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.

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.

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.

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).

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.

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.

A retrospective study of antibacterial iodine-coated implants for postoperative infection.

Postoperative infection is one of the most serious complications in orthopedic surgery. We have developed and use iodine-coated implants to prevent and treat postoperative infection in compromised hosts. This study evaluated outcomes using iodine-coated implants for postoperative infections.We treated 72 postoperative infected patients using iodine-coated implants. Of these, 38 were males and 34 were females, with a mean age of 59.3 years. The mean follow-up period was 5.6 years. The patients included 23 with an infection following total knee arthroplasty, 20 following total hip arthroplasty, 11 following osteosynthesis, 11 following spine surgery, 6 following tumor excision, and 1 following osteotomy. Of these, 37 underwent single-stage surgery and 35 underwent staged revision surgery. We performed staged surgery in any case with active infection. The survival of iodine-coated implants was determined using Kaplan-Meier analysis. White blood cell (WBC) and C-reactive protein (CRP) levels were measured pre- and postoperatively. To evaluate the systemic effects of iodine, serum thyroid hormone levels were examined.Five patients underwent re-revision surgery. In 3 patients, periprosthetic infection recurred at an average of 18 months after surgery. The reinfection rate was 4.2%. These patients recovered following reimplantation of iodine-coated prostheses. No patients required amputation. The survival rate of iodine-coated implants was 91%. There were no signs of infection at the latest follow-up. The median WBC level was nearly in the normal range, and CRP levels returned to normal within 4 weeks after surgery. No abnormalities of thyroid gland function were detected.Iodine-coated titanium implants can be very effective in the treatment of postoperative infections. An iodine coating can be safely applied to infected regions.

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.

The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma.

PURPOSE: CD81 is a member of the tetraspanin family of membrane proteins. Recently, it has been shown that CD81 may be involved in cancer cell proliferation and metastasis. As yet, however, there have been few reports on the expression and role of CD81 in osteosarcoma. METHODS: The expression of CD81 was investigated in human osteoblast cell line hFOB1.19 and in human osteosarcoma cell lines Saos2, MG63 and 143B. The expression of CD81 was inhibited in osteosarcoma cells using siRNA after which cell proliferation, migration and invasion were assessed. We also used Western blotting to investigate the phosphorylation status of Akt, Erk, JNK and p38, and measured the expression of MMP-2, MMP-9 and MT1-MMP. In addition, we used a CRISPR/Cas9 system to stably knock out CD81 expression in 143B cells, transplanted the cells into mice, and assessed tumor formation and lung metastasis in these mice compared to those in the control group. RESULTS: We found that CD81 was expressed in the human osteoblast cell line and in all osteosarcoma cell lines tested. The osteosarcoma cell line 143B exhibited a particularly high level of expression. In addition, we found that osteosarcoma cell proliferation, migration and invasion were decreased after CD81 inhibition, and that the phosphorylation of Akt and Erk was suppressed. Also, the expression levels of MMP-2, MMP-9 and MT1-MMP were found to be suppressed, with MMP-9 showing the greatest suppression. In vivo, we found that mice transplanted with CD81 knockout 143B cells exhibited significantly less tumor formation and lung metastasis than mice in the control group. CONCLUSION: Based on our findings we conclude that inhibition of CD81 suppresses intracellular signaling and reduces tumorigenesis and lung metastasis in osteosarcoma cells.

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.

Chondroid lipoma of the neck: a case report.

