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Kazuo Tarao,
Shinichi Ohkawa, Yohei Miyagi,
Soichiro Morinaga,
Kenji Ohshige,
Naoto Yamamoto,
Makoto Ueno,
Satoshi Kobayashi,
Ryo Kameda,
Setsuo Tamai,
Yoshiyasu Nakamura,
Kaoru Miyakawa,
Yoichi Kameda,
Masahiko Okudaira
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ABSTRACT: Abstract Objective. It is accepted that inflammation promotes malignant progression in the development of cancers. Whether, this is true for hepatocellular carcinoma (HCC) remains as an open question. We examined the relationship between the inflammatory histology activity index (HAI) in the background liver cirrhosis (LC) and the histological grading of the HCC in the hepatectomized HCC patients with HCV-associated LC. Material and methods. Out of 264 HCC patients who underwent curative hepatic resection, 197 had HCV-associated LC. Among them, 52 patients with a small solitary HCC nodule (< 5 cm in diameter) were studied. Inflammation in the background LC was evaluated by modified Knodell's HAI. To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (0-4, each) were estimated. The average HAI was calculated. The grade of malignancy of HCC was determined by WHO classification. Results. The average HAI in the 15 patients with moderately differentiated HCC (4.3 ± 0.8, mean ± SD) was significantly larger than that in 11 patients with well differentiated HCC (3.5 ± 0.6, p = 0.036). The HAI in the 24 patients whose HCC nodules contained poorly differentiated HCC (5.2 ± 1.1) was significantly larger than that in patients with moderately differentiated HCC (p = 0.025). Thus, the HAI order was well differentiated group < moderately differentiated group < poorly differentiated group. Conclusions. Inflammation in the background non-cancerous cirrhotic portion would evoke malignant progression in HCC development from HCV-associated LC.
Scandinavian journal of gastroenterology 04/2013; · 2.08 Impact Factor
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Toru Aoyama,
Takaki Yoshikawa, Yohei Miyagi,
Yoichi Kameda,
Junya Shirai,
Tsutomu Hayashi,
Haruhiko Cho,
Takashi Oshima,
Norio Yukawa,
Yasushi Rino,
Munetaka Masuda,
Akira Tsuburaya
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ABSTRACT: PURPOSES: The trastuzumab for Gastric Cancer study newly defined tumors that were positive for human epidermal receptor-2 (Her-2) and created a Her-2-oriented treatment strategy that is also applicable in the adjuvant setting for stage 2/3 cancers. However, there is currently no information available on the rate of Her-2 positivity and the relapse-free survival (RFS) stratified by Her-2 status in stage 2/3 patients. METHODS: The Her-2 status, defined by the current standard method, was examined in 100 gastric cancer patients who underwent curative D2 surgery, who were pathologically diagnosed with stage 2/3 cancer, and received adjuvant S-1 chemotherapy between June 2002 and December 2011. RESULTS: Ten of the 100 patients were Her-2 positive. Her-2-positive status was more frequently seen in tumors with a differentiated histology. The 5-year RFS rate was 56.3 % in Her-2-positive cases, and 48.8 % in Her-2 negative cases, which was not significantly different (P = 0.786). CONCLUSIONS: The Her-2-positive rate for stage 2/3 gastric cancer patients was low, at only 10 %. Although the RFS was not significantly different based on the Her-2 status, the low positive rate made interpretation difficult. A multi-center study with a large sample size is necessary to clarify the prognostic impact of Her-2 in stage 2/3 gastric cancer patients.
Surgery Today 03/2013; · 1.22 Impact Factor
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ABSTRACT: SIRT1, class III histone deacetylase, has been described to be up-regulated in various malignancies. However, the opposite results have been reported in other malignancies. Therefore, we investigated SIRT1 expression to clarify its biological behavior and identify its usefulness as a biomarker for head and neck squamous cell carcinoma (HNSCC).
SIRT1 expression was assessed by immunohistochemistry (IHC) conducted using samples from 437 consecutive HNSCC patients. Acetylated histone status and p53 expression were also examined.
IHC revealed 79.6% staining of SIRT1 in HNSCC, while almost all normal tissues showed positive staining. SIRT1 expression predominated in cases involving patients aged >65 years, lymph node negative, and early clinical stage cases. It was positively and statistically correlated with expression of acetylated histone H3K9 and H4K16, but not with p53. Multivariate analyses revealed that expression of SIRT1 was an independent and good indicator of prognosis.
Oral surgery, oral medicine, oral pathology and oral radiology. 03/2013; 115(3):385-92.
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Masakatsu Numata,
Soichiro Morinaga,
Takuo Watanabe,
Hiroshi Tamagawa,
Naoto Yamamoto,
Manabu Shiozawa,
Yoshiyasu Nakamura,
Yoichi Kameda,
Shinichi Okawa,
Yasushi Rino,
Makoto Akaike,
Munetaka Masuda, Yohei Miyagi
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ABSTRACT: Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study was to clarify the clinical significance of the SWItch/sucrose non-fermentable (SWI/SNF) complex in patients with pancreatic cancer. A total of 68 patients with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180 and BAF47. The correlation of expression levels and clinicopathological outcomes were analyzed, followed by the multivariate analysis of prognostic factors for overall survival. The expression levels of the SWI/SNF components were categorized as low or high according to the median value of Histoscore. Statistical analysis revealed that BRM expression was related to tumor size, T factor, M factor, lymphatic invasion and stage BRG1 expression to histology and stage BAF180 expression to tumor size and BAF47 expression to lymphatic invasion, respectively. Multivariate Cox proportional hazard analysis showed that high BRM and low BAF180 expression levels were independent predictors of worse survival in patients with pancreatic cancer. High BRM, and low BAF180 were also independent prognostic factors for poor survival in the subgroup with adjuvant gemcitabine. These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High BRM, and low BAF180 are useful biomarkers for poor prognosis in pancreatic cancer.
International Journal of Oncology 11/2012; · 2.40 Impact Factor
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ABSTRACT: BACKGROUND: The management of T1 colorectal cancer after local resection is controversial. Regional lymph node metastasis often occurs, requiring subsequent colonic resection. The aim of this study was to reevaluate the risk factors of nodal metastasis of T1 colorectal cancer, especially to examine lymphatic vessel invasion in serially prepared hematoxylin and eosin sections and D2-40 immunostained sections to determine which is a better indicator of lymph node metastasis of T1 colorectal cancer. METHODS: The study investigated 120 patients who underwent bowel resection and were histologically diagnosed to have T1 colorectal cancer in Kanagawa Cancer Center Hospital from 1995 to 2005. Serially prepared paraffin sections were stained with hematoxylin and eosin, or immunostained with D2-40 antibody or von Willebrand factor, and reevaluated for lymphatic vessel invasion and other risk factors, including venous invasion, histological grade, depth of submucosal invasion, and budding. RESULTS: Lymphatic invasion diagnosed with either hematoxylin and eosin staining (p = 0.022), or D2-40 immunostaining (p = 0.001), and budding (p = 0.013) were significant risk factors for lymph node metastasis in the univariate analysis. Venous involvement, histological grade, or depth of submucosal invasion was not significant. The multivariate logistic regression analysis for the three risk factors found lymphatic invasion diagnosed with D2-40 as an independent risk factor (odds ratio 6.048, p = 0.018, CI 1.360-26.89). The sensitivity, specificity, positive predictive value, and negative predictive value were 58 %, 88 %, 35 %, and 95 %, respectively. CONCLUSIONS: Lymphatic vessel invasion diagnosed with D2-40 was a better indicator to evaluate the risk for lymph node metastasis by T1 colorectal cancer.
