastasis of differentiated thyroid cancer in the subchondral bone of the femoral head: a case report.

BACKGROUND: Differentiated thyroid cancer (DTC) is relatively rare and can metastasize to both the lungs and bones. The great majority of bone metastases occur in red marrow regions where blood flow is high. Only one patient has been described with direct DTC metastasis to the subchondral bone of the femoral head. CASE PRESENTATION: The patient was a 68-year-old Japanese female who had presented with left hip joint pain at age 63 years. At age 51 years, she had been diagnosed with DTC and underwent partial excision. X-rays showed partial femoral head collapse, suggesting osteoarthritis or idiopathic necrosis of the left femoral head. Three years later, a (131) I whole-body scan showed accumulation in the left femoral head, resulting in a diagnosis of DTC metastasis to the left femoral head. Bipolar hip arthroplasty was performed. Examination of the excised femoral head resulted in a final diagnosis of metastasis of follicular thyroid cancer, which was limited histopathologically to the subchondral bone of the femoral head. CONCLUSION: Tumor metastasis to the subchondral bone of the femoral head is exceedingly rare. Overall survival of patients with bone metastasis is improved by complete resection. Differential diagnosis of patients with a previous history of DTC who present with femoral head collapse should include bone metastasis of DTC.

Factors affecting range of motion after total knee arthroplasty in patients with more than 120 degrees of preoperative flexion angle.

PURPOSE: The postoperative flexion angle reportedly shows a positive correlation with the preoperative flexion angle, but in some cases, the postoperative flexion angle decreases in patients with a large preoperative flexion angle. The purpose of this study was to investigate factors affecting the range of motion after total knee arthroplasty (TKA) in patients with a large preoperative flexion angle. METHODS: The study evaluated 120 knees with more than 120 degrees of preoperative flexion angle that underwent NexGen LPS-Flex mobile bearing. The groups with and without a reduction in the postoperative flexion angle were compared. Also, a logistic regression analysis was performed, where the presence or absence of a reduction in the postoperative flexion angle was the dependent variable and age, sex, body mass index (BMI), preoperative femorotibial angle (FTA), γ angle, δ angle, pre/postoperative change amount in posterior condylar offset (PCO), pre/postoperative change amount in joint line, and pre/postoperative change amount in patellar thickness were independent variables. RESULTS: Those with preoperative FTA of 186° or larger did not have a reduction in the postoperative flexion angle, compared with the angle of 185° or smaller. Those with δ angle of 83° or smaller also did not have a reduction in the postoperative flexion angle, compared with the angle of 84° or larger. CONCLUSIONS: Our results showed that preoperative FTA and δ angle had an impact on a reduction in the postoperative flexion angle. The installation angle of the tibial component in the sagittal plane is important.

Hydrostatic pressure influences HIF-2 alpha expression in chondrocytes.

Hypoxia-inducible factor (HIF)-2α is considered to play a major role in the progression of osteoarthritis. Recently, it was reported that pressure amplitude influences HIF-2α expression in murine endothelial cells. We examined whether hydrostatic pressure is involved in expression of HIF-2α in articular chondrocytes. Chondrocytes were cultured and stimulated by inflammation or hydrostatic pressure of 0, 5, 10, or 50 MPa. After stimulation, heat shock protein (HSP) 70, HIF-2α, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-13, MMP-3, and vascular endothelial growth factor (VEGF) gene expression were evaluated. The levels of all gene expression were increased by inflammatory stress. When chondrocytes were exposed to a hydrostatic pressure of 5 MPa, HIF-2α, MMP-13, and MMP-3 gene expression increased significantly although those of HSP70 and NF-κB were not significantly different from the control group. In contrast, HIF-2α gene expression did not increase under a hydrostatic pressure of 50 MPa although HSP70 and NF-κB expression increased significantly compared to control. We considered that hydrostatic pressure of 5 MPa could regulate HIF-2α independent of NF-κB, because the level of HIF-2α gene expression increased significantly without upregulation of NF-κB expression at 5 MPa. Hydrostatic pressure may influence cartilage degeneration, inducing MMP-13 and MMP-3 expression through HIF-2α.

Prevention of pin tract infection with iodine-supported titanium pins.

