Yasuo Yoshimura

Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice

The administration of either Pentoxifylline (PTX), a methylxanthine derivative and an inhibitor of cyclic AMP (c-AMP) phosphodiesterases (PDEs), or Rolipram, an inhibitor specific to type-4 PDE (PDE4) in normal mice, significantly increased both cortical and cancellous bone mass. Vertebrae and tibiae from mice treated with PTX or Rolipram were analyzed by means of bone densitometry and histomorphometry. The results revealed that both PTX and Rolipram increased bone mass in normal mice mainly through the acceleration of bone formation. These findings suggest that both PTX and Rolipram can enhance physiological bone formation and thereby increase bone mass in normal mice. The possibility that these agents may be of value for the treatment of osteoporosis is discussed.

Colocalization of Noggin and Bone Morphogenetic Protein‐4 During Fracture Healing

The regulation of callus formation during fracture repair involves the coordinate expression of growth factors and their receptors. This article describes the temporal and spatial expression of noggin gene, an antagonist to bone morphogenetic protein (BMP), during the fracture repair process. Noggin expression was examined by means of Northern blotting and in situ hybridization and compared with the expression pattern of BMP‐4 in a model of fracture repair in adult mice. Expression levels of noggin messenger RNA (mRNA) were enhanced in the early phase of fracture callus formation. The localization of the noggin mRNA was similar to that of BMP‐4 mRNA. Distinct noggin mRNA signals were located predominantly in cells lining the periosteum and the cortical endosteum near the fracture site at 2 days after fracture. At 5, 10, and 21 days after fracture, noggin mRNA was detected in the chondrocytes and osteoblasts in the newly formed callus. The pattern of localization was indistinguishable from that of BMP‐4. These results suggest that the noggin/BMP‐4 balance could be an important factor in the regulation of callus formation during fracture healing.

Sequential expression of bone morphogenetic protein, tumor necrosis factor, and their receptors in bone-forming reaction after mouse femoral marrow ablation

Tumor necrosis factor-alpha (TNF-alpha) is considered a promoter of bone resorption and a suppressor of osteogenesis, whereas bone morphogenetic protein (BMP) is a promoter of bone formation. In the present study, the osteogenic potential of the medullary cavity after bone marrow ablation was evaluated in association with the pattern of BMP, bone morphogenetic protein receptor (BMPR), TNF-alpha, and tumor necrosis factor receptor (TNFR) expression. Immunostaining, in situ hybridization, and TRAP staining were performed following marrow ablation. By day 4, BMP-4 mRNA was detected by in situ hybridization in growing undifferentiated cells and, on day 7, the osteoblastic cells that covered abundant woven bone also showed evidence of BMP-4 expression. BMPR-IA and BMPR-II were immunolocalized from days 4 to 10 after ablation, and became negative on days 21 and 28. At 10 days postablation, osteoclasts were revealed by TRAP staining. TNF-alpha expression disappeared transiently after ablation and then reappeared on day 7, predominantly in osteoblastic cells. On days 7, 10, and 14, immunostaining for TNFR-I was observed in osteoblasts lining the woven bone and later disappeared. No evidence of TNFR-II staining was observed on osteoblastic cells throughout the reaction. From day 14, newly formed bone decreased in quantity and was replaced by hematopoietic cells and, by day 28, the bone marrow had regenerated to its original state. This study suggests that TNF-alpha is produced and secreted by the osteoblast and acts on these cells in an autocrine manner to suppress osteoblastic function. TNF-alpha may also play a role in the recruitment of osteoclasts because TRAP-positive osteoclasts appeared after TNF-alpha expression.

Clinical classification of cardiovascular tumors and tumor-like lesions, and its incidences

Tumors of the heart and the great vessels are very rare disease, and there are many disorders such as tumors originated from the heart and great vessels, metastatic tumors, and tumor-like lesions which do not fit into the usual concept of tumor or neoplasm; thus, it is very difficult to classify these tumors. We proposed a new classification of cardiovascular tumors for clinical use based on the accumulated biological analyses and clinical data of the reported literatures and our own study as benign tumors, malignant tumors, ectopic hyperplasia/ectopic tumors/others, and tumors of great vessels, with reference to the series of Atlas of tumor pathology of the Armed Forces Institute of Pathology and the recent World Health Organization classification of cardiac tumors issued in 2004. More than 50 disorders have been reported as tumors originated from the cardiovascular system, and various metastatic tumors from nearby organs, distant lesions, and intravascular extension tumors to the heart were reported. Based on the new classification, we reviewed epidemiology and incidence of cardiovascular tumors. Metastatic tumors are more frequent than tumors originated from the heart and great vessels, and cardiac myxoma is the most frequent tumors in all cardiac tumors.

