Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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PTEN and other tumor suppressor gene mutations as secondary genetic alterations in synovial sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-Ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi

Oncology reports 11 ( 5 ) 1011 - 5 2004.5

Language：English Publishing type：Research paper (scientific journal)

Synovial sarcomas (SS) consistently show a characteristic chromosomal translocation, t(X;18)(p11;q11), which usually leads to the formation of 2 chimeric fusion transcripts, SYT-SSX1 and -SSX2. A recent multi-institutional retrospective study revealed that the SYT-SSX fusion type emerged as the only independent significant factor for overall survival in cases of SS. The aims of this study were; i). to investigate the frequency of PTEN gene alteration, ii). to evaluate whether the mutation status in various tumor suppressor genes (TSG) is responsible for the clinical and histologic heterogeneity in SS. Forty-nine cases of SS were examined for the presence of PTEN gene mutation by polymerase chain reaction - single-strand conformation polymorphism followed by DNA direct sequencing. The obtained data was combined with those of previously reported TSG mutations such as p53, adenomatous polyposis coli, and E-cadherin genes. Follow-up was available for 44 patients, and survival analysis was performed according to the mutation status of these TSG. PTEN mutations were detected in 7 cases (14.3%), and all of these were monophasic tumors. More than half of the mutations detected were located in exon 9, which has been shown to play a less important role in PTEN functioning, and the PTEN mutation was not associated with patients' prognosis. Mutations in these TSG other than silent mutations were detected in 20 out of 49 cases (40.8%), although the mutation status in TSG was not associated with overall survival rate in patients with SS. Secondary genetic alterations in these TSG seem to have a less important prognostic impact on patients with SS.

c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Reviewed International journal

Hidetaka Yamamoto, Yoshinao Oda, Ken-ichi Kawaguchi, Norimoto Nakamura, Tomonari Takahira, Sadafumi Tamiya, Tsuyoshi Saito, Yumi Oshiro, Masayuki Ohta, Takashi Yao, Masazumi Tsuneyoshi

The American journal of surgical pathology 28 ( 4 ) 479 - 88 2004.4

Language：English Publishing type：Research paper (scientific journal)

Extragastrointestinal stromal tumor (EGIST) is a unique tumor that occurs outside the gastrointestinal tract. EGIST shows a c-kit expression and histologic appearance similar to those of gastrointestinal stromal tumor (GIST). Most GISTs have gain-of-functional mutation of the c-kit gene, and some have mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. However, the frequency of mutation of those genes in EGISTs remains unclear. We examined the clinicopathologic features, prognostic factors, and c-kit and PDGFRA mutation in 39 cases of EGIST. Tumors with high mitotic counts (>or=5/50 high power fields) or a high Ki-67 labeling index (>or=10%) were significantly correlated with worse prognoses. The c-kit mutation was found in the juxtamembrane domain (exon 11) and the extracellular domain (exon 9) in 12 of 29 cases (41.4%) and 2 of 29 cases (6.9%), respectively. The PDGFRA gene mutation was found at the juxtamembrane domain (exon 12) and the tyrosine kinase domain (exon 18) in one case each. The pattern of kit and PDGFRA mutation in EGIST was essentially similar to that in GIST. Our results suggest that the c-kit and PDGFRA mutations play an important role in the tumorigenesis of EGIST. High mitotic counts and a high Ki-67 labeling index may be useful for predicting the aggressive biologic behavior in EGIST. Furthermore, STI-571, targeting c-kit and PDGFR tyrosine kinase, seems to be a possible therapeutic strategy for EGISTs, especially advanced cases.

H-ras mutation is an additional event of sarcomatous transformation in aerodigestive spindle cell carcinoma. Reviewed International journal

Hideki Shiratsuchi, Naoya Hirakawa, Tsuyoshi Saito, Yoshinao Oda, Hidetaka Yamamoto, Kichinobu Tomita, Tomoya Yamamoto, Masazumi Tsuneyoshi

Oncology reports 11 ( 3 ) 597 - 604 2004.3

Language：English Publishing type：Research paper (scientific journal)

The conversion from a carcinomatous component to a sarcomatous one in spindle cell carcinoma (SPCC) of the upper aerodigestive tract is thought to occur via a series of molecular alterations; however the detailed mechanism is still unknown. We examined mutations at the H-ras and p53 genes in 16 SPCCs of upper aerodigestive tracts using PCR-RFLP, PCR-SSCP and direct sequencing analysis. The two distinct components, sarcomatous and carcinomatous components in SPCC, were analyzed independently. p53 mutations were detected in both components of SPCC (50.0%, 8/16), and those in the sarcomatous component were completely in accordance with those in the carcinomatous one. In contrast, H-ras mutations were detected only in the sarcomatous component (12.5%, 2/16), and not in the carcinomatous one (0%, 0/16). There was a statistically significant difference in prognosis between the patients with the H-ras mutation (n=2) and those without (n=14); the former had poorer prognosis (P=0.0049). Our results seem to suggest that the H-ras mutation is a relatively uncommon event in SPCC; however, the presence of H-ras mutations may be associated with a more malignant potential in SPCC, while actually occurring during the sarcomatous change itself.

Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. Reviewed International journal

Takashi Kuwano, Shintaro Nakao, Hidetaka Yamamoto, Masazumi Tsuneyoshi, Tomoya Yamamoto, Michihiko Kuwano, Mayumi Ono

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 ( 2 ) 300 - 10 2004.2

Language：English Publishing type：Research paper (scientific journal)

Cyclooxygenase1 (COX1) and COX2 mediate the rate-limiting step in arachidonic acid metabolism. Expression of COX2 mRNA and protein is often enhanced in various human cell types by inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). IL-1beta enhanced expression of various prostanoids and this expression was blocked by COX2 selective inhibitors. IL-1beta markedly induced angiogenesis in vitro and in vivo, which was significantly inhibited by COX2 selective inhibitors but not by a vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. In contrast, COX2 selective inhibitors only partially blocked VEGF-induced angiogenesis. EP2, EP4 (prostaglandin E2 receptors) agonists and thromboxane A2 (TXA2) receptor agonists induced angiogenesis in vitro and in vivo; IL-1beta-induced angiogenesis was blocked by an EP4 antagonist and a TXA2 receptor antagonist. IL-1beta induced much less angiogenesis in cornea of COX2 knockout mice than that of wild-type mice. This is the first report that COX2 and some prostanoids play a key role in IL-1beta-induced angiogenesis.

Microsatellite instability and p53 mutation associated with tumor progression in dermatofibrosarcoma protuberans. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Hidetaka Yamamoto, Kenichi Kawaguchi, Chikashi Kobayashi, Shinya Oda, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 35 ( 2 ) 240 - 5 2004.2

Language：English Publishing type：Research paper (scientific journal)

Dermatofibrosarcoma protuberans (DFSP) is a dermal and subcutaneous tumor categorized as a tumor of intermediate malignancy, and its progression in some cases to fibrosarcoma is well known. However, molecular analysis of tumor progression has been limited. The present study investigated microsatellite instability (MSI) of 7 microsatellite markers through high-resolution microsatellite analysis in addition to a mutational analysis of the p53 gene in 44 tumors in 36 patients. The patients were divided into 2 groups: 9 patients with a fibrosarcomatous component in the primary or recurrent/metastasized tumor, designated as the DFSP+FS group, and the remaining 27 patients, designated as the DFSP group. Cases in which the percentage of markers with an additional peak among the markers successfully analyzed was more than 30% was considered MSI high (MSI-H); cases in which microsatellites were stable at all of the successfully examined markers were considered microsatellite stable (MSS); and the remaining cases were considered MSI low (MSI-L). MSI-H cases were observed more frequently in the DFSP+FS group (4 of 9 cases) than in the DFSP group (1 of 27 cases) (P = 0.028, Fischer's exact test). The MSI status of recurrent or metastatic tumors in both the DFSP+FS and the DFSP groups was the same as that in the corresponding primary neoplasms. Furthermore, there was no difference in MSI status between an ordinary DFSP area and a fibrosarcomatous area in 7 tumors that exhibited both areas. p53 mutational analysis revealed 10 point mutations, composed of 4 missense mutations and 6 silent mutations, in 6 of 36 cases (16.7%). A missense mutation was more frequently observed in the DFSP+FS group (3 of 4) than in the DFSP group (1 of 4). Among 3 cases of a missense mutation in the DFSP+FS group, 2 had a mutation only in a fibrosarcomatous area and 1 had a mutation only in a metastatic tumor progressing to fibrosarcoma. These results suggest that MSI and p53 mutations are involved in tumor progression of DFSP to fibrosarcoma as early and late events, respectively.