BACKGROUND: Pin tract infection is one of the most common complications of external fixation. We developed techniques to coat titanium implant surfaces with iodine. This study clinically evaluated the infection-preventive effects and biological safety of iodine-coated external fixation pins. PATIENTS AND METHODS: Iodine-supported pins were placed in 39 limbs of 38 patients. The mean age of the patients was 33.6 years. Twenty-six patients were men and 12 were women. In all patients, the iodine-coated pins were used to prevent infection. There were 476 pin insertion sites. Pin sites were classified according to the Checketts-Otterburn classification (grade 1-6). White blood cells (WBC) and C-reactive protein (CRP) were measured pre- and postoperatively in all patients. To confirm whether iodine from the implant affected physiological functions, thyroid hormone levels in the blood were monitored. The change in the amount of iodine deposited in the body over time was calculated by examining the removed pins. RESULTS: External fixation was used for a mean duration of 6 months. Grade 1 infection was found in 2.5% of patients, and grade 2 infection in 1.1%. There was no patient with an infection of grade 3 or higher. Median WBC levels were in the normal range, and median CRP levels returned to <0.3 mg/dl within 3 weeks after surgery. Abnormalities of thyroid gland function were not detected. The amount of iodine was maintained for a long time, with approximately 40% remaining after 1 year. CONCLUSIONS: Iodine-supported titanium pins were able to decrease the pin tract infection rate and had no impact on thyroid function. These results suggest that iodine-coated titanium pins are biologically safe and effective at preventing pin tract infections.

Urban versus rural differences in the occurrence of hip fractures in Japan's Kyoto prefecture during 2008-2010: a comparison of femoral neck and trochanteric fractures.

BACKGROUND: To investigate the differences in the characteristics of femoral neck and trochanteric fractures between urban and rural areas of Kyoto Prefecture in Japan. METHODS: Fracture type (neck vs. trochanteric), age, sex, place where fracture occurred (indoors vs. outdoors), and cause of injury were surveyed among patients aged ≥65 years who sustained hip fractures between 2008 and 2010 and who were treated at 1 of 13 participating hospitals (5 urban, 8 rural). The ratio of sick beds to total number of beds at the participating hospitals was 19.6% (2,188/11,158) in the urban area and 34.9% (1,963/5,623) in the rural area. We also investigated the incidence of hip fracture in Tango medical district as a representative rural area. RESULTS: There were 1,346 neck (mean age, 82.4 years) and 1,606 trochanteric fractures (mean age, 85.0 years). The ratio of neck to trochanteric fractures was higher in the urban area than in the rural area in all age groups (65-74, 75-84, and ≥ 85 years). There were no apparent differences in place or cause of injury. The incidence of hip fracture in the women of Tango medical district was lower than the national average. CONCLUSIONS: There was a difference in the ratio of neck to trochanteric fractures between urban and rural areas. This difference is estimated to be caused by the high and low incidence of neck fracture in urban and rural areas, respectively.

The fate and role of bone graft-derived cells after autologous tendon and bone transplantation into the bone tunnel.

BACKGROUND: Grafting bone between the tendon graft and the bone tunnel in anterior cruciate ligament reconstruction increases the mechanical strength of the tendon graft. However, the biological role of the bone graft is unclear. The purpose of this research was to elucidate the role of bone graft cells after autologous tendon graft into the bone tunnel with an autologous bone graft in green fluorescent protein (GFP) transgenic rats. METHODS: The Achilles tendons of Sprague-Dawley (SD) wild-type rats and bone of GFP rats were harvested and transplanted into bone tunnels drilled in the femurs at the knees of SD rats. The femurs were harvested at 1, 2, and 4 weeks after transplantation and histologically investigated using hematoxylin and eosin staining and immunostaining of heat shock protein 47 (HSP47), macrophages, and type I and type III collagens. Biomechanical tests were performed on the tendon graft 2 and 4 weeks after transplantation to evaluate the ultimate force to failure. RESULTS: A small number of GFP-positive cells was seen in the tendon graft 2 weeks after transplantation. The cell count in the tendon graft was increased at 4 weeks after transplantation. HSP47-positive cells and macrophage-stained cells present in the tendon graft corresponded with the GFP-positive cells. By 2 weeks after transplantation, the relative areas of immunostained type I and III collagens in the tendon graft had declined significantly in the bone graft group compared to the control. The ultimate failure load in the bone graft group was higher than that in the control group at both 2 and 4 weeks after transplantation. CONCLUSIONS: This research showed that, within 4 weeks of transplantation, bone graft cells migrate to the tendon graft, where they differentiate into cells involved in collagen production and macrophages. Bone graft cells may contribute to the early stage remodeling of tendon grafts.