Clinical outcome of deep-seated atypical lipomatous tumor of the extremities with median-term follow-up study

AIMS There is no consensus on the best surgical treatment for deep-seated atypical lipomatous tumor (ALT) of the extremities; furthermore, the appropriate duration for follow-up observation remains unclear. We investigated clinical and functional median-term outcomes in the primary operations for ALT of the extremities in order to find its best treatment methods and observation periods. METHODS From 1996 to 2009, we diagnosed 41 patients with deep-seated ALT of the extremities. Wide resection was performed on 11 patients and marginal resection was performed on 30 patients. The minimum follow-up was 5 years (median, 8.5; range, 5-17.4). Patients were evaluated for their local recurrence, dedifferentiation, and post-operative function using the ISOLS/MSTS scoring system. RESULTS Recurrence and dedifferentiation rates were both 0% for the wide resection group, while the rates were 23% (7/30) and 3% (1/30) for the marginal resection group, respectively. Median duration before recurrence was 7.2 years (range, 4.0-14.2). Local recurrence-free survival rate was significantly higher in the wide resection group (P = 0.013). In the marginal resection group, 10% (3/30) of the cases showed residual tumor. The localization of these tumors was all intermuscular. The ISOLS/MSTS scores were 98% (range, 90-100) for wide resection and 99% (range, 93-100) for marginal resection, with no statistical difference (P = 0.694). No ALT-related deaths occurred during the observation period. CONCLUSIONS In addition to long-term (at least 8 years) of continuous observation, a wide resection is necessary in order to prevent recurrence, dedifferentiation, and residual tumor.

Metastatic Carcinoma to Subcutaneous Tissue and Skeletal Muscle: Clinicopathological Features in 11 Cases

OBJECTIVE Metastatic carcinoma to subcutaneous tissue or skeletal muscle is relatively rare. The present study aimed to clarify the clinicopathological features for confirming the diagnosis as soft tissue metastasis and determining the primary site. METHODS We reviewed records of 11 patients with soft tissue metastasis who were in our institution from 1996 to 2009. RESULTS In 9 of 10 patients who underwent magnetic resonance imaging, findings consisted of poorly circumscribed high-intensity lesions around the tumor on T2-weighted images, irregular peritumoral enhancement and poorly enhanced lesions at the center of the tumor on T1-weighted images. Systematic immunohistochemical examination was more valuable for diagnosing as soft tissue metastasis and confirming the primary site. The expression patterns of cytokeratins 7 and 20 and tissue-specific antibodies such as thyroid transcription factor-1, MUC5AC and CDX2 were useful diagnostic markers. The primary site could be determined in five patients with cytokeratin 7/20 immunophenotype and positivity for tissue-specific antibodies. In four cases, determination of the primary site finally became possible by comparison with the histological findings of operative specimens in past carcinoma and/or in consideration of radiological findings and the results of cytokeratin 7/20 phenotyping. CONCLUSIONS Systematic immunohistochemical examination is helpful for confirmation of the primary origin in soft tissue metastasis of carcinoma in addition to clinical information such as the history and condition of past carcinoma, radiological findings and comparison between the histology of biopsy specimens and past carcinoma.