Decreased expression of transforming growth factor-beta II receptor is associated with that of p27KIP1 in giant cell tumor of bone: a possible link between transforming growth factor-beta and cell cycle-related protein. Reviewed International journal

Ken-Ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Tomonari Takahira, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 35 ( 1 ) 61 - 8 2004.1

Language：English Publishing type：Research paper (scientific journal)

Transforming growth factor (TGF)-beta is a potential regulator of cell growth that sends its signals through a heteromeric complex composed of type I and II receptors (IR and IIR). This study examined a correlation between TGF-beta1, TGF-beta-IR and -IIR, and cell cycle-related proteins in giant cell tumor (GCT) of bone, using immunohistochemical and Western blot analysis. First, an immunohistochemical study for TGF-beta1, TGF-beta-IR and -IIR, p27KIP1 (p27), p21WAF1 (p21), cyclin D1, and cyclin E was carried out on 92 cases of GCT of bone; the expression of these proteins was evaluated in multinucleated giant cells (MGCs) and mononucleated stromal cells (MSCs) separately; and proliferative activity was assessed using MIB-1. Next, to confirm our immunohistochemical results, Western blot analysis was performed in 19 cases for which frozen samples were available. Immunoreactivity for TGF-beta-IR and -IIR showed a tendency to be greater in MGCs than in MSCs; however, no differences were observed in TGF-beta1. Cyclin D1 expression was correlated with the occurrence of vascular invasion in both MGCs and MSCs (P = 0.0255 and 0.0183, respectively). The expression of TGF-beta-IIR and p27 was concordantly decreased in both MGSs and MSCs (P = 0.0014 and 0.0317, respectively). The expression for TGF-beta-IIR and p27 in Western blot analysis was related to the results from immunohistochemical analysis, and the expression of TGF-beta-IIR and p27 was concordant in almost all GCT cases. Furthermore, there was a statistically significant inverse relationship between p27 expression and MIB-1 labeling index in MSCs (P = 0.0397). In GCT of bone, TGF-beta-IIR and p27 expression were concordantly decreased; this result supports the possibility that these 2 factors may play an important role in cell proliferation of this tumor. Furthermore, our results provide a possible link between the effects of extracellular growth factors and cell cycle control. In addition, p27 expression may be a useful indicator of cell proliferation in MSCs of this tumor.

A case of breast cholesterol granuloma accompanied by cancer. Reviewed

Chizu Furuhira, Akira Ohshima, Kazuo Shimada, Syoji Kuroki, Kenji Nakano, Mikimasa Ishikawa, Hidetaka Yamamoto, Masao Tanaka

Breast cancer (Tokyo, Japan) 11 ( 2 ) 210 - 3 2004

Language：English Publishing type：Research paper (scientific journal)

Cholesterol granuloma of the breast is a very rare benign disease with clinical and imaging features that are often indistinguishable from cancer preoperatively. We report a case of breast cholesterol granuloma accompanied by cancer. The patient was a 78-year-old woman who complained of a lump in her right breast. Mammography and ultrasonography showed a well-circumscribed mass. Fine needle aspiration cytology showed many cholesterol crystals and inflammatory cells without malignancy. With a diagnosis of cholesterol granuloma, tumor extirpation was performed. Histopathologic examination revealed cholesterol granuloma together with breast cancer, and additional partial mastectomy was subsequently performed. It is noted that breast cholesterol granuloma could be accompanied by cancer.

Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis. Reviewed International journal

Ken-ichi Kawaguchi, Yoshinao Oda, Tsuyoshi Saito, Hidetaka Yamamoto, Sadafumi Tamiya, Tomonari Takahira, Kimitaka Miyajima, Yukihide Iwamoto, Masazumi Tsuneyoshi

The Journal of pathology 201 ( 3 ) 487 - 95 2003.11

Language：English Publishing type：Research paper (scientific journal)

The p16INK4a tumour suppressor gene, encoding p16 protein, plays a crucial role in regulation of the G1 cell-cycle phase. To investigate the potential role of p16 in soft tissue leiomyosarcoma (LMS), an immunohistochemical analysis was performed of 77 LMSs for p16 expression. Decreased expression of the p16 protein was identified in 25 of 77 LMSs (32%). Decreased expression of p16 correlated significantly with large tumour size (p=0.0038). In a univariate analysis, large tumour size and decreased expression of p16 were statistically significant adverse prognostic factors (p=0.025 and p=0.0021, respectively). In a multivariate analysis including conventional clinicopathological parameters, decreased expression of p16 protein was revealed as the only independent unfavourable prognostic factor (p=0.012). To elucidate the mechanisms of inactivation of the p16INK4a gene, 49 LMSs for which genomic DNA was available were examined; analysis for homozygous deletion, mutation, and promoter hypermethylation was conducted using differential PCR, PCR-SSCP, and methylation-specific PCR, respectively. Promoter hypermethylation was detected in 11 of 49 LMS cases (22%); homozygous deletion was detected in 3 of 49 cases (6%); and mutation was not recognized in any of the cases studied. Eight of 15 cases (53%) with decreased expression of p16 protein revealed methylation of the p16INK4a gene promoter. Promoter hypermethylation correlated closely with decreased expression and poor prognosis (p=0.0014 and p=0.0088, respectively). These results suggest that decreased expression of p16 protein can be considered as an independent reliable prognostic parameter in patients with soft tissue LMS. Furthermore, promoter methylation was more frequent than either homozygous deletion or mutation in this tumour, and promoter methylation was also shown to have a strong association with inactivation of the p16INK4a gene.