International Journal of Clinical Oncology 11/2012; · 1.41 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells in suspension undergo apoptosis to a greater extent than adherent cells in a monolayer when EGFR autophosphorylation is inhibited by EGFR tyrosine kinase inhibitors (TKIs). This suggests that cell adhesion to a culture dish may activate an anti-apoptotic signaling pathway other than the EGFR pathway. Since the microenvironment of cells cultured in a monolayer are substantially different to that of cells existing in three-dimension (3D) in vivo, we assessed whether two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, were more resistant to EGFR TKI-induced apoptosis when cultured in a 3D extracellular matrix (ECM) as compared with in suspension. The ECM-adherent EGFR-mutant cells in 3D were significantly less sensitive to treatment with WZ4002, an EGFR TKI, than the suspended cells. Further, a marked degradation of IκBα, the inhibitor of nuclear factor (NF)-κB, was observed only in the 3D-cultured cells, leading to an increase in the activation of NF-κB. Moreover, the inhibition of NF-κB with pharmacological inhibitors enhanced EGFR TKI-induced apoptosis in 3D-cultured EGFR-mutant cells. These results suggest that inhibition of NF-κB signaling would render ECM-adherent EGFR-mutant lung adenocarcinoma cells in vivo more susceptible to EGFR TKI-induced cell death.
Biochemical and Biophysical Research Communications 06/2012; 423(4):667-71. · 2.48 Impact Factor
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ABSTRACT: Inflammatory cells play important roles in progression of solid neoplasms including ovarian cancers. Tumor-associated macrophages (TAMs) contribute to angiogenesis and immune suppression by modulating microenvironment. Ovarian cancer develops occasionally on the bases of endometriosis, a chronic inflammatory disease. We have recently demonstrated differential expressions of CXCR3 variants in endometriosis and ovarian cancers. In this study, we showed impaired CXCL4 expression in TAMs of ovarian cancers arising in endometriosis. The expressions of CXCL4 and its variant CXCL4L1 were investigated among normal ovaries (n = 26), endometriosis (n = 18) and endometriosis-associated ovarian cancers (EAOCs) composed of clear cell (n = 13) and endometrioid (n = 11) types. In addition, four cases of EAOCs that contained both benign and cancer lesions contiguously in single cysts were investigated in the study. Western blot and quantitative RT-PCR analyses revealed significant downregulation of CXCL4 and CXCL4L1 in EAOCs compared with those in endometriosis. In all EAOCs coexisting with endometriosis in the single cyst, the expression levels of CXCL4 and CXCL4L1 were significantly lower in cancer lesions than in corresponding endometriosis. Histopathological study revealed that CXCL4 was strongly expressed in CD68 (+) infiltrating macrophages of endometriosis. In microscopically transitional zone between endometriosis and EAOC, CD68 (+) macrophages often demonstrated CXCL4 (-) pattern. The majority of CD68 (+) TAMs in overt cancer lesions were negative for CXCL4. Collective data indicate that that CXCL4 insufficiency may be involved in specific inflammatory microenvironment of ovarian cancers arising in endometriosis. Suppression of CXCL4 in cancer lesions is likely to be attributable to TAMs in part.
Cancer biology & therapy 06/2012; 13(8):671-80. · 2.64 Impact Factor
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Michiko Fukahori,
Akira Yoshida,
Hiroyuki Hayashi,
Mitsuyo Yoshihara,
Shoichi Matsukuma,
Yuji Sakuma,
Shiro Koizume,
Naoyuki Okamoto,
Tetsuo Kondo,
Munetake Masuda, Yohei Miyagi
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ABSTRACT: Many studies on thyroid follicular tumors have reported the presence of somatic mutations to three forms of RAS: HRAS, KRAS, and NRAS. However, the frequency and clinical significance of these RAS mutations remain unclear, in large part due to the different methodologies being used for mutation analysis and the limited number of cases featured in studies. To clarify the significance of RAS mutations, we examined a large number of follicular adenomas and carcinomas obtained from a single institute using established methods for the analysis of RAS.
Tumor samples from 40 follicular adenoma and 58 follicular carcinoma patients treated at the Kanagawa Cancer Center Hospital were analyzed. The three RAS mutations at codons 12 and 61 were assessed with a polymerase chain reaction-based loop-hybrid mobility shift assay followed by confirmation with direct sequencing. The relationships between mutation status and clinicopathological features at the time of the initial operation and the prognosis of the patients were also analyzed.
Twelve out of 40 (30%) adenomas harbored RAS mutations. In contrast, 33 out of 58 (57%) follicular carcinomas harbored RAS mutations, and the mutation was predominantly found in the NRAS codon 61 (22/33, 67%, p<0.01). The rate of gene mutations was significantly higher in the carcinomas than in the adenomas (p<0.01). The NRAS codon 61 mutation in follicular carcinomas was positively associated with distant metastases through the entire clinical course of the patients (p<0.05), and RAS mutations were associated with poor overall patient survival (p<0.05).
We investigated the frequency of RAS mutations in follicular thyroid tumors from a large number of cases obtained from a single institute. The predominance of NRAS codon 61 mutations as a feature of carcinomas indicates that the diagnosis of adenoma alongside the presence of this mutation should be made cautiously. Our study raises the possibility that follicular adenomas with the RAS mutations have an inherent malignant potential; however, the clinical significance of this finding should be further investigated in more patients and over a longer follow-up period.
Thyroid: official journal of the American Thyroid Association 05/2012; 22(7):683-9. · 2.60 Impact Factor
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Hiroshi Tamagawa, Yohei Miyagi,
Masakatsu Numata,
Naoto Yamamoto,
Manabu Shiozawa,
Soichiro Morinaga,
Akiko Sekiyama,
Hironobu Sekiguchi,
Yuji Sakuma,
Yoichi Kameda,
Makoto Akaike,
Munetaka Masuda,
Toshio Imada
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ABSTRACT: Pancreatic metastasis from colorectal cancer is rare, and accounts for less than 2% of all pancreatic metastases. There have been no studies that have reported the differences in the sensitivity to chemotherapy between the primary lesion and the pancreatic metastasis in colorectal cancer. We experienced a rare example of pancreatic metastasis from colorectal cancer, and report here the difference in the sensitivity to the antitumor drug. A 68-year-old female underwent colectomy for rectal carcinoma with a mass in the pancreatic tail and the liver. The patient also underwent a distal pancreatectomy and a segmental liver resection at the same time. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor protein 53 (TP53) gene mutation analyses, in addition to the histopathological examinations, revealed tumors of the liver and the pancreatic tail as being metastases from the primary carcinoma. We employed a collagen gel droplet-embedded culture drug sensitivity test for both the primary lesion and the pancreatic metastasis. The sensitivity to oxaliplatin and FOLFOX (5-flurouracil, folinic acid and oxaliplatin) were lower in the pancreatic metastasis compared to the primary lesion. In conclusion, pancreatic metastasis from colorectal malignancy is rare, and the present results suggest that there are potential differences in the sensitivity to chemotherapy between the primary colorectal tumor and its pancreatic metastasis.
Anticancer research 04/2012; 32(4):1457-61. · 1.73 Impact Factor
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Cancer Science 04/2012; 103(4):Aprilcover. · 3.33 Impact Factor
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Michiko Fukahori,
Akira Yoshida,
Hiroyuki Hayashi,
Mitsuyo Yoshihara,
Shoichi Matsukuma,
Yuji Sakuma,
Shiro Koizume,
Naoyuki Okamoto,
Tetsuo Kondo,
Munetaka Masuda, Yohei Miyagi
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[hide abstract]
ABSTRACT: Background: Many studies on thyroid follicular tumors have reported the presence of somatic mutations to three RAS genes, HRAS, KRAS and NRAS. However, the frequency and clinical significance of these RAS gene mutations remain unclear, in large part due to the different methodologies being used for mutation analysis and the limited number cases featured in studies. To clarify the significance of RAS gene mutations, we examined a large number of follicular adenomas and carcinomas obtained from a single institute using established methods for the analysis of RAS genes. Methods: Tumor samples from 40 follicular adenoma and 58 follicular carcinoma patients treated at the Kanagawa Cancer Center Hospital were analyzed. The three RAS gene mutations at codons 12 and 61 were assessed with a polymerase chain reaction based loop-hybrid mobility shift assay followed by confirmation with direct sequencing. The relationships between mutation-status and clinicopathological features at the time of the initial operation and the prognosis of the patients were also analyzed. Results: Twelve out of 40 (30%) adenomas harbored RAS genes mutations. In contrast, 33 out of 58 (57%) follicular carcinomas harbored RAS gene mutations and the mutation was predominantly found in the NRAS codon 61 (22/33, 67%, p < 0.01). The rate of RAS gene mutations was significantly higher in the carcinomas than in the adenomas (p < 0.01). The NRAS codon 61 mutation in follicular carcinomas was positively associated with distant metastases through the entire clinical course of the patients (p < 0.05), and mutations to the RAS genes were associated with poor overall patient survival (p < 0.05). Conclusions: We investigated the frequency of RAS genes mutations in follicular thyroid tumors from a large numbers of cases obtained from a single institute. The predominance of NRAS codon 61 mutations as a feature of carcinomas indicates that the diagnosis of adenoma alongside the presence of this mutation should be made cautiously. Our study raises the possibility that follicular carcinomas with the RAS genes mutation have an inherent malignant potential; however, the clinical significance of this finding should be further investigated in more patients and over a longer follow-up period.
Thyroid: official journal of the American Thyroid Association 03/2012; · 2.60 Impact Factor
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ABSTRACT: Hypoxia-inducible factors (HIF)-1α and HIF2α are major transcription factors required for adaptive responses to hypoxia. HIFs form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) to bind to the regulatory regions of target genes. The acetylation of histones by histone acetyltransferases (HATs) is one of the epigenetic marks associated with active chromatin. Indeed, HIFs recruit p300 HAT to hypoxia response elements (HREs) within gene regulatory regions. Here, we report an unusual HIF-mediated transcriptional activation in ovarian clear cell carcinoma (CCC). While characterizing coagulation factor VII (FVII) gene induction during hypoxic conditions, we observed that the interaction of HIF2α with Sp1, but not with ARNT, could induce transcription of FVII in a HRE-independent manner. Unexpectedly, this gene activation is associated with histone deacetylation. We found that a class II HDAC, HDAC4, is recruited with HIF2α to the FVII promoter as a co-activator, while p300 HAT negatively regulated this process. Furthermore, this mechanism can be synergistically enhanced via a deacetylation-dependent pathway when cells are simultaneously exposed to hypoxic and serum-free conditions. These results suggest the presence of a stress-responsive transcription mediated by the HIF2α/Sp1/HDAC4 network and explain how CCC shed their procoagulant activity under hypoxia.
Nucleic Acids Research 03/2012; 40(12):5389-401. · 8.03 Impact Factor
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ABSTRACT: Angiomodulin (AGM/IGFBP-rP1), a glycoprotein of about 30 kDa, is overexpressed in tumor vasculature as well as some human cancer cell lines, but it has been suggested to be a tumor suppressor. To elucidate roles of angiomodulin (AGM) in tumor progression, we here examined distribution of AGM in three types of human cancer tissues by immunohistochemistry. The results showed that AGM was overexpressed in the stroma as well as the vasculature surrounding tumor cells in the human cancer tissues. AGM and α-smooth muscle actin (α-SMA) as an activated fibroblast marker were often colocalized in cancer-associated fibroblasts (CAFs). In vitro analysis indicated that transforming growth factor (TGF)-β1 might be an important inducer of AGM in normal human fibroblasts. AGM strongly stimulated the expression of fibronectin and weakly that of α-SMA in normal fibroblasts. AGM significantly stimulated the proliferation and migration of fibroblasts. The AGM-induced expression of fibronectin and α-SMA was blocked by a TGF-β signal inhibitor but neither the stimulation of cell growth nor migration. These results imply that AGM activates normal fibroblasts by TGF-β-dependent and independent mechanisms. These findings also suggest that AGM and TGF-β1 cooperatively or complementarily contribute to the stromal activation and connective tissue formation in human cancer tissues, contributing to tumor progression.
Cancer Science 02/2012; 103(4):691-9. · 3.33 Impact Factor
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ABSTRACT: Colorectal small cell carcinomas (SCCs) are rare tumors and are infrequently associated with ulcerative colitis (UC). We report a case of primary rectal SCC combined with adenocarcinoma arising in left-sided UC. Immunohistochemically, tumor cells were positive for chromogranin A, synaptophysin, and CD56 in the SCC but not in the adenocarcinoma. The patient simultaneously developed multiple lesions of adenocarcinoma and high-grade dysplasia in the sigmoid colon and rectum. To elucidate whether SCC might evolve from multipotential cells in dysplasia and/or adenocarcinoma, we examined the mutational status of TP53 and KRAS. The same clonality of these lesions including SCC was confirmed by the presence of an identical single nucleotide point mutation in TP53. KRAS mutation was not observed in these lesions. Thus, these lesions seem to have developed from the same origin. Long-standing inflammation leading to dysplasia might be responsible for the development of some SCCs in UC particularly when they are combined with dysplasia and/or adenocarcinoma.
Journal of Crohn s and Colitis 02/2012; 6(1):112-5. · 2.57 Impact Factor
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Miki Ohe,
Tomoyuki Yokose,
Yuji Sakuma, Yohei Miyagi,
Naoyuki Okamoto,
Sachie Osanai,
Chikako Hasegawa,
Haruhiko Nakayama,
Yoichi Kameda,
Kouzo Yamada,
Takeshi Isobe
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ABSTRACT: Pulmonary adenocarcinomas with a micropapillary component having small papillary tufts and lacking a central fibrovascular core are thought to result in poor prognosis. However, the component consists of tumor cells often floating within alveolar spaces (aerogenous micropapillary component [AMPC]) rather than invading fibrotic stroma observed in other organs like breast (stromal invasive micropapillary component [SMPC]). We previously observed cases of lung adenocarcinoma with predominant SMPC that was associated with micropapillary growth of tumors in fibrotic stroma observed in other organs. We evaluated the incidence and clinicopathological characteristics of SMPC in lung adenocarcinoma cases.
We investigated the clinicopathological characteristics and prognostic significance of SMPC in lung adenocarcinoma cases by reviewing 559 patients who had undergone surgical resection. We examined the SMPC by performing immunohistochemical analysis with 17 antibodies and by genetic analysis with epidermal growth factor receptor (EGFR) and KRAS mutations.
SMPC-positive (SMPC(+)) tumors were observed in 19 cases (3.4%). The presence of SMPC was significantly associated with tumor size, advanced-stage disease, lymph node metastasis, pleural invasion, lymphatic invasion, and vascular invasion. Patients with SMPC(+) tumors had significantly poorer outcomes than those with SMPC-negative tumors. Multivariate analysis revealed that SMPC was a significant independent prognostic factor of lung adenocarcinoma, especially for disease-free survival of pathological stage I patients (p = 0.035). SMPC showed significantly higher expression of E-cadherin and lower expression of CD44 than the corresponding expression levels shown by AMPC and showed lower surfactant apoprotein A and phospho-c-Met expression level than corresponding expression levels shown by tumor cell components without a micropapillary component. Fourteen cases with SMPC(+) tumors (74%) showed EGFR mutations, and none of them showed KRAS mutations.
SMPC(+) tumors are rare, but they may be associated with a poor prognosis and have different phenotypic and genotypic characteristics from those of AMPC(+) tumors.
Diagnostic Pathology 01/2012; 7:3. · 1.64 Impact Factor
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Kazuo Tarao,
Kaoru Miyakawa, Yohei Miyagi,
Shinichi Ohkawa,
Soichiro Morinaga,
Kenji Oshige,
Naoto Yamamoto,
Makoto Ueno,
Satoshi Kobayashi,
Ryou Kameda,
Setsuo Tamai,
Yoshiyasu Nakamura,
Yuichi Endo,
Yoichi Kameda,
Masahiko Okudaira
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ABSTRACT: Objective Whether severe inflammation in the background liver cirrhosis might correlate with the development of poorly differentiated human hepatocellular carcinoma (HCC) was studied in hepatitis C virus (HCV)-associated liver cirrhosis. Methods Out of 214 HCC patients who underwent curative hepatic resection, 148 patients were HCV-associated liver cirrhosis (LC) patients. Out of these 148, 31 patients with small solitary HCC nodule (diameter ≤3 cm) were included in this study. Inflammation in the background LC was evaluated by modified histology activity index (HAI). To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (each 0-4) were estimated. In each case, the average HAI was calculated. The grade of malignancy of HCC was determined by World Health Organization (WHO) classification. Results The average HAI score in the cirrhotic portion in 17 patients with poorly differentiated HCC (5.21±1.15, mean ± standard deviation (SD)) was significantly larger than that in 14 patients without poorly differentiated HCC (4.05±0.83, p<0.005). The occurrence rate of HCC containing poorly differentiated HCC component in the patients whose HAI was more than 5.0 was 80.0% (12 out of 15), and was significantly higher compared with those in patients whose HAI was less than 5.0 (5 out of 16, 31.3%, p<0.025). In univariate and multivariate analyses for contribution to poorly differentiated HCC development, HAI was the only significant contributor (p=0.011, p=0.012 respectively). Conclusion It is suggested that severe inflammation in the background cirrhosis accelerates the promotion in the HCC development from HCV-associated LC.
Internal Medicine 01/2012; 51(18):2495-501. · 0.94 Impact Factor
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ABSTRACT: Malignant pleural mesothelioma (MPM) is a fatal tumor. It is often hard to discriminate MPM from metastatic tumors of other types because currently, there are no reliable immunopathological markers for MPM. MPM is differentially diagnosed by some immunohistochemical tests on pathology specimens. In the present study, we investigated the expression of intelectin-1, a new mesothelioma marker, in normal tissues in the whole body and in many cancers, including MPM, by immunohistochemical analysis. We found that in normal tissues, human intelectin-1 was mainly secreted from gastrointestinal goblet cells along with mucus into the intestinal lumen, and it was also expressed, to a lesser extent, in mesothelial cells and urinary epithelial cells. Eighty-eight percent of epithelioid-type MPMs expressed intelectin-1, whereas sarcomatoid-type MPMs, biphasic MPMs, and poorly differentiated MPMs were rarely positive for intelectin-1. Intelectin-1 was not expressed in other cancers, except in mucus-producing adenocarcinoma. These results suggest that intelectin-1 is a better marker for epithelioid-type MPM than other mesothelioma markers because of its specificity and the simplicity of pathological assessment. Pleural intelectin-1 could be a useful diagnostic marker for MPM with applications in histopathological identification of MPM.
PLoS ONE 01/2012; 7(7):e39889. · 4.09 Impact Factor
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ABSTRACT: Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R+T790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA.
Laboratory Investigation 12/2011; 92(3):371-83. · 3.64 Impact Factor
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Hiroshi Tamagawa,
Takashi Oshima,
Manabu Shiozawa,
Soichiro Morinaga,
Yoshiyasu Nakamura,
Mitsuyo Yoshihara,
Yuji Sakuma,
Yoichi Kameda,
Makoto Akaike,
Munetaka Masuda,
Toshio Imada, Yohei Miyagi
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ABSTRACT: Post-translational histone modifications are known to be altered in cancer tissues, and differences in the histone modification levels have recently been used to predict the clinical outcome in patients with certain types of cancer. In this study, we evaluated the immunohistochemical staining patterns of histone H3 dimethylation and acetylation in metachronous liver metastasis of colorectal carcinomas and examined its correlation with patient prognosis. Double 2 mm core tissue microarrays were made from 54 paraffin-embedded samples of liver metastasis from colorectal adenocarcinoma, and were examined by an immunohistochemical analysis of histone H3 lysine 4 (H3K4) dimethylation, histone, H3 lysine 9 (H3K9) dimethylation and histone H3 lysine 9 (H3K9) acetylation. Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were then examined for correlations with the clinicopathological parameters and clinical outcome. Dimethylation of H3K4 correlated with the tumor histological type (P=0.043), and acetylation of H3K9 correlated with the tumor histological type (P=0.016). In addition, lower levels of H3K4 dimethylation correlated with a poor survival rate (P=0.035). The multivariate survival analysis showed that the H3K4 dimethylation status is an independent prognostic factor for colorectal cancer patients (P=0.011). We suggest that the pattern of histone modification as detected by immunohistochemistry may be an independent prognostic factor for metachronous liver metastasis of colorectal carcinomas.
Oncology Reports 11/2011; 27(3):637-42. · 1.84 Impact Factor
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11/2011; , ISBN: 978-953-307-776-5
