Haruhiko Satonaka

Expression of hypoxia-inducible factor (HIF)-1α as a biomarker of outcome in soft-tissue sarcomas

Hypoxia-inducible factor (HIF)-1α is a transcription factor that supports the adaptation of human cancer cells to hypoxia and tumor growth and progression. The overexpression of HIF-1α protein has been reported to be associated with a worse prognosis in various cancers. However, the expression of HIF-1α in soft-tissue sarcomas has not yet been characterized. The expression of HIF-1α protein was immunohistochemically determined in 49 specimens of soft-tissue sarcomas including malignant fibrous histiocytoma (29 patients), synovial sarcoma (12 patients), leiomyosarcoma (four patients), and malignant peripheral nerve sheath tumors (four patients). The 49 samples consisted of 40 primary lesions and nine local recurrences. An immunohistochemical analysis showed the nuclear accumulation of HIF-1α protein in 35 (71.4%) samples. The expression of HIF-1α was negative in 14 (28.6%) cases, weak in nine (18.4%), moderate in 17 (35.4%), and strong in nine (18.4%). The patients with a strong or moderate expression of HIF-1α had a significantly shorter overall survival rate in comparison with those with a weak or negative expression in a univariate analysis (P = 0.029; log-rank test) and multivariate analysis (P = 0.018). This is the first report that demonstrated an overexpression of HIF-1α protein to be an independent prognostic factor for soft-tissue sarcomas.

Extracorporeal Photodynamic Image Detection of Mouse Osteosarcoma in Soft Tissues Utilizing Fluorovisualization Effect of Acridine Orange

Various imaging methods have been employed for the extracorporeal detection of malignant tumors in the human body, such as scintigraphy and PET; however, none is sufficiently accurate and all are also very expensive. To resolve these issues, we attempted to develop a new imaging technique of photodynamic diagnosis (PDD) with acridine orange (AO). AO has the ability to rapidly and specifically accumulate in malignant tumors and emit brilliant green fluorescence after blue light excitation. In this study, we investigated the feasibility of PDD utilizing the fluorovisualization effect of AO, for the extracorporeal detection of mouse osteosarcoma inoculated into the soft tissues. At 2 h after intravenous administration of 0.1, 0.2, 0.5, 1.0, 2.0 and 5.0 mg/kg AO, the tumor and the surrounding normal tissues were illuminated by blue light. The visual fluorescence contrast and ratio (X) of the difference in fluorescence intensity between the tumor and the surrounding normal tissues were evaluated using a high-resolution digital camera equipped with an absorption filter. In addition, the fluorescence contrast was also detected sequentially at 0.5, 1, 2, 3, 6 and 12 h after intravenous administration of AO at 1.0 mg/kg. The results revealed that the optimal condition for clear detection of the tumor was evaluation 2 h after intravenous injection of AO at 0.1 mg/kg, because it provided the best visual contrast on the digital images, and the fluorescence intensity as well as the value of X were higher as compared to the values under other conditions of dose and timing. Based on the results of an acute toxicity study of AO, the estimated LD50 of this substance following intravenous administration was 27.30 mg/kg. In conclusion, we believe that PDD using AO administered intravenously may be feasible for the detection of human musculoskeletal sarcomas in the soft tissues at extremities, and this technique might be a less invasive, less expensive, quicker and more accurate imaging modality than other previously reported imaging methods for this purpose.

