Teruya Kawamoto

Neurilemmoma in the Foot as a Cause of Heel Pain: A Report of Two Cases

Two cases of deep-seated neurilemmoma that arose from plantar branches of the posterior tibial nerve and caused chronic heel pain are described. At the initial examination, one case was misdiagnosed as tarsal tunnel syndrome and the other was overlooked as plantar fasciitis; both cases were treated for long periods prior to operation. Deep-seated neurilemmomas in the foot can easily be overlooked and misdiagnosed as tarsal tunnel syndrome or plantar fasciitis because of the rarity, absence of palpable mass, and similarity of symptoms to those of other frequently encountered foot disorders. Magnetic resonance imaging provides the best modality for differential diagnosis. In the present cases, surgical excision of the tumors resulted in immediate and complete relief of chronic heel pain. Surgeons should consider neurilemmoma as a cause of persistent chronic heel pain despite the rarity of the disease.

PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma.

Osteosarcoma (OS) is a primary malignancy of the bone, with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, more than 30% of patients develop distant metastases, and the prognosis of patients with metastases is essentially poor. Members of the protein kinase D (PKD) family are serine/threonine kinases, and have been studied in various cancers. Among the three different isoforms of this family, PKD1 is one of the best understood for its role in human malignancies; however, its role in musculoskeletal tumors has not been studied. In the present study, we investigated the role of PKD1 in human OS. We first analyzed PKD1 mRNA expression in human musculoskeletal tumor tissue samples by quantitative real-time PCR. PKD1 expression in OS samples was significantly lower than that in benign schwannoma samples, and this was correlated with metastatic potential. In in vitro studies, overexpression of PKD1 by plasmid transfection decreased OS cell invasion, migration and proliferation, and significantly decreased matrix metalloproteinase (MMP)2 mRNA expression. Conversely, siRNA knockdown of PKD1 increased invasion, migration and proliferation of OS cells, and MMP2 expression was markedly increased. Furthermore, overexpression of PKD1 significantly reduced in vivo tumor growth of OS cells. These results demonstrated that low expression of PKD1 may contribute to increased cell invasion, migration and proliferation ability of human OS. Taken together, our findings strongly suggest that PKD1 may negatively regulate the malignant potential of human OS, and may be a therapeutic target for human OS in the clinical setting.

Apophysitis of the ischial tuberosity mimicking a neoplasm on magnetic resonance imaging

We present multimodality imaging features of an ischial tuberosity apophysitis in a 13-year-old boy who was an active baseball pitcher. Roentgenography of the pelvis and computed tomography showed mild irregularity in the inferior margin of the left ischial tuberosity. T1-weighted MRI showed a wide area with low signal intensity in the left ischial body; T2-weighted fat-suppression images showed areas with markedly high signal intensity in the ischial apophysis and body and the surrounding periosteum; contrast-enhanced T1-weighted fat-suppression MRI showed that the ischial body, surrounding periosteum, and origin of the hamstring muscles strongly enhanced; technetium-99m scintigraphic scans showed increased isotope uptake in the entire ischial body. Histological specimens obtained from the bone showed increased osteoblastic activity, edema, and proliferation of benign spindle cells and small vessels in the bone marrow spaces. In the present case, because MR imaging demonstrated extensive signal abnormalities involving the apophysis, periosteum, and intramedullary portion of bone, a neoplasm could not be excluded, and a biopsy was undertaken.

Periosteal osteoblastoma of the distal femur.

Osteoblastomas located on the surface of the cortical bone, so-called periosteal osteoblastomas, are extremely rare. We report on a case of periosteal osteoblastoma arising from the posterior surface of the right distal femur in a 17-year-old man. Roentgenographic, computed tomographic, magnetic resonance imaging, and histologic features of the case are presented. Periosteal osteoblastoma should be radiologically and histologically differentiated from myositis ossificans, avulsive cortical irregularity syndrome, osteoid osteoma, parosteal osteosarcoma, periosteal osteosarcoma, and high-grade surface osteosarcoma. Although periosteal osteoblastoma is rare, this tumor should be included in the differential diagnosis of surface-type bone tumors.

Expression of Transforming Growth Factor β Isoforms and Their Receptors in Malignant Fibrous Histiocytoma of Soft Tissues

Purpose: Transforming growth factor β (TGF-β) is a multifunctional growth factor that variably affects proliferation, differentiation, and extracellular matrix formation. Little information is currently available on the TGF-β expression in malignant fibrous histiocytoma (MFH). The aims of the present study were to investigate the expression of TGF-β isoforms and their receptors in human MFH specimens. Experimental Design: The expression of TGF isoforms, and TGF-β receptors (TGF-βR1 and -βR2) were immunohistochemically evaluated in 43 paraffin-embedded MFH specimens. Furthermore, the correlation of the TGF-β and receptor expression with tumor proliferative activity assessed by MIB-1 indices was analyzed. Results: Positive immunoreactivity for TGF-β1, -β2, and -β3 was identified in tumor cells of 42, 40, and 38 of the 43 MFHs, respectively. In each TGF-β isoform immunostaining, the specimens were divided into two groups based on the number of positive tumor cells: those with low (<25%) and those with high (≧25%) immunoreactivity. There were no statistically significant differences in the MIB-1 indices between the two groups. Positive immunoreactivity for TGF-βR1 and -βR2 was identified in tumor cells of 36 and 24 of the MFHs, respectively. The specimens were divided into two groups based on their receptor expression patterns: those with both TGF-βR1- and -βR2-positive immunoreactivity (n = 23), and those with both or either TGF-βR1- and -βR2-negative immunoreactivity (n = 20). The MIB-1 indices in the both-TGF-βR1- and -βR2-positive group were significantly higher than those in the other group (P = 0.0102). There was no significant difference in pulmonary metastasis ratios between the two groups. Conclusions: These findings strongly suggest an association of the TGF-β ligand/receptor system with a significantly higher MIB-1 index in human MFHs. Investigation of the TGF-βR1 and -βR2 coexpression might be useful in predicting tumor behavior of MFHs.

Multimodality imaging features of primary xanthoma of the calcaneus

Secondary xanthomatous features are histologically observed in various bone lesions, but primary xanthoma of bone is rare. We present a primary xanthoma of the right calcaneus in a 51-year-old woman who had no aberrant lipid metabolism. Roentgenograms showed a small osteolytic lesion in the calcaneal triangle, partially surrounded by bone sclerosis. Computed tomographic scans of the calcaneus showed multiple osteolytic areas, with an irregular trabecular pattern in the surrounding sclerotic bone. T1-weighted magnetic resonance images showed a lesion with central low signal intensity, surrounded by a peripheral ring with high signal intensity. The entire lesion showed high signal intensity on T2-weighted images, partially surrounded by areas with low signal intensity, concordant with reactive bone sclerosis. Histologically, the lesion consisted of numerous lipid-laden histiocytes arranged in sheets, scattered multinucleated giant cells and lymphocytes, and granulation tissues. There was no evidence of pre-existing lesions. Total excision of the tumor was curative.

Regulation of Mitochondrial Proliferation by PGC-1α Induces Cellular Apoptosis in Musculoskeletal Malignancies

A number of studies have reported that decreased mitochondrial numbers are linked with neoplastic transformation and/or tumor progression, including resistance to apoptosis. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a multi-functional transcriptional coactivator that regulates the activities of multiple nuclear receptors and transcriptional factors involved in mitochondrial biogenesis. In this study, we observed that the number of mitochondria in sarcoma tissues, such as osteosarcoma and malignant fibrous histiocytoma, is significantly lower than that in normal muscle tissue or benign tumors and that increasing the number of mitochondria by PGC-1α overexpression induces mitochondrial apoptosis in human sarcoma cell lines. The findings suggest that decreased mitochondrial numbers may contribute to musculoskeletal tumor progression and that regulation of mitochondrial numbers by PGC-1α could be a potent therapeutic tool for human malignancies. Electronic supplementary material The online version of this article (doi:10.1038/srep03916) contains supplementary material, which is available to authorized users.

Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells.

Osteosarcoma is the most common primary solid malignant bone tumor. Despite substantial improvements in surgery and chemotherapy, metastasis remains a major cause of fatal outcomes, and the molecular mechanisms of metastasis are still poorly understood. Hypoxia, which is common in malignant tumors including osteosarcoma, increases expressions of hypoxia inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2 and MMP-9, and can induce invasiveness. As we previously showed a novel transcutaneous CO2 application to decrease HIF-1α expression and induce apoptosis in malignant fibrous histiocytoma, we hypothesize that transcutaneous CO2 application could suppress metastatic potential of osteosarcoma by improving hypoxic conditions. Here, we examined the effects of transcutaneous CO2 application on apoptosis, and development of pulmonary metastasis using a highly metastatic osteosarcoma cell line, LM8. Transcutaneous CO2 application significantly decreased tumor growth and pulmonary metastasis in LM8 cells. Apoptotic activity increased, and intratumoral hypoxia was improved with decreased expressions of HIF-1α, MMP-2 and MMP-9, significantly, in the CO2-treated tumors. In conclusion, we found that transcutaneous CO2 application can induce tumor cell apoptosis and might suppress pulmonary metastasis by improvement of hypoxic conditions with decreased expressions of HIF-1α and MMPs in highly metastatic osteosarcoma cell. These findings strongly indicate that this novel transcutaneous CO2 therapy could be a therapeutic breakthrough for osteosarcoma patients.

Transcutaneous Application of Carbon Dioxide (CO2) Induces Mitochondrial Apoptosis in Human Malignant Fibrous Histiocytoma In Vivo

Mitochondria play an essential role in cellular energy metabolism and apoptosis. Previous studies have demonstrated that decreased mitochondrial biogenesis is associated with cancer progression. In mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) regulates the activities of multiple nuclear receptors and transcription factors involved in mitochondrial proliferation. Previously, we showed that overexpression of PGC-1α leads to mitochondrial proliferation and induces apoptosis in human malignant fibrous histiocytoma (MFH) cells in vitro. We also demonstrated that transcutaneous application of carbon dioxide (CO2) to rat skeletal muscle induces PGC-1α expression and causes an increase in mitochondrial proliferation. In this study, we utilized a murine model of human MFH to determine the effect of transcutaneous CO2 exposure on PGC-1α expression, mitochondrial proliferation and cellular apoptosis. PGC-1α expression was evaluated by quantitative real-time PCR, while mitochondrial proliferation was assessed by immunofluorescence staining and the relative copy number of mitochondrial DNA (mtDNA) was assessed by real-time PCR. Immunofluorescence staining and DNA fragmentation assays were used to examine mitochondrial apoptosis. We also evaluated the expression of mitochondrial apoptosis related proteins, such as caspases, cytochorome c and Bax, by immunoblot analysis. We show that transcutaneous application of CO2 induces PGC-1α expression, and increases mitochondrial proliferation and apoptosis of tumor cells, significantly reducing tumor volume. Proteins involved in the mitochondrial apoptotic cascade, including caspase 3 and caspase 9, were elevated in CO2 treated tumors compared to control. We also observed an enrichment of cytochrome c in the cytoplasmic fraction and Bax protein in the mitochondrial fraction of CO2 treated tumors, highlighting the involvement of mitochondria in apoptosis. These data indicate that transcutaneous application of CO2 may represent a novel therapeutic tool in the treatment of human MFH.

Intra-tendinous ganglion in the long head of the biceps humeri

We present details of a case of intra-tendinous ganglion arising from the long head of the biceps at an unusual location. MRI scans have important implications for surgical planning and treatment. After excision of the ganglion, the tendon remaining could be repaired. Five months after surgery, there was no sign of recurrence.