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Papers - KANAI Yae

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Bile duct carcinoma involving the common channel associated with pancreaticobiliary maljunction shows an extension pattern similar to ductal carcinoma of the pancreas

Yoshida, Nao, Esaki, Minoru, Kishi, Yoji, Shimada, Kazuaki, Ojima, Hidenori, Kanai, Yae, Hiraoka, Nobuyoshi

PATHOLOGY INTERNATIONAL (WILEY-BLACKWELL) 63 ( 8 ) 415 - 418 2013.08

Research paper (scientific journal), ISSN 1320-5463

Biliary tract cancer occurs frequently in patients with pancreaticobiliary maljunction (PBM), although no details of its clinicopathological characteristics have been reported. Here we describe a case of bile duct (BD) cancer that developed in association with PBM. This BD cancer involved the common channel, extended to the main pancreatic duct (MPD) via the common channel, and invaded the pancreatic parenchyma, where its growth and spread, and features of its recurrence, were similar to those of ductal carcinoma of the pancreas. We assumed that MPD extension of BD cancer via the common channel was the reason for its deep spread to the pancreas, since BD cancer usually spreads along the BD and rarely reaches the common channel of the ampulla of Vater. During the follow-up of patients with PBM, attention should be paid to involvement of the common channel by BD cancer and also to cancer developing silently in the pancreas after extrahepatic BD resection.

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SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis

Ohtomo, Rie, Mori, Taisuke, Shibata, Shinsuke, Tsuta, Koji, Maeshima, Akiko M., Akazawa, Chihiro, Watabe, Yukio, Honda, Kazufumi, Yamada, Tesshi, Yoshimoto, Seiichi, Asai, Masao, Okano, Hideyuki, Kanai, Yae, Tsuda, Hitoshi

MODERN PATHOLOGY (Modern Pathology) 26 ( 8 ) 1041 - 1050 2013.08

Research paper (scientific journal), ISSN 0893-3952

Salivary gland tumors are relatively rare and morphologically diverse and heterogeneous tumors
therefore, histogenesis-based tumor markers are sorely needed to aid in diagnosing and determining the cell type of origin. SRY-related HMG-box 10 (SOX10) protein is a transcription factor known to be crucial in the specification of the neural crest and maintenance of Schwann cells and melanocytes. In addition, positive expression has also been implicated in the major salivary gland. Here, we examined SOX10 expression in various salivary gland tumors to correlate this expression with myoepithelial markers. Overall, 76 malignant and 14 benign tumors were examined. SOX10 expression clearly delineated two distinct subtypes of human salivary gland tumors
acinic cell carcinomas, adenoid cystic carcinomas, epithelial-myoepithelial carcinomas, myoepithelial carcinomas, and pleomorphic adenomas, including the pleomorphic adenoma component of carcinoma, were SOX10 positive, while salivary duct carcinomas, mucoepidermoid carcinomas, an oncocytic carcinoma, Oncocytomas, and Warthin tumors were SOX10 negative. Also, SOX10 was expressed in solid-type or non-specific morphology salivary gland tumors, but was not expressed in poorly differentiated squamous cell carcinomas. In normal human salivary gland tissue, SOX10 expression was specific to the nuclei of acini and both luminal and abluminal cells of intercalated ducts but not in other sites. Moreover, the murine model suggested that SOX10 continued to be expressed from the developmental stage to adulthood in the acinar and both luminal and abluminal intercalated ducts in the major salivary gland. Thus, SOX10 is a novel marker for diagnosing and understanding the histogenesis of salivary gland tumors. © 2013 USCAP, Inc. All rights reserved.

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Tumor immunoediting, from T cell-mediated immune surveillance to tumor-escape of uterine leiomyosarcoma

Takuma Hayashi, Akiko Horiuchi, Kenji Sano, Nobuyoshi Hiraoka, Tomoyuki Ichimura, Osamu Ishiko, Yae Kanai, Nobuo Yaegashi, Hiroyuki Aburatani, Tanri Shiozawa, Susumu Tonegawa, Ikuo Konishi

Journal of Vaccines and Vaccination (Journal of Vaccines and Vaccination) 4 ( SPL.ISSUE ) 2013.07