BACKGROUND: Chondroid lipoma, first described in 1993 by Meis and Enzinger, is a very rare lipomatous tumor. Because it is a benign tumor, it does not require radiotherapy, chemotherapy, or extensive resection. However, histologically, it is often confused with a sarcoma. It is crucial to differentiate chondroid lipoma from sarcoma to avoid choosing an inappropriate treatment strategy. Although MRI, radiography, and ultrasound have been used to evaluate chondroid lipomas, imaging cannot accurately differentiate chondroid lipoma from sarcoma. CASE PRESENTATION: A 39-year-old man presented to a local clinic with a 1-month history of a painless mass in his left neck. Results of a needle biopsy suggested an atypical lipomatous tumor, and the patient was referred to our hospital. Physical examination revealed a hard and mobile mass in the left neck. Plain X-ray radiographs showed an absence of calcification in the soft tissue mass. MRI revealed a well-defined and lobulated mass, and on T1-weighted images, the lesion showed heterogeneity, with higher signal intensity than that of muscle. On T2-weighted images, the septum had low-signal intensity. On T2-weighted fat-suppressed images, the signal of the mass was completely suppressed. The SUVmax of the mass on FDG PET was 1.84. An additional needle biopsy was performed, and on the basis of the results, we arrived at a diagnosis of well-differentiated liposarcoma. The mass was resected marginally. Macroscopically, the mass was encapsulated and markedly harder than well-differentiated liposarcoma. Histologically, the tumor was composed of myxoid and cartilaginous matrix, and mature fat cells and lipoblast-like cells were present. The final diagnosis was chondroid lipoma, and no recurrence was observed 1 year after surgery. CONCLUSIONS: Chondroid lipoma is an extremely rare benign soft tissue tumor that is often confused with sarcoma. It is very important to differentiate chondroid lipoma from sarcoma when the SUVmax value of the mass is low, even when biopsy results suggest that it is a sarcoma.

Hepatic metastases from primary extremity leiomyosarcomas: Two case reports.

INTRODUCTION: Leiomyosarcoma is a highly malignant soft tissue sarcoma. Most leiomyosarcomas of the extremities metastasize initially to the lungs, with few metastasizing to the liver. Also, it is difficult to diagnose metastases to other regions of the lung during follow-up. CASE PRESENTATION: The first patient was a 51-year-old Japanese woman diagnosed with a leiomyosarcoma of the left distal femur. She underwent chemotherapy, followed by wide tumor excision and reconstruction using frozen autograft with total knee arthroplasty. Eleven months later, a focal lesion was observed in her right liver, despite the absence of lung metastases. Partial hepatic resection was performed, and the hepatic lesion was diagnosed a metastasis of leiomyosarcoma. Two years later, there has been no evidence of local recurrence. The second patient was a 60-year-old Japanese male diagnosed with a leiomyosarcoma of the left thigh. He underwent preoperative chemotherapy followed by wide excision. Three years later, a focal lesion was found in his medial liver, despite the absence of lung metastases. Partial hepatic resection was performed, and the hepatic lesion was diagnosed as a metastasis of leiomyosarcoma. At the latest follow-up, there has been no evidence of local recurrence. CONCLUSIONS: The lung is the most common site of metastases from leiomyosarcomas of the extremeties, because these metastases are hematogenous. Both our patients presented with metastases of the liver, despite the absence of lung metastases. Hepatic metastasis is commonly found in computed tomography (CT) scan. Periodic CT scans of the chest and abdomen are necessary in following-up patients who undergo resection of primary leiomyosarcomas of the extremities.

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.

Antitumor effects of pristimerin on human osteosarcoma cells in vitro and in vivo.

There are very few treatments for musculoskeletal tumors, compared to other cancers; thus, novel therapeutic drugs are needed. Pristimerin (PM) is a triterpene compound isolated from plant extracts that reportedly has antitumor effects on various cancers, such as of the breast and prostate. The purpose of this study was to evaluate the antitumor effects of PM on human osteosarcoma cells. Treatment of the human osteosarcoma cell lines, MNNG and 143B, with PM led to a dose-dependent decrease in cell viability. The effects of PM on apoptosis were evaluated with the Annexin V/propidium iodide assay and analysis of caspases 3, 8, and 9 activities. Western blot analysis showed that PM caused a decrease in the expression of Akt, mTOR, and NF-κB. The volumes and weights of human osteosarcoma xenografts decreased significantly with PM treatment. The results of this study revealed that PM can inhibit human osteosarcoma growth in vitro and in vivo, and may be a novel therapeutic agent for the disease.

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells.

