Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. Reviewed International journal

Hiroshi Matono, Yoshinao Oda, Mari Nakamori, Sadafumi Tamiya, Hidetaka Yamamoto, Ryohei Yokoyama, Tsuyoshi Saito, Yukihide Iwamoto, Masazumi Tsuneyoshi

Human pathology 39 ( 12 ) 1802 - 8 2008.12

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

Desmoid tumors (desmoid-type fibromatoses) are locally aggressive soft tissue tumors associated with the Wnt/beta-catenin signaling pathway (APC-beta-catenin-Tcf pathway). Matrix metalloproteinase-7, which is one of the target genes of the Wnt/beta-catenin signaling pathway, has been reported to play an important role in tumor progression. We examined the immunohistochemical expression of beta-catenin and matrix metalloproteinase-7 in 72 samples (63 primary and 9 recurrent samples, 63 patients) of sporadic desmoid tumors without familial adenomatous polyposis, and the genetic alteration of the beta-catenin gene in 33 frozen materials (22 primary and 11 recurrent samples, 22 patients). We further examined messenger RNA expression of matrix metalloproteinase 7 by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and compared the results with those of normal skeletal muscles. Immunohistochemically, there was a statistically significant correlation between widespread nuclear expression of beta-catenin and overexpression of matrix metalloproteinase-7 (P < .01 in extra-abdominal desmoid, Fisher test). There were 7 missense point mutations in the 22 primary frozen samples (32%). In the beta-catenin mutated group, matrix metalloproteinase-7 messenger RNA expression was significantly higher than that of the beta-catenin wild-type group (P = .0018, Mann-Whitney U test). Our results suggest that the matrix metalloproteinase-7 gene may be up-regulated by mutated or continuously elevated beta-catenin protein and that the matrix metalloproteinase-7 gene may also be targeted in the Wnt/beta-catenin signaling pathway in sporadic desmoid tumors.

DOI： 10.1016/j.humpath.2008.05.005

Enhanced mass on contrast-enhanced breast MR imaging: Lesion characterization using combination of dynamic contrast-enhanced and diffusion-weighted MR images. Reviewed International journal

Hidetake Yabuuchi, Yoshio Matsuo, Takashi Okafuji, Takeshi Kamitani, Hiroyasu Soeda, Taro Setoguchi, Shuji Sakai, Masamitsu Hatakenaka, Makoto Kubo, Noriaki Sadanaga, Hidetaka Yamamoto, Hiroshi Honda

Journal of magnetic resonance imaging : JMRI 28 ( 5 ) 1157 - 65 2008.11

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

PURPOSE: To evaluate the diagnostic accuracy of a combination of dynamic contrast-enhanced MR imaging (DCE-MRI) and diffusion-weighted MR imaging (DWI) in characterization of enhanced mass on breast MR imaging and to find the strongest discriminators between carcinoma and benignancy. MATERIALS AND METHODS: We analyzed consecutive breast MR images in 270 patients; however, 13 lesions in 93 patients were excluded based on our criteria. We analyzed tumor size, shape, margin, internal mass enhancement, kinetic curve pattern, and apparent diffusion coefficient (ADC) values. We applied univariate and multivariate analyses to find the strongest indicators of malignancy and calculate a predictive probability for malignancy. We added the corresponding categories to these prediction probabilities for malignancy and calculated diagnostic accuracy when we consider category 4b, 4c, and 5 lesions as malignant and category 4a, 3, and 2 lesions as benign. In a validation study, 75 enhancing lesions in 71 patients were examined consecutively. RESULTS: Irregular margin, heterogeneous internal enhancement, rim enhancement, plateau time-intensity curve (TIC) pattern, and washout TIC pattern were the strongest indicators of malignancy as well as past studies, and ADC values less than 1.1x10(-3) mm2/s were also the strongest indicators of malignancy. In a validation study, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 92% (56/61), 86% (12/14), 97% (56/58), 71% (12/17), and 91% (68/75), respectively. CONCLUSION: The combination of DWI and DCE-MRI could produce high diagnostic accuracy in the characterization of enhanced mass on breast MR imaging.

DOI： 10.1002/jmri.21570

Alterations of RB1 gene in embryonal and alveolar rhabdomyosarcoma: special reference to utility of pRB immunoreactivity in differential diagnosis of rhabdomyosarcoma subtype. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomonari Takahira, Yukiko Takahashi, Tatsuro Tajiri, Tomoaki Taguchi, Sachiyo Suita, Masazumi Tsuneyoshi

Journal of cancer research and clinical oncology 134 ( 10 ) 1097 - 103 2008.10

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

PURPOSE: Rhabdomyosarcoma (RMS), which is the most common pediatric soft tissue sarcoma, is classified into two major histologic subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). RMS is occasionally reported to be the second neoplasm of hereditary retinoblastoma. Osteosarcoma is known as the most common second neoplasm of hereditary retinoblastoma, and tumorigenesis of osteosarcoma has been proven in previous studies to be related to the RB gene (RB1) alteration. Therefore, there might be a correlation between the tumorigenesis of RMS and RB1 alteration. METHODS: We examined the RB protein (pRB) expression and RB1 alteration such as allelic imbalance (gain or loss) and homozygous deletion, using immunohistochemistry, microsatellite makers, and quantitative real-time PCR in 57 sporadic RMS. RESULTS: Allelic imbalance was more frequently detected in ERMS (13/27), than in ARMS (3/20) (P = 0.04). Homozygous deletion on the protein-binding pocket domain of RB1 was found in 6 of 27 ERMS and in 2 of 20 ARMS (P = 0.24). Furthermore, immunohistochemical pRB labeling indexes (LI) in 31 ERMS (median value, 31%) were significantly reduced in comparison with those observed in 26 ARMS (median value, 85%) (P < 0.0001). CONCLUSIONS: Our results support the assertion that tumorigenesis of RMS may be associated with RB1 alteration especially in ERMS, as previously reported for osteosarcoma. As for the RB pathway, each subtype of RMS may have a different tumorigenesis. In addition, immunohistochemical pRB LI may have the potential to be a useful ancillary tool in the differential diagnosis of RMS subtypes.

DOI： 10.1007/s00432-008-0385-3

SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yumi Oshiro, Teiyu Izumi, Tomoaki Taguchi, Masazumi Tsuneyoshi

The American journal of surgical pathology 32 ( 8 ) 1168 - 74 2008.8

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

Several previous studies have demonstrated the lack of SMARCB1/INI1 protein expression in only the malignant rhabdoid tumor (MRT). Several sarcoma groups are associated with a tumor-specific translocation involving EWS. Moreover, the EWS and SMARCB1/INI1 genes are located on the same 22q chromosome. We analyzed the status of SMARCB1/INI1 protein expression in 93 cases of sarcomas associated with chromosomal translocation involving EWS, comprising 52 Ewing's sarcoma/primitive neuroectodermal tumors, 24 extraskeletal myxoid chondrosarcomas (EMCS), 14 clear cell sarcomas of soft tissue, 2 desmoplastic small round cell tumors, and 1 myxoid/round cell liposarcoma. In addition, we analyzed the detailed SMARCB1/INI1 gene alteration in cases, which lacked its protein expression. Consequently, 4 EMCS showed no SMARCB1/INI1 expression, and 2 of these 4 cases revealed homozygous deletion and frameshift mutation of the SMARCB1/INI1 gene, respectively. These cases showed histologic findings compatible with EMCS, according to the most recent WHO classification, but no major fusion gene transcripts were detected. Moreover, 3 out of 4 SMARCB1/INI1 negative variant EMCS disclosed rhabdoid features. Therefore, the lack of SMARCB1/INI1 protein expression may be associated with rhabdoid features. The immunohistochemical result of the SMARCB1/INI expression is not an absolute diagnostic criteria for MRT and careful histologic evaluation is required to make a precise diagnosis of MRT.

DOI： 10.1097/PAS.0b013e318161781a

An unexpected cause of a febrile patient with huge splenomegaly. Reviewed International journal

Atsushi Nonami, Hidetaka Yamamoto, Masafumi Nakamura, Koji Nagafuji, Takanori Teshima

Clinical rheumatology 27 ( 7 ) 941 - 3 2008.7

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

We report an unexpected cause of a febrile patient with huge splenomegaly. A 32-year-old patient with fever and huge splenomegaly was admitted to our hospital. Diagnostic splenectomy revealed that the enlarged spleen adhered strongly to the abdominal organs. Pathologically, the splenic parenchyma showed no malignant cells, and the soft tissue adjacent to the splenic hilum showed a proliferation of fibroblastic or myofibroblastic spindle cells with fibrosis and lymphoplasmacytic infiltration. These findings lead to a diagnosis of peritoneal fibrosis, and an administration of 50 mg/day of prednisolone alleviated all the symptoms. The differential diagnosis of huge splenomegaly with fever usually includes hematolymphoid malignancies and infectious diseases; however, our case was diagnosed as idiopathic retroperitoneal fibrosis. Our case suggests that when we see patients with fever and huge splenomegaly, differential diagnosis should include retroperitoneal fibrosis.

DOI： 10.1007/s10067-008-0856-6

Aggressive invasive micropapillary salivary duct carcinoma of the parotid gland. Reviewed International journal

Hidetaka Yamamoto, Hideoki Uryu, Yuichi Segawa, Masazumi Tsuneyoshi

Pathology international 58 ( 5 ) 322 - 6 2008.5

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

The presence of invasive micropapillary component has been reported to be associated with salivary duct carcinoma and poor outcomes. Herein is described a rare case of invasive micropapillary salivary duct carcinoma of the parotid gland in a 60-year-old man. The micropapillary component was approximately 70% of the area of the tumor. Squamous differentiation was focally seen adjacent to the micropapillary component. On immunohistochemistry the ordinary salivary duct carcinoma component was positive for gross cystic disease fluid protein-15 (GCDFP-15), androgen receptor (AR), and HER2/neu, whereas both micropapillary and squamous components were negative for GCDFP-15 and AR. Immunohistochemical staining for D2-40 highlighted the lymph vessel invasion of tumor cells. This patient developed metastases in the lymph nodes of the neck, and also in the liver, lung, and brain. The lymph nodes and liver metastases had both ordinary salivary duct carcinoma and micropapillary components. The patient died of tumor 11 months after the initial surgical operation. The results support that the presence of micropapillary component is associated with more aggressive behavior of salivary duct carcinoma. It is also important for pathologists to recognize that GCDFP-15 and AR expression can be reduced in micropapillary carcinoma in the differential diagnosis of metastatic tumor.

DOI： 10.1111/j.1440-1827.2008.02231.x

Different expression profiles of Y-box-binding protein-1 and multidrug resistance-associated proteins between alveolar and embryonal rhabdomyosarcoma. Reviewed International journal

Yoshinao Oda, Kenichi Kohashi, Hidetaka Yamamoto, Sadafumi Tamiya, Kimitoshi Kohno, Michihiko Kuwano, Yukihide Iwamoto, Tatsuro Tajiri, Tomoaki Taguchi, Masazumi Tsuneyoshi

Cancer science 99 ( 4 ) 726 - 32 2008.4

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

Nuclear expression of the Y-box-binding protein-1 (YB-1) has been reported to regulate the expression of both P-glycoprotein (P-gp) and major vault protein (MVP), and to regulate proliferative activities in human malignancies. Based on morphology and molecular biology, rhabdomyosarcoma (RMS) can be divided into two major types: embryonal type and the more aggressive alveolar type. Thirty-five cases of embryonal RMS (ERMS) and 28 cases of alveolar RMS (ARMS) were examined immunohistochemically for the nuclear expression of YB-1 and the intrinsic expression of P-gp, multidrug resistance (MDR)-associated protein (MRP) 1, 2, and 3, breast-cancer resistant protein (BCRP) and MVP, and the findings were compared with proliferative activities as evaluated by the MIB-1-labeling index (LI). Moreover, mRNA levels of these MDR-related molecules were assessed using a quantitative reverse transcriptase-PCR method in 18 concordant frozen materials. P-gp expression was more frequently observed ARMS, compared with ERMS (P = 0.0332), whereas immunoreactivity for BCRP was more frequently recognized in ERMS (P = 0.0184). Nuclear expression of YB-1 protein was correlated with P-gp (P = 0.0359) and MVP (P = 0.0044) expression, and a higher MIB-1-labeling index (P = 0.0244) in ERMS, however, in ARMS no such relationships were observed. These immunohistochemical results indicate that different expression profiles of MDR-related molecules and their correlation with YB-1 nuclear expression support the concept that ERMS and ARMS are molecular biologically distinct neoplasms. Apart from ERMS, frequent P-gp expression in ARMS may be independent from YB-1 regulation. However, YB-1 may be a candidate for a molecular target in rhabdomyosarcoma therapy, especially in ERMS.

DOI： 10.1111/j.1349-7006.2008.00748.x

Detection and characterization of vascular endothelial growth factors and their receptors in a series of angiosarcomas. Reviewed International journal

Eijun Itakura, Hidetaka Yamamoto, Yoshinao Oda, Masazumi Tsuneyoshi

Journal of surgical oncology 97 ( 1 ) 74 - 81 2008.1

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

BACKGROUND: Angiosarcomas are malignant mesenchymal neoplasms, including sarcomas of presumptive vascular endothelial origin and sarcomas of probable lymphatic origin. It is, however, often difficult to determine whether they are from blood vascular or lymphatic endothelium. The majority of angiosarcomas are thought to originate from vascular endothelia and spread via bloodstream to lung, but lymphatic metastases can occur. METHODS: We investigated immunohistochemical expression of vascular endothelial growth factors (VEGF-A, VEGF-C) and their receptors (VEGFR-1, VEGFR-2, VEGFR-3) in a series of 34 angiosarcomas. RESULTS: VEGF-A was expressed by 32/34 (94%), VEGF-C by 4/34 (12%), VEGFR-1 by 32/34 (94%), VEGFR-2 by 22/34 (65%), and VEGFR-3 by 27/34 (79%). Patients who expressed low or no VEGFR-2 showed a significantly unfavorable prognosis by log-rank test (P = 0.010) and multivariate analysis (hazard ratio, 5.16; 95% CI, 1.40-19.04; P = 0.014). VEGFR-1 and VEGFR-3 were not significantly associated with patients' prognosis. CONCLUSIONS: VEGF-A and VEGFR-1 were detected in diverse subtypes of angiosarcomas. In cooperation, VEGF-A and VEGF-C are likely to be involved in the development of angiosarcoma associated with lymphedema. VEGF-C expression may cause susceptibility to lymphatic metastasis through tumor lymphangiogenesis. Angiosarcoma of the scalp, which is traditionally considered as a true hemangiosarcoma, may include some cases of lymphatic origin.

Overexpression of inducible nitric oxide synthase and accumulation of 8-OHdG in nasopharyngeal carcinoma

Y. Segawa, Y. Oda, H. Yamamoto, H. Uryu, H. Shiratsuchi, N. Hirakawa, K. Tomita, T. Yamamoto, S. Oda, T. Yamada, S. Komune, M. Tsuneyoshi

Histopathology 52 ( 2 ) 213 - 223 2008.1

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

Aims: Nitric oxide (NO), produced by inducible NO synthase (iNOS), has been suggested to cause oxidative stress, leading to 8-hydroxydeoxyguanosine (8-OHdG) accumulation and subsequent transversion mutation of DNA. The aim was to evaluate iNOS expression and the status of oxidative stress in nasopharyngeal carcinoma (NPC). Methods and results: Seventy-three cases of NPC were investigated to examine the immunohistochemical expression of iNOS, 8-OHdG and latent membrane protein-1 (LMP-1) and Epstein-Barr virus-encoded small RNA (EBER) expression using in situ hybridization. iNOS mRNA expression and p53 gene mutations were also assessed. Overexpression of iNOS, LMP-1 and EBER was observed in 62 (84.9%), 28 (38.4%) and 53 (72.6%) cases respectively. p53 gene mutation was found in 10 of 73 (13.7%) cases. Immunohistochemical iNOS expression was associated with the 8-OHdG labelling index, iNOS mRNA expression and p53 gene alteration (P &lt
0.0001, P = 0.016 and 0.0082 respectively). Conclusions: Our present findings suggest that the expression of iNOS induces oxidative stress in NPC. Although the presence of p53 mutation was associated with iNOS overexpression, the type of acid-base change of p53 was transition, but not transversion, which suggests that the p53 gene is not the direct target of DNA damage by 8-OHdG accumulation. © 2008 The Authors.

DOI： 10.1111/j.1365-2559.2007.02920.x

Circumscribed mass lesions on mammography: dynamic contrast-enhanced MR imaging to differentiate malignancy and benignancy. Reviewed

Takashi Okafuji, Hidetake Yabuuchi, Hiroyasu Soeda, Yoshio Matsuo, Takeshi Kamitani, Shuji Sakai, Masamitsu Hatakenaka, Syoji Kuroki, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 7 ( 4 ) 195 - 204 2008

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

PURPOSE: We evaluated the magnetic resonance (MR) features of breast lesions showing circumscribed mass on mammography to understand the characteristics that differentiate malignancy and benignancy. MATERIALS AND METHODS: Our institutional review board approved the study, and informed consent was waived. Using logistic regression analysis, we examined morphologic and kinetic MR imaging data of 90 breast lesions (43 malignant, 47 benign) that showed circumscribed mass on mammography. RESULTS: Features identified as having high odds for malignancy included: rim enhancement (odds ratio, 70.894; 95% confidence interval (CI), 7.525-667.938); heterogeneous enhancement (odds ratio, 10.839; 95% CI, 1.032-113.856); and washout dynamic pattern (odds ratio, 46.262; 95% CI, 3.716-575.901). Combinations of washout dynamic pattern and either rim or heterogeneous enhancement reflected excessively high prediction probability for malignancy (>0.95), whereas combinations lacking washout dynamic pattern and with either homogeneous enhancement or dark internal septation revealed excessively low prediction probability for malignancy (<0.05). CONCLUSION: Breast cancers with circumscribed mass on mammography could be differentiated from benign masses using internal enhancement and the kinetic pattern of contrast-enhanced breast MR imaging.

Highly aggressive behavior of malignant rhabdoid tumor: a special reference to SMARCB1/INI1 gene alterations using molecular genetic analysis including quantitative real-time PCR. Reviewed International journal

Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Teiyu Izumi, Shigeru Ohta, Tomoaki Taguchi, Sachiyo Suita, Masazumi Tsuneyoshi

Journal of cancer research and clinical oncology 133 ( 11 ) 817 - 24 2007.11

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

PURPOSE: SMARCB1/INI1, which negatively regulates cell cycle progression from G0/G1 into the S-phase via the p16INK4a-RB-E2F pathway, has been reported to be inactivated homozygously by deletion and/or mutations in malignant rhabdoid tumor (MRT). In the current study, we investigated the alteration of the SMARCB1/INI1 gene using simple methods, and its gene product at the protein level. Moreover, we investigated the status of hyperphosphorylation in RB protein, known as a key cell cycle molecule. METHODS: Three cell lines and 11 formalin-fixed, paraffin-embedded specimens of MRT were investigated. SMARCB1/INI1 gene alteration was analyzed with simple methods as a quantitative real-time PCR and direct sequencing method. Furthermore, SMARCB1/INI1 and RB protein were immunohistochemically evaluated. RESULTS: In 12 of 14 cases, we detected genetic alterations comprised of nine (including three cell lines) homozygous deletions and three mutations, which can induce abnormal expression of gene products. At the protein level, SMARCB1/INI1 immunohistochemical expressions were not detected in any cases. Twelve out of 14 cases showed high-level (+5) expression of tRB (both hyperphosphorylated and underphosphorylated RB), combined with low-level (+1) expression of uRB (underphosphorylated RB), indicating a high rate of hyperphosphorylation. CONCLUSIONS: We could analyze the SMARCB1/INI1 gene alteration with simple methods, and SMARCB1/INI1 gene alteration was found in 12 of 14 cases. Especially, quantitative real-time PCR was a convenient and accurate method. In addition, a high rate of hyperphosphorylation of RB gene was recognized. These results suggest that the clinically aggressive character of MRT is caused by the inactivation of the SMARCB1/INI1 gene.

Phosphoglyceride crystal deposition disease originating from the myocardium. Reviewed International journal

Fumihiro Shoji, Ichiro Yoshino, Takuro Kometani, Hidetaka Yamamoto, Yoshihiko Maehara

The Journal of thoracic and cardiovascular surgery 134 ( 2 ) 508 - 9 2007.8

Congenital pseudarthrosis of the tibia: analysis of the histology and the NF1 gene. Reviewed

Akio Sakamoto, Tatsuya Yoshida, Hidetaka Yamamoto, Yoshinao Oda, Masazumi Tsuneyoshi, Yukihide Iwamoto

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 12 ( 4 ) 361 - 5 2007.7

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

BACKGROUND: Congenital pseudarthrosis of the tibia (CPT) is frequently, but not always, associated with neurofibromatosis type 1 (NF1). Double inactivation of the NF1 gene has been reported to be the pathogenesis of CPT in NF1 cases. METHODS: We analyzed the loss of heterozygosity (LOH) of the NF1 gene in cases of CPT with NF1 to examine whether double inactivation was seen in the case. In addition to morphological analysis, immunoexpression of differentiation markers was examined. RESULTS AND DISCUSSION: The tibia tapered with the zone phenomenon from mature to immature bone with osteoblastic rimming, resembling osteofibrous dysplasia. Osteosclerotic bowed bone with a small number of osteoclasts suggested dysfunction of bone remodeling. Fibrous tissue at the site of pseudarthrosis was associated with the periosteum and demonstrated myofibroblastic differentiation accompanied by massive cartilage formation, suggesting some misdirection during the differentiation of periosteum to myofibroblasts or chondrocytes. LOH of the NF1 gene locus was not seen in fibrous tissue. This result suggests that CPT is not accompanied by double inactivation in every NF1 case.

Detection of COL1A1-PDGFB fusion transcripts and PDGFB/PDGFRB mRNA expression in dermatofibrosarcoma protuberans. Reviewed International journal

Tomonari Takahira, Yoshinao Oda, Sadafumi Tamiya, Koichi Higaki, Hidetaka Yamamoto, Chikashi Kobayashi, Teiyu Izumi, Naomi Tateishi, Yukihide Iwamoto, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 ( 6 ) 668 - 75 2007.6

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

Fusion of the collagen type I alpha 1 (COL1A1) gene with the platelet-derived growth factor beta chain (PDGFB) gene has been described in dermatofibrosarcoma protuberans. The abnormal fusion transcripts probably cause PDGFB and its receptor (platelet-derived growth factor receptor beta, PDGFRB) autocrine stimulation and cell proliferation, which are responsible for the development of dermatofibrosarcoma protuberans. A reverse transcription-polymerase chain reaction assay was performed to detect the COL1A1-PDGFB fusion transcripts in 57 samples. In addition, the PDGFB gene amplification and PDGFB/PDGFRB mRNA levels were quantified by a real-time PCR system for the samples in which the fusion transcripts had been successfully detected. The fusion transcripts were detected in 42 of 57 samples. Various exons of the COL1A1 gene were fused in frame with the PDGFB gene; exons 7 and 25 were found to be slightly more frequently involved than the other exons. The PDGFB gene amplification levels varied from 0.6 to 8.3 (mean 2.4) in 42 tumor samples and from 0.4 to 3.0 (mean 1.2) in 20 adjacent normal tissue samples. In the 20 paired samples, the PDGFB gene amplification in the tumor was significantly higher than that in the normal tissue. The presence of PDGFB and PDGFRB mRNAs was demonstrated in 26 and 21 of 26 cases, respectively. The PDGFB and PDGFRB mRNA expression levels showed a good correlation (r=0.76, P<0.0001). These results indicate that the fusion protein, which is processed by the COL1A1-PDGFB transcripts, can serve as a functional ligand for PDGFRB.

A case of an inflammatory myofibroblastic tumor in the lung which expressed TPM3-ALK gene fusion

Y. Kinoshita, T. Tajiri, S. Ieiri, K. Nagata, T. Taguchi, S. Suita, K. Yamazaki, I. Yoshino, Y. Maehara, K. Kohashi, H. Yamamoto, Y. Oda, M. Tsuneyoshi

PEDIATRIC SURGERY INTERNATIONAL 23 ( 6 ) 595 - 599 2007.6

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

We herein describe a 4-year-old boy who after being treated for pneumonia showed an abnormal shadow at the hilus of the right lung on chest X-rays with continued inflammatory findings in his laboratory data. CT and MR investigations suggested the existence of a neoplasm at that site. An open biopsy was thus performed for a definite diagnosis. The histological findings and the expression of TPM3-ALK fusion gene confirmed a diagnosis of an inflammatory myofibroblastic tumor. A right upper and middle lobectomy including the tumor was thus performed for a complete resection. In addition to the histological diagnosis, the detection of the tumor specific fusion gene provided objective evidence in making a diagnosis.

DOI： 10.1007/s00383-006-1821-6

Prognostic significance of angiogenesis in gastrointestinal stromal tumor. Reviewed International journal

Masakazu Imamura, Hidetaka Yamamoto, Norimoto Nakamura, Yoshinao Oda, Takashi Yao, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara, Masazumi Tsuneyoshi

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20 ( 5 ) 529 - 37 2007.5

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

Angiogenesis is important in the growth and metastasis of various kinds of solid tumors. To investigate the potential role of angiogenesis in gastrointestinal stromal tumor (GIST), an immunohistochemical analysis was performed in 95 cases of GISTs for microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression. MVD was evaluated with immunohistochemical staining for CD31. A high level of MVD was significantly correlated with overexpression of VEGF, tumor location (intestine>stomach), tumor size (> or =5 cm), tumor grade (high>intermediate>low grade) (P=<0.0001, 0.0422, 0.0006, 0.0359, respectively). Of the 70 GISTs analyzed, KIT exon 11 mutations were detected in 45 cases (64.3%) and KIT exon 9 mutations in two cases (2.9%). No mutations were found in KIT exons 13 and 17, and platelet-derived growth factor receptor-alpha exons 12 and 18. Interestingly, VEGF expression level was significantly higher in the non-KIT exon 11 mutant group than in the KIT exon 11 mutant group (P=0.0266). In univariate analysis, tumor grade (high grade), tumor size (> or =5 cm), mitotic count (> or =5/50 high-power fields), Ki-67 labeling index (> or =4.6%), MVD (> or =7.0/0.95 mm(2)) and VEGF expression (high) were significantly associated with a shorter period of disease-free survival (P=<0.0001, 0.0199, 0.0055 0.0027, 0.0028 and 0.0302, respectively). In multivariate analysis, tumor grade and MVD were identified as independent worse prognostic factors (P=0.0007, 0.0152, respectively). In conclusion, our results suggest that the evaluation of MVD and VEGF expression is useful for predicting the aggressive biologic behavior of GIST, and that angiogenesis associated with VEGF may play an important role, at least in part, in the progression of GIST.

Dysadherin expression as a significant prognostic factor and as a determinant of histologic features in synovial sarcoma: special reference to its inverse relationship with E-cadherin expression. Reviewed International journal

Teiyu Izumi, Yoshinao Oda, Tadashi Hasegawa, Yukihiro Nakanishi, Akira Kawai, Hiroshi Sonobe, Tomonari Takahira, Chikashi Kobayashi, Hidetaka Yamamoto, Sadafumi Tamiya, Setsuo Hirohashi, Yukihide Iwamoto, Masazumi Tsuneyoshi

The American journal of surgical pathology 31 ( 1 ) 85 - 94 2007.1

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

Dysadherin is a cancer-associated cell membrane glycoprotein, which down-regulates E-cadherin and promotes metastasis. Synovial sarcoma is a very rare mesenchymal tumor that exhibits an epithelial profile. To confirm the diagnosis of synovial sarcoma, we evaluated several immunohistochemical markers, or detected SYT-SSX fusion gene transcript. We studied the clinicopathologic features in 92 synovial sarcoma patients and also assessed the immunohistochemical expression of dysadherin and E-cadherin to examine their possible association with histologic subtype and biologic behavior. Moreover, among 30 patients, for whom frozen materials were available, dysadherin mRNA expression was examined by reverse transcription-polymerase chain reaction and real-time quantitative reverse transcription-polymerase chain reaction analysis. Dysadherin-positive expression was significantly correlated with E-cadherin-reduced expression (P=0.0004). Dysadherin-positive immunostaining was diffusely observed in the membranes of tumor cells in 30/68 (44%) patients with monophasic fibrous type and in 1/2 (50%) patients with poorly differentiated type. However, in biphasic tumors, dysadherin expression in the fibrous component was not diffusely observed, but often sporadically or focally observed [20/22 (91%) patients]. In addition, dysadherin mRNA expression in monophasic fibrous type was significantly higher than in biphasic type (P=0.0079). Synovial sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P=0.0006). Patients with combined dysadherin-positive expression and E-cadherin-reduced expression had a significantly worse prognosis than those with other combinations of dysadherin and E-cadherin expression (P=0.0007). SYT-SSX fusion gene transcript was detected in 39 patients. In our series, SYT-SSX fusion type was found to have no correlation with histologic subtype, prognosis, or dysadherin expression. In multivariate analysis, dysadherin immunopositivity (P=0.0411) was an independent adverse prognostic factor, in addition to a high MIB-1 labeling index (> or =10%). We conclude that E-cadherin dysfunction by dysadherin is associated with reduced E-cadherin expression and morphologic change from epithelioid to spindle phenotype. Dysadherin expression is considered to be one of the determinants of histologic subtype in synovial sarcoma. Moreover, dysadherin expression is an excellent and independent prognostic indicator.

Desmoplastic fibroblastoma (collagenous fibroma) with a specific breakpoint of 11q12. Reviewed

Sakamoto A, Yamamoto H, Yoshida T, Tanaka K, Matsuda S, Oda Y, Tsuneyoshi M, Iwamoto Y

Histopathology 2007

Absence of human herpesvirus-8 and Epstein-Barr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene. Reviewed International journal

Hidetaka Yamamoto, Kenichi Kohashi, Yoshinao Oda, Sadafumi Tamiya, Yukiko Takahashi, Yoshiaki Kinoshita, Shin Ishizawa, Masayuki Kubota, Masazumi Tsuneyoshi

Pathology international 56 ( 10 ) 584 - 90 2006.10

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

Inflammatory myofibroblastic tumor (IMT) is clinically and histologically characterized by inflammation. Some populations of IMT have anaplastic large cell lymphoma kinase (ALK) gene rearrangements. Infection with Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) in tumor cells of IMT has been reported; these reports, however, have been limited to ALK-negative IMT. The purpose of the present paper was to evaluate 21 cases of IMT for the presence of EBV and HHV-8. Immunohistochemically, 15 cases were ALK positive and six were negative. Of eight cases analyzed using reverse transcription-polymerase chain reaction, tropomyosin 3 (TPM3)-ALK, TPM4-ALK and clathrin heavy chain-ALK fusion genes were detected in one, two and two cases, respectively. All 21 IMT, irrespective of ALK expression, were negative for EBV by in situ hybridization for EBV-encoded RNA and immunohistochemical stain for latent membrane antigen-1. HHV-8 was also negative in all IMT by PCR for HHV-8 DNA sequence (KS330/233) and immunohistochemical stain for latent nuclear antigen. These results suggest that IMT may be a heterogeneous group in terms of pathogenesis, and EBV and HHV-8 do not play a major role in the pathogenesis of ALK-positive tumor.

Dedifferentiated chondrosarcoma with leukocytosis and elevation of serum G-CSF. A case report. Reviewed International journal

Akio Sakamoto, Hidetaka Yamamoto, Kazuhiro Tanaka, Shuichi Matsuda, Katsumi Harimaya, Yoshinao Oda, Masazumi Tsuneyoshi, Yukihide Iwamoto

World journal of surgical oncology 4 37 - 37 2006.7

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

BACKGROUND: G-CSF is known to function as a hematopoietic growth factor and it is known to be responsible for leukocytosis. G-CSF-producing tumors associated with leukocytosis include various types of malignancies. CASE PRESENTATION: We report the case of a 72-year-old man with dedifferentiated chondrosarcoma characterized by dedifferentiated components of malignant fibrous histiocytoma- or osteosarcoma-like features in addition to conventional chondrosarcoma, arising from his pelvic bone. After hemipelvectomy, when local recurrence and metastasis were identified, leukocytosis appeared and an elevated level of serum granulocyte-colony-stimulating factor (G-CSF) was also recognized. The patient died of multiple organ failure 2 months after surgery. Autopsy specimens showed that the histological specimens of the recurrence and metastasis were dedifferentiated components, without any conventional chondrosarcoma components. G-CSF was expressed only in the dedifferentiated components, not in the chondrosarcoma components, immunohistochemically. CONCLUSION: This is the first report of chondrosarcoma, or any other primary bone tumor, with leukocytosis, probably stimulated by tumor-produced G-CSF from the dedifferentiated components.

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