Iodine-supported implants in prevention and treatment of surgical site infections for compromised hosts: a prospective study.

BACKGROUND: Surgical site infection (SSI) is a common complication following orthopedic implantation. We developed an iodine coating for titanium implants to reduce implant-related infections and conducted a prospective clinical study to evaluate the efficacy and potential drawbacks of iodine-supported implants. PATIENTS AND METHODS: Between July 2008 and July 2017, 653 patients (377 male and 27 female patients; mean age, 48.6) with postoperative infection or a compromised status were treated using iodine-loaded titanium implants. The mean follow-up period was 41.7 months. In 477 patients, iodine-supported implants were used to prevent infection and in 176 patients, to treat active infection (one-stage surgery, 89 patients; two-stage surgery, 87 patients). In the limbs and pelvis, the primary diagnoses included the following: 161 tumors, 92 deformities/shortening, 47 pseudarthrosis, 42 fractures, 32 infected TKA, 25 osteoarthritis, 21 pyogenic arthritis, 20 infected THA, and 6 osteomyelitis. In the spinal cases, there were 136 cases of tumors, 36 cases of pyogenic spondylitis, and 35 cases of degeneration. Five modes of implant failure were identified and classified as follows: soft tissue failure (type 1), aseptic loosening (type 2), structural failure (type 3), infection (type 4), and tumor progression (type 5). RESULTS: The overall failure rate in our series was 26.3% (172/653). There were 101 mechanical failures, including 22 type 1, 20 type 2, and 59 type 3 failures. Non-mechanical causes accounted for 71 failures, including 45 type 4 and 26 type 5 failures. The overall incidence of infections was 6.8%. The mean time to the onset of infection after implantation was 9.1 months. The overall infection rate was 3.7% in the prevention cases and 15.3% in the treatment cases. There was no difference between one-stage replacement (14.6%) and two-stage replacement (16.0%). There were 11 cases of treatment for SSI of spine surgery, and the re-infection rate was 0% using iodine-coated instruments. CONCLUSIONS: The five modes of failure of the iodine-supported implant were satisfactory compared with previous reports. In particular, because the infection rate of iodine-coated implants used for compromised hosts is low compared with other methods, postoperative infection is more easily controlled. It can be considered highly effective for spinal infections that require one-stage revision surgery. LEVEL OF EVIDENCE IV: Trial registration Prospective, Observation study.

Pleomorphic liposarcoma of the extremity with solitary huge liver metastasis at initial diagnosis treated with conversion surgery combined with adjuvant chemotherapy: a case report.

BACKGROUND: Pleomorphic liposarcoma is the rarest subtype of liposarcoma. Pleomorphic liposarcomas are generally unresponsive to chemotherapy and radiotherapy. Moreover, metastasis in the liver, as the first and sole site, from a primary extremity soft tissue sarcoma, including pleomorphic liposarcoma, is extremely rare. Information regarding the appropriate management of these lesions is limited. CASE PRESENTATION: A 50-year-old Japanese woman presented with a mass in the left thigh. Imaging examination revealed a soft tissue sarcoma on the left posterior thigh. The tumor was histologically diagnosed as pleomorphic liposarcoma. Computed tomography examination for assessment of metastases incidentally detected a huge liver mass. Wide excision of sarcoma was performed prior to chemotherapy. Right trisectionectomy was necessary to achieve hepatic clearance; however, the future liver remnant volume was insufficient. Therefore, we decided to administer anthracycline-based chemotheraphy to shrink the tumor. After seven courses of adriamycin-based chemotherapy, the liver tumor size was reduced from 211 mm × 106 mm × 180 mm to 105 mm × 66 mm × 90 mm. Finally, a right hemihepatectomy was performed. The patient was continuously monitored and was metastasis or local recurrence free within 5 months after liver surgery. CONCLUSION: Chemotherapy is effective in some cases for the treatment of unresectable liver metastases of pleomorphic liposarcoma, and complete resection is possible with conversion surgery. If the patient's general condition permits, anthracycline-based chemotherapy can be used for the treatment of stage 4 pleomorphic liposarcoma.