ISSN 2157-7560

The majority of smooth muscle tumors found in the uterus are benign, but uterine leiomyosarcomas (LMSs) are extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with female hormone secretion
however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not clearly understood. The presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules is important for tumor rejection by cytotoxic T-lymphocytes (CTLs). Such antigenic peptides are generated as a result of the degradation of intracellular proteins by the proteasome pathway, a process that is influenced by the interferon (IFN)-γ-inducible low molecular mass polypeptide-2 (LMP2) subunit of the 20S proteasome. Homozygous deficient mice for LMP2 are now known to spontaneously develop uterine LMS. LMP2 expression is reportedly absent in human uterine LMS, but present in human myometrium. Further studies revealed a few infiltrating CD56+ NK cells in human uterine LMS tissues. This review aims at summarizing recent insights into the regulation of NK cell function and the T cell-mediated immune system as tumor immune surveillance, first attempts to exploit NK cell activation to improve immunity to tumors. © 2012 Hayashi T, et al.

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Pancreatic Intraglandular Metastasis Predicts Poorer Outcome in Postoperative Patients With Pancreatic Ductal Carcinoma

Oguro, Seiji, Shimada, Kazuaki, Ino, Yoshinori, Esaki, Minoru, Nara, Satoshi, Kishi, Yoji, Kosuge, Tomoo, Kanai, Yae, Hiraoka, Nobuyoshi

AMERICAN JOURNAL OF SURGICAL PATHOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 37 ( 7 ) 1030 - 1038 2013.07

Research paper (scientific journal), ISSN 0147-5185

Intraorgan metastasis of a primary cancer within the organ of origin, such as intrahepatic metastasis of hepatocellular carcinoma, is one of the key features for clinicopathologic staging of the cancer. Pancreatic intraglandular metastasis (P-IM) of pancreatic ductal carcinoma (PDC) is encountered occasionally but has not yet been evaluated. The aim of this study was to investigate the clinicopathologic characteristics and prognostic value of P-IM in patients with PDC. The histopathologic features of 393 consecutive patients with PDC who had undergone pancreatic resection at the National Cancer Center Hospital, Tokyo, between 2003 and 2010 were reviewed. For the purposes of the study, P-IM was defined as an independent tumor showing histopathologic features similar to those of the primary one. Twenty-six cases of P-IM were identified in 21 (5.3%) of the reviewed patients. The incidence of P-IM at each stage of the TNM classification was 0% (0/7) at stage IA, 17% (1/6) at stage IB, 5% (5/92) at stage IIA, 4% (11/252) at stage IIB, 0% (0/1) at stage III, and 11% (4/35) at stage IV. Univariate survival analysis showed that both overall survival and disease-free survival for patients with P-IM were significantly shorter than for those without P-IM (P < 0.001 and P = 0.019, respectively). Multivariate survival analysis showed that P-IM was significantly correlated with shorter overall survival (P = 0.002; hazard ratio = 2.239; 95% confidence interval: 1.328-3.773). Our findings suggest that the presence of P-IM in patients with PDC is an independent prognosticator and may represent aggressive tumor behavior.

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Diagnostic markers of urothelial cancer based on DNA methylation analysis

Chihara, Yoshitomo, Kanai, Yae, Fujimoto, Hiroyuki, Sugano, Kokichi, Kawashima, Kiyotaka, Liang, Gangning, Jones, Peter A., Fujimoto, Kiyohide, Kuniyasu, Hiroki, Hirao, Yoshihiko

BMC CANCER (BIOMED CENTRAL LTD) 13 794 - 798 2013.06

Research paper (scientific journal), ISSN 1471-2407

Background: Early detection and risk assessment are crucial for treating urothelial cancer (UC), which is characterized by a high recurrence rate, and necessitates frequent and invasive monitoring. We aimed to establish diagnostic markers for UC based on DNA methylation.
Methods: In this multi-center study, three independent sample sets were prepared. First, DNA methylation levels at CpG loci were measured in the training sets (tumor samples from 91 UC patients, corresponding normal-appearing tissue from these patients, and 12 normal tissues from age-matched bladder cancer-free patients) using the Illumina Golden Gate methylation assay to identify differentially methylated loci. Next, these methylated loci were validated by quantitative DNA methylation by pyrosequencing, using another cohort of tissue samples (Tissue validation set). Lastly, methylation of these markers was analyzed in the independent urine samples (Urine validation set). ROC analysis was performed to evaluate the diagnostic accuracy of these 12 selected markers.
Results: Of the 1303 CpG sites, 158 were hyper ethylated and 356 were hypo ethylated in tumor tissues compared to normal tissues. In the panel analysis, 12 loci showed remarkable alterations between tumor and normal samples, with 94.3% sensitivity and 97.8% specificity. Similarly, corresponding normal tissue could be distinguished from normal tissues with 76.0% sensitivity and 100% specificity. Furthermore, the diagnostic accuracy for UC of these markers determined in urine samples was high, with 100% sensitivity and 100% specificity.
Conclusion: Based on these preliminary findings, diagnostic markers based on differential DNA methylation at specific loci can be useful for non-invasive and reliable detection of UC and epigenetic field defect.

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Prognostic Risk Stratification of Patients with Urothelial Carcinoma of the Bladder with Recurrence After Radical Cystectomy

Nakagawa, Tohru, Hara, Tomohiko, Kawahara, Takashi, Ogata, Yoshihiko, Nakanishi, Hiroyuki, Komiyama, Motokiyo, Arai, Eri, Kanai, Yae, Fujimoto, Hiroyuki

JOURNAL OF UROLOGY (Journal of Urology) 189 ( 4 ) 1275 - 1281 2013.04

Research paper (scientific journal), ISSN 0022-5347

Purpose: We identify clinicopathological variables predicting overall survival in patients with recurrent bladder urothelial carcinoma after radical cystectomy. Materials and Methods: We retrospectively collected data on 114 patients treated with radical cystectomy for bladder urothelial carcinoma who subsequently had remote metastasis and/or local recurrence. The Kaplan-Meier method with the log rank test and multivariate Cox regression models were used to address overall survival after recurrence. Results: During followup 99 of the 114 patients died. Median survival in the 114 patients was 11.2 months. One and 3-year overall survival rates were 48.0% and 12.1%, respectively. On multivariate analysis independent predictors of poorer overall survival included less than 1 year to recurrence, symptoms at recurrence, 2 or more metastatic organs at recurrence, high serum C-reactive protein, high lactate dehydrogenase, no post-recurrence platinum based chemotherapy and no metastasectomy. Based on the 4 variables (time to recurrence, symptoms, number of metastatic organs and C-reactive protein), we constructed a risk model predicting post-recurrence overall survival that classified patients into 3 groups with significantly different overall survival (p &lt
0.0001). Conclusions: Our data confirm that recurrent urothelial carcinoma after radical cystectomy is a highly aggressive, lethal disease. Seven clinicopathological factors were identified that predicted post-recurrence overall survival. Our risk model based on the 4 variables could be useful to provide relevant prognostic information to patients and physicians, and better stratify patients in clinical trials. © 2013 American Urological Association Education and Research, Inc.

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The tumor suppressor microRNA-29c is downregulated and restored by celecoxib in human gastric cancer cells

Saito, Yoshimasa, Suzuki, Hidekazu, Imaeda, Hiroyuki, Matsuzaki, Juntaro, Hirata, Kenro, Tsugawa, Hitoshi, Hibino, Sana, Kanai, Yae, Saito, Hidetsugu, Hibi, Toshifumi

INTERNATIONAL JOURNAL OF CANCER (International Journal of Cancer) 132 ( 8 ) 1751 - 1760 2013.04

Research paper (scientific journal), ISSN 0020-7136

MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous silencers of target genes and play critical roles during carcinogenesis. The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib has been highlighted as a potential drug for treatment of gastrointestinal tumors. The aim of this study was to investigate the role of miRNAs in gastric carcinogenesis and the feasibility of a new therapeutic approach for gastric cancer. miRNA expression profiles were examined in 53 gastric tumors including gastric adenomas (atypical epithelia), early gastric cancers and advanced gastric cancers and in gastric cancer cells treated with celecoxib. miRNA microarray analysis revealed that miR-29c was significantly downregulated in gastric cancer tissues relative to nontumor gastric mucosae. miR-29c was significantly activated by celecoxib in gastric cancer cells. Downregulation of miR-29c was associated with progression of gastric cancer and was more prominent in advanced gastric cancers than in gastric adenomas and early gastric cancer. In addition, expression of the oncogene Mcl-1, a target of miR-29c, was significantly increased in gastric cancer tissues relative to nontumor gastric mucosae. Activation of miR-29c by celecoxib induced suppression of Mcl-1 and apoptosis in gastric cancer cells. These results suggest that downregulation of the tumor suppressor miR-29c plays critical roles in the progression of gastric cancer. Selective COX-2 inhibitors may have clinical promise for the treatment of gastric cancer via restoration of miR-29c. What's new? MicroRNAs (miRNAs) play critical roles in carcinogenesis and may be valuable therapeutic targets for malignant disease. Here, the miRNA tumor suppressor miR-29c was found to be significantly downregulated in gastric cancer cells and to be reactivated by the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib. Reactivation led to miR-29c-induced suppression of the anti-apoptotic protein Mcl-1. The data reveal that selective COX-2 inhibitors may have clinical promise for the treatment of gastric cancer via restoration of miR-29c. Copyright © 2012 UICC.

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Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma

Kondo, Shunsuke, Ojima, Hidenori, Tsuda, Hitoshi, Hashimoto, Jun, Morizane, Chigusa, Ikeda, Masafumi, Ueno, Hideki, Tamura, Kenji, Shimada, Kazuaki, Kanai, Yae, Okusaka, Takuji

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY (SPRINGER JAPAN KK) 18 ( 2 ) 207 - 213 2013.04

Research paper (scientific journal), ISSN 1341-9625

c-Met is an oncogene encoding a receptor for hepatocyte growth factor and, as such, plays a key role in hepatocellular carcinomas (HCC). We evaluated c-Met protein expression and its gene amplification in order to assess whether they were related to tumor recurrence and survival rates among patients who had undergone tumor resection.
We used the polymer-based method to perform an immunohistochemistry analysis of c-Met expression on 59 formalin-fixed, paraffin-embedded sections of surgical specimens. c-Met gene amplification was investigated with fluorescence in-situ hybridization. Kaplan-Meier methods and Cox proportional hazards models were used to investigate relationships between c-Met expression, patient characteristics, tumor recurrence, and survival.
c-Met expression was associated with portal vein invasion (p = 0.006). Recurrence-free survival rates were significantly lower in patients with high levels of c-Met expression (p < 0.001). However, c-Met expression levels did not significantly affect overall survival rates (p = 0.12). Only 1 patient was found to have c-Met gene amplification; 22 patients were found to have aneuploidy of chromosome 7, on which the c-Met gene is located. Tumors with chromosome 7 polysomy tended to have higher levels of c-Met expression than those with chromosome 7 monosomy or disomy, but this difference was not statistically significant.
Although c-Met expression was not significantly associated with c-Met gene amplification, it may be a useful predictive marker of recurrence in resected HCC patients.

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Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms

G. Nishikawa, S. Sekine, R. Ogawa, A. Matsubara, T. Mori, H. Taniguchi, R. Kushima, N. Hiraoka, K. Tsuta, H. Tsuda, Y. Kanai

British Journal of Cancer (British Journal of Cancer) 108 ( 4 ) 951 - 958 2013.03

ISSN 00070920

Background:The molecular basis for the development of appendiceal mucinous tumours, which can be a cause of pseudomyxoma peritonei, remains largely unknown.Methods:Thirty-five appendiceal mucinous neoplasms were analysed for GNAS and KRAS mutations. A functional analysis of mutant GNAS was performed using a colorectal cancer cell line.Results:A mutational analysis identified activating GNAS mutations in 16 of 32 low-grade appendiceal mucinous neoplasms (LAMNs) but in none of three mucinous adenocarcinomas (MACs). KRAS mutations were found in 30 LAMNs and in all MACs. We additionally analysed a total of 186 extra-appendiceal mucinous tumours and found that GNAS mutations were highly prevalent in intraductal papillary mucinous tumours of the pancreas (88%) but were rare or absent in mucinous tumours of the colorectum, ovary, lung and breast (0-9%). The prevalence of KRAS mutations was quite variable among the tumours. The introduction of the mutant GNAS into a colorectal cancer cell line markedly induced MUC2 and MUC5AC expression, but did not promote cell growth either in vitro or in vivo.Conclusion:Activating GNAS mutations are a frequent and characteristic genetic abnormality of LAMN. Mutant GNAS might play a direct role in the prominent mucin production that is a hallmark of LAMN. © 2013 Cancer Research UK.

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DNA Methylation Profiles at Precancerous Stages Associated with Recurrence of Lung Adenocarcinoma

Sato, Takashi, Arai, Eri, Kohno, Takashi, Tsuta, Koji, Watanabe, Shun-ichi, Soejima, Kenzo, Betsuyaku, Tomoko, Kanai, Yae

PLOS ONE (PUBLIC LIBRARY SCIENCE) 8 ( 3 ) 798 - 798 2013.03

Research paper (scientific journal), ISSN 1932-6203

The aim of this study was to clarify the significance of DNA methylation alterations at precancerous stages of lung adenocarcinoma. Using single-CpG resolution lnfinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue obtained from patients without any primary lung tumor, 145 samples of non-cancerous lung tissue (N) obtained from patients with lung adenocarcinomas, and 145 samples of tumorous tissue (T). Stepwise progression of DNA methylation alterations from normal lung tissue to non-cancerous lung tissue obtained from patients with lung adenocarcinomas, and then tumorous tissue samples, was observed at 3,270 CpG sites, suggesting that non-cancerous lung tissue obtained from patients with lung adenocarcinomas was at precancerous stages with DNA methylation alterations. At CpG sites of 2,083 genes, DNA methylation status in samples of non-cancerous lung tissue obtained from patients with lung adenocarcinomas was significantly correlated with recurrence after establishment of lung adenocarcinomas. Among such recurrence-related genes, 28 genes are normally unmethylated (average beta-values based on lnfinium assay in normal lung tissue samples was less than 0.2) and their DNA hypermethylation at precancerous stages was strengthened during progression to lung adenocarcinomas (Delta beta(T-N)>0.1). Among these 28 genes, we focused on 6 for which implications in transcription regulation, apoptosis or cell adhesion had been reported. DNA hypermethylation of the ADCY5, EVX1, GFRA1, PDE9A, and TBX20 genes resulted in reduced mRNA expression in tumorous tissue samples. 5-Aza-2'-deoxycytidine treatment of lung cancer cell lines restored the mRNA expression levels of these 5 genes. Reduced mRNA expression in tumorous tissue samples was significantly correlated with tumor aggressiveness. These data suggest that DNA methylation alterations at precancerous stages determine tumor aggressiveness and outcome through silencing of specific genes.

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Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum

Matsubara, Akiko, Sekine, Shigeki, Kushima, Ryoji, Ogawa, Reiko, Taniguchi, Hirokazu, Tsuda, Hitoshi, Kanai, Yae

JOURNAL OF PATHOLOGY (WILEY-BLACKWELL) 229 ( 4 ) 579 - 587 2013.03

Research paper (scientific journal), ISSN 0022-3417

Gastric and duodenal adenomas exhibit a significant morphological and phenotypical diversity and are classified into intestinal-type, foveolar-type and pyloric gland adenomas. We analysed the mutations in GNAS, KRAS, BRAF and CTNNB1 and the expressions of mismatch repair (MMR) proteins in 80 gastric and 32 duodenal adenomas with histologically distinct subtypes, as well as in 71 gastric adenocarcinomas. Activating GNAS mutations were found in 22 of the 35 pyloric gland adenomas (PGAs; 63%) but in none of the foveolar-type or intestinal-type adenomas or the adenocarcinomas. Fourteen PGAs (41%), two foveolar-type adenomas (9%), five intestinal-type adenomas (9%) and one adenocarcinoma (1%) had KRAS mutations. BRAF mutations were absent in all the adenomas and adenocarcinomas that were examined. CTNNB1 mutations were only found in two intestinal-type adenomas (4%). Notably, 13 of the 14 KRAS-mutated gastric and duodenal PGAs had concurrent GNAS mutations. The loss of the MMR proteins, which is indicative of microsatellite instability, was observed in one PGA (3%), 12 foveolar-type adenomas (52%), one intestinal-type adenoma (2%) and five adenocarcinomas (7%). These observations indicate that each histological subtype of gastric and duodenal adenomas has a distinct genetic background. In particular, the present study identified the frequent presence of activating GNAS mutations, which are often associated with KRAS mutations, as a characteristic genetic feature of PGAs of the stomach and duodenum.

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Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours

Matsubara, Akiko, Sekine, Shigeki, Yoshida, Masayuki, Yoshida, Akihiko, Taniguchi, Hirokazu, Kushima, Ryoji, Tsuda, Hitoshi, Kanai, Yae

HISTOPATHOLOGY (Histopathology) 62 ( 4 ) 657 - 661 2013.03

Research paper (scientific journal), ISSN 0309-0167

Aims: To determine the prevalence of MED12 mutations in smooth muscle tumours of different organs. Methods and results: A total of 142 smooth muscle tumours of the uterus, gastrointestinal tract, retroperitoneum and soft tissue were analysed for MED12 mutations using Sanger sequencing. Among the uterine tumours that were examined, MED12 mutations were identified in 36 of 45 conventional leiomyomas (80%), two of six cellular leiomyomas (33%), one of four bizarre leiomyomas (25%), none of four lipoleiomyomas (0%), and two of 12 leiomyosarcomas (17%). The two MED12-mutated leiomyosarcomas were associated with benign leiomyomatous components that also harboured MED12 mutations identical to those in the respective leiomyosarcomatous components. None of the extrauterine smooth muscle tumours, including the leiomyomas, leiomyosarcomas, and angioleiomyomas, had MED12 mutations. Conclusions: Among uterine smooth muscle tumours, MED12 mutations are frequently present in conventional leiomyomas, but are significantly less common in histological variants of leiomyoma and leiomyosarcoma. In contrast to uterine lesions, none of the extrauterine smooth muscle tumours had MED12 mutations. © 2012 Blackwell Publishing Ltd.

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3.0-Tesla MRIによる前立腺移行領域癌の診断能とその手術適応について

鳴川司, 中西弘之, 冨田晋太郎, 尾形吉彦, 河原貴史, 原智彦, 込山元清, 新井恵吏, 金井弥栄, 三宅基隆, 眞鍋知子, 藤元博行

日本泌尿器科学会雑誌 ((一社)日本泌尿器科学会) 104 ( 2 ) 358 - 358 2013.03

ISSN 0021-5287

Arginase II Expressed in Cancer-Associated Fibroblasts Indicates Tissue Hypoxia and Predicts Poor Outcome in Patients with Pancreatic Cancer

Ino, Yoshinori, Yamazaki-Itoh, Rie, Oguro, Seiji, Shimada, Kazuaki, Kosuge, Tomoo, Zavada, Jan, Kanai, Yae, Hiraoka, Nobuyoshi

PLOS ONE (PLoS ONE) 8 ( 2 ) 1742 - 1747 2013.02

Research paper (scientific journal), ISSN 1932-6203

An adequate level of arginine in the tissue microenvironment is essential for T cell activity and survival. Arginine levels are regulated by the arginine-catabolizing enzyme, arginase (ARG). It has been reported that arginase II (ARG2), one of two ARGs, is aberrantly expressed in prostate cancer cells, which convert arginine into ornithine, resulting in a lack of arginine that weakens tumor-infiltrating lymphocytes and renders them dysfunctional. However, immune suppression mediated by ARG2-expressing cancer cells in lung cancer has not been observed. Here we studied the expression of ARG2 in pancreatic ductal carcinoma (PDC) tissue clinicopathologically by examining over 200 cases of PDC. In contrast to prostate cancer, ARG2 expression was rarely demonstrated in PDC cells by immunohistochemistry, and instead ARG2 was characteristically expressed in α-smooth muscle actin-positive cancer-associated fibroblasts (CAFs), especially those located within and around necrotic areas in PDC. The presence of ARG2-expressing CAFs was closely correlated with shorter overall survival (OS
P = 0.003) and disease-free survival (DFS
P = 0.0006). Multivariate Cox regression analysis showed that the presence of ARG2-expressing CAFs in PDC tissue was an independent predictor of poorer OS (hazard ratio [HR] = 1.582, P = 0.007) and DFS (HR = 1.715, P = 0.001) in PDC patients. In addition to the characteristic distribution of ARG2-expressing CAFs, such CAFs co-expressed carbonic anhydrase IX, SLC2A1, or HIF-1α, markers of hypoxia, in PDC tissue. Furthermore, in vitro experiments revealed that cultured fibroblasts extracted from PDC tissue expressed the ARG2 transcript after exposure to hypoxia, which had arginase activity. These results indicate that cancer cell-mediated immune suppression through ARG2 expression is not a general event and that the presence of ARG2-expressing CAFs is an indicator of poor prognosis, as well as hypoxia, in PDC tissue. © 2013 Ino et al.

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前立腺癌のADC値と被膜外浸潤の有無との関連についての検討(Can Apparent Diffusion Coefficient (ADC) values contribute to assess the extra capsular extension (ECE) of prostate cancer?)

眞鍋知子, 三宅基隆, 新井恵吏, 金井弥栄, 中西弘之, 込山元清, 藤元博行, 楠本昌彦, 荒井保明

日本医学放射線学会学術集会抄録集 ((公社)日本医学放射線学会) 72回 S369 - S369 2013.02

ISSN 0048-0428

Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in gastric cancer

Yamanoi, Kazuhiro, Fukuma, Mariko, Uchida, Hiroshi, Kushima, Ryoji, Yamazaki, Ken, Katai, Hitoshi, Kanai, Yae, Sakamoto, Michiie

PATHOLOGY INTERNATIONAL (Pathology International) 63 ( 1 ) 13 - 19 2013.01

Research paper (scientific journal), ISSN 1320-5463

Gastric cancer is one of the most common malignancies worldwide and patients with advanced gastric cancer still have poor clinical outcomes. The overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) mRNA in colorectal cancer and its correlation with clinicopathological factors were recently reported by us. In this study, we show LGR5 mRNA overexpression in human gastric cancer specimens by quantitative RT-PCR and in situ hybridization and assess a correlation with clinicopathological factors. The mean expression of LGR5 mRNA in cancerous tissues was five times higher than that in normal tissue (P=0.0002). Furthermore, LGR5 mRNA expression show marked variation among cases and significantly increased in cases where lymphatic invasion was present compared with those where it was absent (P=0.0056). Although the mean expression level of LGR5 was observed to be higher in nodal metastasis and venous invasion positive cases compared to negative cases, a significant difference was not observed. These results suggest that LGR5 can be a biomarker for malignancy in gastric cancer. © 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

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Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer.

Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, Hiraoka N.

Br J Cancer (NATURE PUBLISHING GROUP) 108 ( 4 ) 914 - 923 2013

Accepted, ISSN 00070920

Background: The host immune reaction is represented by immune/inflammatory cell infiltrates. Here we systematically analysed tumour-infiltrating immune/inflammatory cells in pancreatic ductal carcinoma (PDC) and evaluated their clinicopathological impact.
Methods: Using immunohistochemistry, we examined tumour-infiltrating CD68(+) pan-macrophages, HLA-DR(+)CD68(+) M1 macrophages (M1), CD163(+) or CD204(+) M2 macrophages (M2), CD66b(+) neutrophils (Neu), CD4(+) T cells (CD4(+) T), CD8(+) T cells (CD8(+)T), and FOXP3(+)CD4(+) regulatory T cells (Treg) in 212 cases of PDC, and conducted correlation and survival analyses using the Kaplan Meier method and Cox proportional hazards model.
Results: Higher levels of tumour-infiltrating pan-macrophages, M2, Neu, or the ratio of Tregs to CD4(+)T (%Treg) were significantly associated with shorter survival, whereas higher levels of tumour-infiltrating CD4(+)T, CD8(+)T, or the ratio of M1 to pan-macrophages (%M1) were significantly associated with longer survival. Survival analysis of pairs of these variables revealed that some of the resulting patient groups had exclusively longer survival. We then connected the apparently related factors, and two significant variables emerged: tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and tumour-infiltrating %M1(high)/M2(low). Multivariate survival analysis revealed that these variables were significantly correlated with longer survival and had a higher hazard ratio.
Conclusion: Tumour-infiltrating CD4(+)T(high)/CD8(+)T(high)/%Treg(low) and %M1(high)/M2(low) are independent prognosticators useful for evaluating the immune microenvironment of PDC.

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DNA Methylation Alterations in Human Cancers

Kanai Y., Arai E.

Epigenetics in Human Disease (Epigenetics in Human Disease) 29 - 52 2012.12

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Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad.

Matsubara D, Kanai Y, Ishikawa S, Ohara S, Yoshimoto T, Sakatani T, Oguni S, Tamura T, Kataoka H, Endo S, Murakami Y, Aburatani H, Fukayama M, Niki T

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7 ( 12 ) 1872 - 1876 2012.12

Accepted, ISSN 1556-0864

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Characteristics of Lymph Node Metastases Defining the Outcome After Radical Cystectomy of Urothelial Bladder Carcinoma

Nakagawa, Tohru, Kanai, Yae, