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Futoshi Kawamata,
Shigenori Homma,
Hirofumi Kamachi, Takahiro Einama,
Yasutaka Kato,
Masumi Tsuda,
Shinya Tanaka,
Masahiro Maeda,
Kazunori Kajino,
Okio Hino,
Norihiko Takahashi,
Toshiya Kamiyama,
Hiroshi Nishihara,
Akinobu Taketomi,
Satoru Todo
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ABSTRACT: BACKGROUND: Lymph node metastasis is a key event of colorectal cancer (CRC) progression. Mesothelin is expressed in various types of malignant tumor and associated with an unfavorable prognosis. The full-length mesothelin (Full-ERC) is cleaved by protease into membrane-bound C-ERC/mesothelin and N-ERC/mesothelin which is secreted into the blood. The aim of this study was to examine the biological role of mesothelin in CRC by clinicopathological analysis and in vitro lymphatic invasion assay. METHODS: Ninety-one cases of CRC specimens were immunohistochemically examined and the localization of mesothelin in luminal membrane and/or cytoplasm was also evaluated. Lymphatic invasion assay was also performed using the human CRC cell line, WiDr, which was transfected with Full-, N- and C-ERC/mesothelin expression plasmids (Full-WiDr, N-WiDr and C-WiDr). RESULTS: Immunohistochemically, "luminal membrane positive" of mesothelin was identified in 37.4 %, and correlated with lymphatic permeation and lymph node metastasis, but not with patients' prognosis. Interestingly, among the patients with lymph node metastasis (N = 38), "luminal membrane positive" of mesothelin significantly correlated with unfavorable patients' outcome. In addition, lymphatic invasion assay revealed that Full-WiDr and C-WiDr more significantly invaded human lymphatic endothelial cells than the Mock-WiDr (P < 0.01). CONCLUSION: The luminal membrane expression of mesothelin was associated with unfavorable prognosis of CRC patients with lymph node metastasis. Moreover, this is the first report to prove the biological function of C-ERC/mesothelin associated with lymphatic invasion of cancer in vitro.
Journal of Gastroenterology 03/2013; · 4.16 Impact Factor
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Futoshi Kawamata,
Hirofumi Kamachi, Takahiro Einama,
Shigenori Homma,
Munenori Tahara,
Masaya Miyazaki,
Shinya Tanaka,
Toshiya Kamiyama,
Hiroshi Nishihara,
Akinobu Taketomi,
Satoru Todo
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ABSTRACT: Mesothelin is expressed in various types of malignant tumors, and we recently reported that the expression of mesothelin was related to unfavorable patient outcome in pancreatic ductal adenocarcinoma and gastric adenocarcinoma. In this study, we examined the clinicopathological significance of mesothelin expression in extrahepatic bile duct cancer (EHBDCA), especially in terms of its association with the staining pattern. Tissue samples from 61 EHBDCA (16 hilar cholangiocarcinoma, 17 upper bile duct adenocarci-noma, 20 middle bile duct adenocarcinoma and 8 distal bile duct adenocarcinoma) were immunohistochemically examined. The expression levels of mesothelin in tumor cells was classified into the localization of mesothelin in luminal membrane and/or cytoplasm, in addition to high and low according to the staining intensity and proportion as a conventional analysis. 'High-level expression' of mesothelin (47.5%) was statistically correlated with liver metastasis (P=0.013) and poorer patient outcome (P=0.022), while 'luminal membrane positive' of mesothelin (52.5%) was more significantly correlated with liver metastasis (P=0.006), peritoneal metastasis (P=0.024) and unfavorable patient outcome (P=0.017). Moreover, we found that 'cytoplasmic expression' isolated from 'luminal membrane negative' of mesothelin represented the best patient prognosis throughout this study. We describe the expression pattern level of mesothelin, i.e., in luminal membrane or cytoplasm both high and low level, evidently indicate the patient prognosis of EHBDCA, suggesting the pivotal role of mesothelin in cancer promotion depending on its intracellular localization.
International Journal of Oncology 10/2012; · 2.40 Impact Factor
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ABSTRACT: Recent studies indicate the clinical significance of the cellular localization of epidermal growth factor receptor (EGFR) in a variety of cancer types. Internalization of activated EGFR is reported to be closely associated with patient prognosis. This study investigated the clinical significance of the immunohistochemical localization of EGFR in patients with metastatic pancreatic cancers compared to those with surgically resected pancreatic cancers. Using 44 surgically resected primary pancreatic cancers and 40 primary or meta-static tumors from 20 autopsied patients with far advanced pancreatic cancers, the incidence of membranous and cytoplasmic EGFR overexpression was compared between primary tumors and far advanced tumors by immunohistochemistry using the Dako EGFR pharmDx™ kit, a global standard kit for EGFR assay. In the 44 surgically resected cancers, 13 (30%) exhibited membranous overexpression of EGFR, comprising 1 case (2%) with score 3+ and 12 cases (27%) with score 2+ and 10 (23%) exhibited cytoplasmic overexpression of EGFR. In the 40 tumors at a far advanced stage, the percentage of samples exhibiting positivity for membranous and cytoplasmic EGFR overexpression was 48% (19 of 40) comprising 7 (18%) with score 2+ and 12 (30%) with score 3+ and 33% (13 of 40), respectively. The far advanced tumors tended to show membranous and cytoplasmic EGFR overexpression more frequently than the surgically resected tumors, although the difference was not significant. These findings suggest that membranous and cytoplasmic overexpression of EGFR may be indicative of the potential aggressiveness of pancreatic cancers.
Experimental and therapeutic medicine 06/2012; 3(6):931-936.
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ABSTRACT: Pancreatic adenocarcinoma is a lethal disease that often develops a desmoplastic reaction in tumor stroma. In general, desmoplasia is thought to promote tumor growth. However, its molecular pathology and prognostic potential have not been fully investigated. Here, we investigate 26 cases of pancreatic ductal adenocarcinoma and examine the clinicopathological association between survival and expression levels of several molecular markers for stromal cells. These include alpha-smooth muscle actin (SMA) and platelet-derived growth factor (PDGF) receptor β (PDGFRβ). Both are markers of activated fibroblasts or pancreatic stellate cells (PSCs) that play an important role in desmoplasia. The staining patterns of both molecular markers were not uniform, so we categorized them into 3 grades (high, middle, and low) according to intensity. Interestingly, Kaplan-Meier analysis revealed that higher expression of PDGFRβ matched shorter prognosis (p = 0.0287, log-rank test) as well as lymphatic invasion and lymph node metastasis, whereas SMA did not (p = 0.6122). Our results suggest the prognostic potential of cancer stroma via PDGF-B signaling. Regulation of PDGF-B-associated signaling crosstalk between cancer cells and stroma cells, therefore, may indicate a possible therapeutic target for desmoplastic malignant tumors such as pancreatic adenocarcinoma.
Medical Oncology 03/2012; 29(4):2824-30. · 2.14 Impact Factor
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Takahiro Einama,
Hirofumi Kamachi,
Hiroshi Nishihara,
Shigenori Homma,
Hiromi Kanno,
Kenta Takahashi,
Ayami Sasaki,
Munenori Tahara,
Kuniaki Okada,
Shunji Muraoka,
Toshiya Kamiyama,
Yoshihiro Matsuno,
Michitaka Ozaki,
Satoru Todo
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ABSTRACT: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma.
Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level expression, defined as expression by more than 50% of tumor cells and/or moderate to strong staining, or low-level expression otherwise.
A high level of mesothelin was correlated with a higher histological grade (P = 0.049) and the level of blood vessel permeation (P = 0.0006), whereas a high level of CA125 expression was correlated with a higher recurrence rate (P = 0.015). The expression of mesothelin was strongly correlated with that of CA125 (P = 0.0041). Co-expression of mesothelin and CA125 were associated with an unfavorable patient outcome (P = 0.0062).
This is the first report showing that co-expression of mesothelin and CA125 were in pancreatic ductal adenocarcinoma, and such co-expression is associated with a poor prognosis. Our finding suggests that co-expression of these two factors plays a significant role in the acquisition of aggressive clinical behavior.
Pancreas 07/2011; 40(8):1276-82. · 2.39 Impact Factor
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ABSTRACT: Chylous ascites (CA) is an extremely rare complication of abdominal surgery in children. This report describes a 4-month-old girl with malignant rhabdoid tumor of the kidney (MRTK), who developed CA after left nephrectomy without lymphadenectomy, and who was successfully treated conservatively with enteral therapy. The literature on CA after nephrectomy without lymphadenectomy for MRTK is reviewed herein, and the clinical problems of postoperative CA are discussed.
Journal of Indian Association of Pediatric Surgeons 10/2009; 14(4):215-7.