A Natural Organic Compound "Decursin" Has Both Antitumor and Renal Protective Effects: Treatment for Osteosarcoma.

Osteosarcoma is a rare malignant tumor that commonly occurs in children. Anticancer drugs, for example, cisplatin, aid in postsurgery recovery but induce side effects such as renal damage, affecting the life prognosis of patients. Decursin which is one of the bioactive components has been reported for its anti-inflammatory, antioxidant, and antitumor effects, but the effect on osteosarcoma is unexplained. In this study, the research theme was to examine the sensitizing effect of decursin and its influence on cisplatin-induced nephrotoxicity. The cell viability and half maximal inhibitory concentration (IC50), apoptosis induction, and effect on cell cycle and Akt pathways were examined. In vivo, we examine the effects of decursin on tumors and mice bodies. Additionally, the effects of the cisplatin-decursin combination were evaluated in vitro and in vivo. Decursin suppressed cell viability and induced apoptosis via the cell cycle. Decursin also inhibited the Akt pathway by suppressing the phosphorylation of Akt. It enhanced apoptosis induction and lowered cell viability in combination with cisplatin. The increasing tumor volume was suppressed in the decursin-administrated group with further suppression in combination with cisplatin compared to sole cisplatin administration. The decrease in renal function and renal epithelial cell damage caused by cisplatin was improved by the combinatorial treatment with decursin. Therefore, decursin demonstrated an antitumor effect on the osteosarcoma cells and a renal protective effect in combination with cisplatin. Therefore, decursin is a prospective therapeutic agent against osteosarcoma.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: The REALIZE study.

Background: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs. Methods: This randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion). Results: Forty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group. Discussion: This is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).

Pristimerin inhibits the proliferation of HT1080 fibrosarcoma cells by inducing apoptosis.

Fibrosarcoma is a soft tissue sarcoma that is classified as a rare cancer. Therefore, no standard anti-tumor drug therapy has been established for fibrosarcoma. Although pristimerin (PM) has been reported to exert an anti-tumor effect on various types of cancer, no studies have examined the therapeutic effect of PM on soft tissue sarcoma. The purpose of the current study was to investigate the anti-tumor effect of PM on human fibrosarcoma cells (HT1080). The present study examined the cell viability, IC50 values and ability to induce apoptosis of PM in HT1080 and normal human dermal fibroblast (aHDF) cells. The effect of PM on the following signaling pathways associated with cell proliferation was also evaluated: AKT and mitogen-activated protein kinase (MAPK). Using mice subcutaneously transplanted with fibrosarcoma cells, the effect of PM treatment was investigated on tumor growth inhibition, body weight and liver and renal function. The results revealed that PM administration reduced cell viability and induced apoptosis in a dose-dependent matter. In HT1080 cells, the IC50 value of PM was 0.16 µM at 24 h and 0.13 µM at 48 h. PM treatment also decreased the levels of phosphorylated AKT, mTOR, NF-κB and phosphorylated ERK in a dose-dependent manner. In the PM injection group, the increase in tumor volume was significantly reduced and the effect on weight loss and liver and renal function were revealed to be insignificant. PM exerted little effect on normal human dermal fibroblasts and was highly effective against human fibrosarcoma cells. The results indicated that PM may be used as a potential therapeutic agent against fibrosarcoma.

Hyperthermia for the treatment of articular cartilage with osteoarthritis.

Osteoarthritis (OA) is one of the most frequent musculoskeletal disorders in the elderly population. OA is characterised by a gradual loss of extracellular matrix in the articular cartilage of joints. OA can only be managed by artificial joint replacement when joint destruction becomes severe. Therefore, it is preferable to administer conservative therapy that is easy, simple and effective in inhibiting OA progression at the early stage. Heat shock protein 70 (Hsp70) has a protective effect on the cartilage and inhibits the apoptosis of chondrocytes. Heat stimulation by microwave to the joints can increase Hsp70 expression in chondrocytes, and at the same time, Hsp70 expression partially enhances matrix metabolism of the cartilage. These findings suggest that hyperthermia can be positively applied to the treatment of OA. Hyperthermia is therefore expected to be an inexpensive and less-invasive conservative therapy for OA.