Although advances in chemotherapy have improved the prognosis for osteosarcoma, some patients do not respond sufficiently to treatment. Heat shock protein 70 (Hsp70) is expressed at high levels in cancer cells and attenuates the therapeutic efficacy of anticancer agents, resulting in a poorer prognosis. This study investigated whether small interfering RNA (siRNA)-mediated inhibition of Hsp70 expression in an osteosarcoma cell line would enhance sensitivity to cisplatin. The expression of Hsp70 with cisplatin treatment was observed by using Western blotting and real-time reverse transcription polymerase chain reaction (RT-PCR). Changes in the IC50 of cisplatin when Hsp70 was inhibited by siRNA were evaluated. Cisplatin's effectiveness in inducing apoptosis was assessed by assay of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), caspase-3 activity, and mitochondrial membrane potential. Up-regulation of Hsp70 expression was dependent on the concentration of cisplatin. Inhibition of Hsp70 expression significantly reduced the IC50 of cisplatin. When cisplatin was added to osteosarcoma cells with Hsp70 expression inhibited, a significant increase in apoptosis was demonstrated in TUNEL, caspase-3, and mitochondrial membrane potential assays. Inhibition of Hsp70 expression induced apoptosis in cultured osteosarcoma cells, indicating that Hsp70 inhibition enhanced sensitivity to cisplatin. Inhibition of Hsp70 expression may provide a new adjuvant therapy for osteosarcoma.

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.

Population Pharmacokinetic-Toxicodynamic Modeling and Simulation of Cisplatin-Induced Acute Renal Injury in Rats: Effect of Dosing Rate on Nephrotoxicity.

Nephrotoxicity is the major dose-limiting toxicity of cisplatin (CDDP). The aim of this study was to develop a pharmacokinetic (PK)/toxicodynamic (TD) model of CDDP-induced acute renal injury in rats and to simulate nephrotoxicity at various dosing rates. CDDP was administered to rats by a 30-s bolus or a 2-h infusion (1.0, 2.5, 5.0, and 7.5 mg/kg). Unbound CDDP concentrations in plasma and urine were determined up to 2 h after administration in the PK study, and plasma creatinine (Cr) levels were monitored for up to 7 days as an index of nephrotoxicity in the TD study. The PK was linear and was fitted with a traditional 2-compartment model. The TD was nonlinear and differed between dosing rates. The creatinine concentration profiles were fitted with a signal transduction-indirect response model. Population analysis using a nonlinear mixed-effect model was adapted to the developed PK/TD model and was well-validated. Dosing simulations from the developed population PK/TD model indicated that CDDP-induced nephrotoxicity was due to not only Cmax but also the time above the toxic concentration of CDDP. Prolongation of infusion time will not necessarily attenuate acute nephrotoxicity. This study demonstrated the potential utility of PK/TD modeling for preventing nephrotoxicity.

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.

Expression of Connexin 43 in Synovial Tissue of Patients With Rheumatoid Arthritis.

OBJECTIVES: This study aims to identify the distribution and expression level of connexin 43 (Cx43) in synovial tissue in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: The expression of Cx43 in synovial tissue from eight patients with RA (2 males, 6 females; mean age 59.5±2.7 years; range 52 to 71 years), five patients with osteoarthritis (2 males, 3 females; mean age 68.4±2.7 years; range 61 to 81 years), and one normal female subject (mean age 61 year) was analyzed by quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry of tissue sections. Induction of Cx43 following stimulation of human RA synovial fibroblasts with tumor necrosis factor-alpha (TNF-a) cultures was examined by quantitative reverse transcriptase polymerase chain reaction. The effect of small interfering ribonucleic acid targeting Cx43 (siCx43) on the expression of TNF-a and interleukin-6 was examined using quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assays. RESULTS: Connexin 43 was highly expressed in RA synovial tissue, which also expressed TNF-a, but was expressed lower in osteoarthritis and normal synovial tissue. Expression of Cx43 was markedly up-regulated in RA synovial fibroblasts after stimulation with TNF-a. The over-expression of pro- inflammatory cytokines was suppressed by transfection of siCx43. CONCLUSION: This study shows that Cx43 is expressed in RA synovial tissue and that its expression is induced by stimulation with TNF-a. The expression of the pro-inflammatory cytokines was inhibited by transfection of siCx43. Cx43 may be a novel marker of inflammation in RA synovial tissue.