Protective effect of edaravone for tourniquet-induced ischemia-reperfusion injury on skeletal muscle in murine hindlimb

BackgroundStudies have shown that ischemia-reperfusion (I/R) produces free radicals leading to lipid peroxidation and damage to skeletal muscle. The purposes of this study were 1) to assess the histological findings of gastrocnemius muscle (GC) and tibialis anterior muscle (TA) in I/R injury model mice, 2) to histologically analyze whether a single pretreatment of edaravone inhibits I/R injury to skeletal muscle in murine models and 3) to evaluate the effect of oxidative stress on these muscles.MethodsC57BL6 mice were divided in two groups, with one group receiving 3 mg/kg intraperitoneal injections of edaravone (I/R + Ed group) and the other group receiving an identical amount of saline (I/R group) 30 minutes before ischemia. Edaravone (3-methy-1-pheny1-2-pyrazolin-5-one) is a potent and novel synthetic scavenger of free radicals. This drug inhibits both nonenzymatic lipid peroxidation and the lipoxygenase pathway, in addition to having potent antioxidant effects against ischemia reperfusion. The duration of the ischemia was 1.5 hours, with reperfusion at either 24 or 72 hours (3 days). Specimens of gastrocnemius (GC) and anterior tibialis (TA) were removed for histological evaluation and biochemical analysis.ResultsThis model of I/R injury was highly reproducible in histologic muscle damage. In the histologic damage score, the mean muscle fibers and inflammatory cell infiltration in the I/R + Ed group were significantly less than the corresponding values of observed in the I/R group. Thus, pretreatment with edaravone was observed to have a protective effect on muscle damage after a period of I/R in mice. In addition, the mean muscle injury score in the I/R + Ed group was also significantly less than the I/R group. In the I/R + Ed group, the mean malondialdehyde (MDA) level was lower than in the I/R group and western-blotting revealed that edaravone pretreatment decreased the level of inducible nitric oxide synthase (iNOS) expression.ConclusionsEdaravone was found to have a protective effect against I/R injury by directly inhibiting lipid peroxidation of the myocyte by free radicals in skeletal muscles and may also reduce the secondary edema and inflammatory infiltration incidence of oxidative stress on tissue.

Histiocytic Osteolysis Secondary to Hyperbilirubinaemia: A Case Report

A 6-year-old boy with Alagille syndrome, characterised by marked hyperbilirubinaemia, presented with malunion of a pathological fracture of the femur with local bone atrophy and insufficient callus formation. During corrective osteotomy, it was noted that the femur was stained dark green, suggestive of bilirubin deposition. Histology of the resected bone revealed the presence of many histiocytes and osteoclast-like multinucleate giant cells containing bilirubin particles in the cytoplasm causing bone resorption. These findings suggest that bilirubin may activate macrophages to form osteoclast-like multinucleate giant cells, resulting in histiocytic osteolysis.

Transfection of nuclear factor-kappaB decoy oligodeoxynucleotide protects against ischemia/reperfusion injury in a rat epigastric flap model.

Nuclear factor‐kappaB (NF‐κB) is considered to play an important role in the response to ischemia/reperfusion (I/R) injury in flap surgery. To inhibit NF‐κB, synthetic double‐stranded oligodeoxynucleotide (ODN) was used as a decoy. The present study aimed to evaluate the suppressive effects of NF‐κB against I/R injury of experimental rat flap model.

Usefulness and complications associated with thenar and standard portals during arthroscopic surgery of thumb carpometacarpal joint

PURPOSE Advances in small arthroscopy have enabled a minimally invasive surgery for thumb carpometacarpal joints. However, surgery is often difficult using standard CM-radial (CM-R) and CM-ulnar portals (CM-U). Here, we describe the clinical applications and complications associated with using thenar portal (TP) and standard portals. METHODS Arthroscopic surgeries of thumb carpometacarpal joint were performed in 21 patients including 15 patients with osteoarthritis and six Bennetts fracture-dislocations. Complications and the frequency of use associated with each portal were evaluated. RESULTS Complications associated with the CM-R portal comprised paresthesia due to damage of the radial nerve branches in two patients. No nerves were damaged but the operation scar became tender at the TP in three patients. The CM-R was used at a lower frequency when the TP was utilized. CONCLUSION The clinical use of TP may decrease the risk of radial sensory nerve damage through decreasing frequency of use of the CM-R that is located near the nerve. LEVEL OF STUDY IV.