Altered expression of cell cycle regulators in myxofibrosarcoma, with special emphasis on their prognostic implications. Reviewed International journal

Yoshinao Oda, Tomonari Takahira, Kenichi Kawaguchi, Hidetaka Yamamoto, Sadafumi Tamiya, Shuichi Matsuda, Kazuhiro Tanaka, Naoko Kinukawa, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 34 ( 10 ) 1035 - 42 2003.10

Language：English Publishing type：Research paper (scientific journal)

Myxofibrosarcoma/myxoid malignant fibrous histiocytoma (MFH) has continued to be considered a distinct entity even after recently published reassessments of pleomorphic sarcomas and MFH. Several cell cycle-regulated proteins have already been screened by immunohistochemistry with the aim of finding the reliable prognostic indicator of soft tissue sarcomas; however, it is still unknown whether their altered expression affects patient survival in myxofibrosarcoma. In this study, we evaluated the expression of p53, MDM2, MIB-1 (Ki-67), p21, p27, p16, cyclin A, cyclin D1, and cyclin E by immunohistochemistry in 45 cases of myxofibrosarcoma. First, we searched for possible clinicopathologic prognostic factors in 61 cases of myxofibrosarcoma for which follow-up data were available. In univariate analysis, large tumor size (> or =5 cm), deeply situated tumor, and high histological grade (grade 2 or 3) significantly decreased survival (log-rank test, P <0.05). Among 43 cases of myxofibrosarcoma for which immunohistochemical findings were available, high MIB-1 labeling index (LI) (cutoffs of 10 and 22.5 on average), high cyclin A LI (cutoffs 10% and 13.8% on average), low p21 LI (cutoffs 10 and 20.7 on average), and reduced abnormal expression of p16 were adverse prognostic factors. In multivariate analysis (Cox proportional hazards model), high mitotic rate (>15/10 high-power fields), p53 immunoreactivity (cutoff 10%), high MIB-1 LI (>22.5), low p21 LI (<20.7), and low p27 LI (<47.8 on average) were independent poor prognostic factors. Our results suggest that reduced expression of p21 could be considered a new parameter to be evaluated, along with classical clinicopathologic prognostic factors, for identifying those at high risk for myxofibrosarcoma.

ALK-positive anaplastic large cell lymphoma of the parotid gland

H Yamamoto, H Shiratsuchi, T Yao, H Uryu, Y Oda, S Tamiya, M Tsuneyoshi

HISTOPATHOLOGY 43 ( 4 ) 397 - 398 2003.10

Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-Ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Akio Sakamoto, Sadafumi Tamiya, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 34 ( 9 ) 841 - 9 2003.9

Language：English Publishing type：Research paper (scientific journal)

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.

Mucinous cystic tumor of the pancreas: Immunohistochemical assessment of 'ovarian-type stroma'

Akihiko Izumo, Koji Yamaguchi, Takashi Eguchi, Ken-Ichi Nishiyama, Hidetaka Yamamoto, Hirotoshi Yonemasu, Takashi Yao, Masao Tanaka, Masazumi Tsuneyoshi

Oncology Reports 10 ( 3 ) 515 - 525 2003.5

Language：English Publishing type：Research paper (scientific journal)