Serum soluble interleukin-2 receptor levels in patients with malignant lymphoma of bone

BackgroundThe reliability of selected serum markers and radiological features for distinguishing malignant lymphoma of the bone from other osteolytic bone lesions was examined in an effort to improve the differential diagnosis.MethodsA total of 23 patients with histologically verified malignant lymphoma of the bone, 57 patients with other osteolytic malignancies (35 males, 22 females; mean age 62.8 years, range 13–89 years), and 13 patients with benign bone lesions that resemble malignant tumor radiographically (6 men, 7 women; mean age 48.1 years, range 20–73 years) were retrospectively reviewed. We evaluated the serum levels of soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, and C-reactive protein in addition to radiographic examination and gallium-67 scanning.ResultsAlthough every clinical feature examined was found to show significant differences between lymphoma and the other two groups, the feature most highly suggestive of malignant lymphoma is a high serum sIL-2R level (sensitivity 0.95, specificity 0.70, accuracy 0.81).ConclusionsThe serum sIL-2R level can be a valuable marker for diagnosing malignant lymphoma of the bone.

Increased CD45RO+ CD62L+ CD4+ T-cell subpopulation responsible for Th2 response in Kimura's disease.

Kimuras disease is characterized by subcutaneous masses, eosinophilia, and markedly elevated serum immunoglobulin E, suggesting that T helper (Th)2 cells may play a role in the pathogenesis. We investigated Th2 cytokine synthesis by mononuclear cells and possible Th1/Th2 subpopulations in Kimuras disease. Peripheral blood samples were obtained from seven patients with Kimuras disease and CD4(+) T-cell subpopulations separated by CD45RO and CD62L were isolated. Purified cells were stimulated with PHA or anti-CD3 mAb, and the cytokine levels were measured by Cytometric Bead Array kit. Peripheral blood mononuclear cells in the majority of the patients produced Th2 cytokines such as interleukin (IL)-3, IL-4, IL-5, IL-13 or GM-CSF higher than those of controls. The ratio of CD45RO(+) CD62L(+) cells in CD4(+) T cells was increased in six out of seven patients compared to age-matched controls. Especially, patient 1 had remarkably increased levels of CD45RO(+) CD62L(+) population in CD4(+) T cells. In addition, IL-4 production levels by CD45RO(+) CD62L(+) CD4(+) T cells of patients 1 and 2 were higher than those of their CD45RO(+) CD62L(-) CD4(+) T cells, in the same manner as those by a normal control. Taken together, the synthesis of Th2 cytokines and CD62L-positive subpopulation in CD45RO(+) CD4(+) T cells, which may represent characteristics of Th2, are increased in patients with Kimuras disease, suggesting that deviation to Th2 may involve in pathogenesis of the disease.

Preoperative radiographic and histopathologic evaluation of central chondrosarcoma

BackgroundDistinguishing grade 1 chondrosarcoma from grade 2 chondrosarcoma is critical both for planning the surgical procedure and for predicting the outcome. We aimed to review the preoperative radiographic and histologic findings, and to evaluate the reliability of preoperative grading.MethodsWe retrospectively reviewed the medical records of 17 patients diagnosed with central chondrosarcoma at our institution between 1996 and 2011. In these cases, we compared the preoperative and postoperative histologic grades, and evaluated the reliability of the preoperative histologic grading. We also assessed the preoperative radiographic findings obtained using plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI).ResultsPreoperative histologic grade was 1 in 12 patients, 2 in 4 patients, and 3 in 1 patient. However, 6 of the 12 cases classified as grade 1 before surgery were re-classified as grade 2 postoperatively. In the radiographic evaluation, grade 1 was suspected by the presence of a ring-and-arc pattern of calcification on plain radiography and CT and entrapped fat and ring-and-arc enhancement on MRI. Grades 2 and 3 were suspected by the absence of calcification and the presence of cortical penetration and endosteal scalloping on plain radiography and CT, as well as soft-tissue mass formation on MRI.ConclusionAlthough the combination of radiographic interpretation and histologic findings may improve the accuracy of preoperative grading in chondrosarcoma, the establishment of a standard evaluation system with the histologic and radiographic findings and/or the development of new biologic markers are necessary for preoperative discrimination of low-grade chondrosarcoma from high-grade chondrosarcoma.

A recurrent solitary fibrous tumor of the thigh with malignant transformation: A case report

Highlights • Solitary fibrous tumors (SFTs) of the extremities are rare.• We report a case of recurrent SFT in the thigh with malignant transformation.• Our current case showed a long-term benign course before the operation.• This tumor displayed a homogeneously high-grade area at recurrence.• Careful consideration is necessary for treating this tumor.