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ABSTRACT: We report a case of metastatic breast cancer with pericardial effusion that was successfully treated with weekly paclitaxel. A 46-year-old woman underwent modified radical mastectomy in April 1997 and was readmitted to the hospital for dyspnea in March 2002. A diagnosis of cardiac tamponade due to breast cancer relapse was made, and the patient was treated with weekly paclitaxel (80 mg/m2) and insertion of a drainage catheter. This treatment was effective in preventing reaccumulation of the pericardial effusion until her death. The concentration of paclitaxel in the cardiac effusion was 45 ng/ml at 3 h, 15 ng/ml at 12 h, and less than 10 ng/ml at 24 h after paclitaxel infusion, indicating good transportation of the drug from the blood to the pericardial effusion. These findings suggest that weekly intravenous infusion of paclitaxel could be effective for the treatment of patients with malignant pericardial effusion.
International Journal of Clinical Oncology 11/2006; 11(5):412-5. · 1.41 Impact Factor
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Shigeto Ueda,
Kazuo Hatsuse,
Hitoshi Tsuda,
Sho Ogata,
Nobuaki Kawarabayashi,
Toshimichi Takigawa, Takahiro Einama,
Daisaku Morita,
Kazuhiko Fukatsu,
Yoshiaki Sugiura,
Osamu Matsubara,
Hidetaka Mochizuki
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ABSTRACT: The insulin-like growth factor receptor type 1 (IGF1R) and epidermal growth factor receptor (EGFR) are reportedly overexpressed in pancreatic cancer. However, the correlation between activated EGFR and IGF1R and their clinicopathological implications still remain unclear. The cellular localization and overexpression of IGF1R and EGFR were investigated immunohistochemically in primary invasive ductal pancreatic carcinomas obtained from 74 patients who underwent radical surgical resection. We also compared the status of IGF1R and EGFR overexpression between primary tumors and hepatic metastatic tumors obtained from 44 autopsied patients. Among the 74 surgically resected primary tumors, cytoplasm- and membrane-dominant EGFR overexpression was detected in 22 (30%) and 7 (9%), respectively, whereas cytoplasm- and membrane-dominant IGF1R overexpression was detected in 8 (11%) and 28 (38%), respectively. Membrane-dominant EGFR and cytoplasm-dominant IGF1R were more frequent in lower-grade tumors and correlated with favorable prognosis, whereas cytoplasm-dominant EGFR and membrane-dominant IGF1R were more frequent in higher-grade tumors and correlated with poor prognosis. In 36 autopsy specimens of pancreatic tumor with concurrent overexpression of IGF1R and EGFR, there was an inverse correlation between the IGF1R and EGFR localization patterns (P = 0.001). In the hepatic metastatic tumors obtained by autopsy, the incidences of both IGF1R and EGFR overexpression were much higher than in the surgically resected primary tumors. More than half of the autopsy cases consistently showed membrane-dominant EGFR expression in both the primary tumor and hepatic metastases, whereas IGF1R expression showed considerable variation. Crosstalk between differently localized IGF1R and EGFR might play a role in determining the biological aggressiveness of pancreatic cancer, although their cellular localization may often alter during the process of metastasis.
Modern Pathology 07/2006; 19(6):788-96. · 4.79 Impact Factor
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Takahiro Einama,
Yutaka Kagata,
Hitoshi Tsuda,
Daisaku Morita,
Sho Ogata,
Shigeto Ueda,
Toshimichi Takigawa,
Nobuaki Kawarabayashi,
Kazuhiko Fukatsu,
Yoshiaki Sugiura,
Osamu Matsubara,
Kazuo Hatsuse
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ABSTRACT: Recent studies have shown that overexpression of S-phase kinase-associated protein 2 (Skp2) occurs in many cancers at an advanced stage. We examined the clinicopathologic significance and prognostic implication of Skp2 expression in pancreatic invasive ductal carcinoma.
Tissue samples from 46 pancreatic carcinomas were examined immunohistochemically for Skp2. The proportion of constituent tumor cells with Skp2 expression was analyzed and classified as high-level nuclear expression when more than 20% of the cancer cells were positive, or low-level nuclear expression otherwise.
High-level Skp2 overexpression was detected in 13 (28.3%) of the 46 tumors. The incidence of high-level Skp2 was correlated with higher histological grade (P = 0.0056), the extent of lymph node metastasis (P = 0.0086), the level of lymphatic permeation (P = 0.0024), and poorer patient outcome (P = 0.0189). Multivariate analysis showed that high-level Skp2 expression was an independent predictor of overall patient survival (P = 0.0140).
It is suggested that examination of Skp2 expression might be clinically useful for prognostication in patients with pancreatic carcinoma and that Skp2 protein might be a novel therapeutic molecular target.
Pancreas 06/2006; 32(4):376-81. · 2.39 Impact Factor