The new histopathological classification of exocrine pancreatic tumors by the World Health Organization, now includes 'ovarian-type stroma' ('OS') in the definition of mucinous cystic tumor of the pancreas (MCT-P). This study investigated the clinicopathological findings of the MCT-P according to WHO classification and scrutinize the function of 'OS' in MCT-P immunohistochemically. Thirty-four cases of MCT-P (28 adenomas, 2 borderline tumors and 4 adenocarcinomas) were examined clinicopathologically. The 'OS' of 34 MCTs-P were studied immunohistochemically and compared with the stroma of 10 mucinous cystic tumors of the ovary (MCTs-O), 10 conventional pancreatic carcinomas and 6 normal ovaries. Almost all 34 MCTs-P were located in the body-tail of the pancreas of middle-aged women. Histologically the 'OS' cells exhibited luteinization in 11/34 (32.4%). Immunohistochemically, both 'OS' cells and the stromal cells in MCT-O showed similar positivity rates
calponin (34/34 and 9/10), h-caldesmon (28/34 and 8/10), α-inhibin (29/34 and 9/10), estrogen-receptor (21/34 and 6/10) and progesterone-receptor (28/34 and 9/10, respectively). Some neoplastic epithelial cells of MCT-P were positive for human chorionic gonadotropin (hCG) (21/34, 61.8%). This study indicates the predominance of MCT in the distal pancreas of middle-aged women. Furthermore, the immunohistochemical and histological results demonstrate that the 'OS' of MCT-P and the stroma of MCT-O share the same characteristics. The results also suggested that the hCG produced by the neoplastic epithelium probably plays an important role in the luteinization of the stroma of MCT-P. We therefore conclude there is a possibility that MCT-P originates from the left remnant primordial gonadal cells which migrated to the pancreatic anlage during the early development of the fetus.

p53 mutation and MDM2 amplification in inflammatory myofibroblastic tumours Reviewed

H Yamamoto, Y Oda, T Saito, A Sakamoto, K Miyajima, S Tamiya, M Tsuneyoshi

HISTOPATHOLOGY 42 ( 5 ) 431 - 439 2003.5

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING LTD

Aims: The pathogenic mechanism and predictive indicators of biological behaviour of inflammatory myofibroblastic tumour are poorly understood. We investigated molecular abnormalities of p53 and MDM2 in order to assess whether these play an important role in pathogenesis, and whether they also contribute to clinicopathological aggressive phenotype in inflammatory myofibroblastic tumour.
Methods and results: We compared the immunohistochemical expression of calponin, h-caldesmon, ALK, and p53 gene mutation and MDM2 gene amplification with clinicopathological findings in 15 cases of inflammatory myofibroblastic tumour. Histologically, cellular atypia was observed in five (33.3%) out of 15 cases. Local recurrences were observed in two (14.3%) of 14 informative cases, but no distant metastasis was observed. The expression of calponin (9/14; 64%) but not h-caldesmon (0/14; 0%) was seen, which suggested myofibroblastic differentiation. ALK expression was seen in eight (53.3%) out of 15 cases, particularly in patients under 40 years old. Nuclear expression of p53 protein was recognized in only one (6.7%) of 15 cases, and polymerase chain reaction single-strand conformation polymorphism followed by direct sequencing revealed p53 gene missense mutations in two (13.3%) of 15 cases. Nuclear expression of MDM2 was seen in four (26.7%) of 15 cases, and the MDM2 gene amplification was observed in two of the four cases.
Conclusion: Inflammatory myofibroblastic tumour shows a wide spectrum of cellular atypia and biological behaviour with p53 and MDM2 expression. However, the alterations in the p53 pathway seem not to play a major role in the pathogenesis of inflammatory myofibroblastic tumour.

DOI： 10.1046/j.1365-2559.2003.01611.x

PTEN/MMAC1 gene mutation is a rare event in soft tissue sarcomas without specific balanced translocations. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Ken-ichi Kawaguchi, Tomonari Takahira, Hidetaka Yamamoto, Sadafumi Tamiya, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi

International journal of cancer 104 ( 2 ) 175 - 8 2003.3

Language：English Publishing type：Research paper (scientific journal)

The tumor suppressor gene PTEN/MMAC1 was identified on chromosome 10q23.3, which is homozygously deleted in many human malignancies. The loss of chromosome 10q was also frequently reported in some types of soft tissue sarcomas. Our study was designed to investigate the frequency of PTEN/MMAC1 gene mutation and to evaluate the role of the PTEN/MMAC1 gene in the tumorigenesis of soft tissue sarcomas without specific balanced translocations. We analyzed 51 cases of soft tissue sarcomas without specific balanced translocations for PTEN/MMAC1 mutations by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. Mutations in the PTEN/MMAC1 gene were found in only 2 cases (3.9%). Both tumors with PTEN/MMAC1 mutation were leiomyosarcomas arising from the retroperitoneum and inferior vena cava, respectively. Two of 3 leiomyosarcomas arising from the intra-abdominal cavity examined harbored mutations of this tumor suppressor gene. This result suggests that leiomyosarcomas derived from the intra-abdominal cavity might have different tumorigenesis from those of an extremity or the trunk, from the viewpoint of PTEN/MMAC1 mutation, although PTEN/MMAC1 gene mutations are rare event in these soft tissue sarcomas.

Low-grade fibrosarcoma of the proximal humerus. Reviewed International journal

Tsuyoshi Saito, Yoshinao Oda, Kazuhiro Tanaka, Shuichi Matsuda, Akio Sakamoto, Hidetaka Yamamoto, Yukihide Iwamoto, Masazumi Tsuneyoshi

Pathology international 53 ( 2 ) 115 - 20 2003.2

Language：English Publishing type：Research paper (scientific journal)

We present the clinical, radiographical and pathological features of low-grade fibrosarcoma of the left proximal humerus in a 23-year-old man in whom it was necessary to distinguish the tumor from desmoplastic fibroma, malignant fibrous histiocytoma and intramedullary well-differentiated osteosarcoma. The patient presented with a 10-day history of pain in his left upper arm sustained when trying to break his fall with his left hand when slipping in the street. Plain radiography revealed an expanding multilobular osteolytic lesion from the proximal metaphysis to the diaphysis of his left humerus, accompanied by a pathological fracture at the distal portion of the lesion. Open biopsy of the lesion was performed twice; however, a conclusive diagnosis could not be obtained. The patient underwent wide excision and prosthetic replacement of the left proximal humerus. Histologically, the resected tumor was composed of both cellular areas and hypocellular areas. Cellular areas revealed a proliferation of bundles of uniform fibroblastic spindle-shaped cells with minimal cellular atypia, mixed with abundant intercellular collagenization. Mitotic figures were occasionally seen. Hypocellular areas showed myxoid features with loose bundles of collagen fibers. The patient demonstrates no evidence of disease 42 months after surgery. It is important to detect the scant atypical cells for the differential diagnosis of low-grade fibrosarcoma and desmoplastic fibroma of bone.

Follicular dendritic cell sarcoma of the neck; a case report and literature review. Reviewed International journal

Torahiko Nakashima, Yuichiro Kuratomi, Hideki Shiratsuchi, Hidetaka Yamamoto, Ryuji Yasumatsu, Tomoya Yamamoto, Sohtaro Komiyama

Auris, nasus, larynx 29 ( 4 ) 401 - 3 2002.10

Language：English Publishing type：Research paper (scientific journal)

Follicular dendritic cell (FDC) sarcomas, also known as dendritic reticulum cell tumors, are uncommon neoplasms arising from antigen-presenting cells in B-lymphofollicles of nodal and extra-nodal sites. It is considered as an intermediate grade malignancy since it has significant recurrent and metastatic potential. We report a case of FDC sarcoma arising in the neck. A 56-year-old female presented with a left neck tumor. Neck dissection was performed. Microscopically, the tumor showed spindle-shaped stromal cells with large oval and polygonal nuclei. Immunohistologically, the cells were positive for CD21 and CD35, consistent with FDC sarcomas. Adjuvant chemotherapy of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) was given. Literature review provides the current information for the diagnosis and treatment of this unusual tumor.

Severe pulmonary hypertension in a patient with systemic lupus erythematosus and minimal lupus activity. Reviewed

Nobutoshi Kawamura, Hiroyuki Tsutsui, Kae Fukuyama, Shunji Hayashidani, George Koike, Kensuke Egashira, Yasunobu Abe, Hidetaka Yamamoto, Masazumi Tsuneyoshi, Akira Takeshita

Internal medicine (Tokyo, Japan) 41 ( 2 ) 109 - 12 2002.2

Language：English Publishing type：Research paper (scientific journal)

Pulmonary hypertension (PH) sometimes occurs in patients with systemic lupus erythematosus (SLE). We report a case of 51-year-old-woman with PH associated with SLE. She had been diagnosed as SLE on the basis of pericardial effusion, hematological disorder, positive antinuclear antibody, and hypocomplementemia. Despite minimal lupus activity, she had marked elevation of pulmonary arterial pressure (101/53 mmHg) and decreased cardiac index (1.5 l/min/m2). Symptoms related to PH were progressive under treatment with oral corticosteroids, oxygen, calcium antagonists, and warfarin. After 17 months of epoprostenol treatment, she died of pulmonary infarction. SLE-associated PH is often severe and progressive even in association with minimal activity.

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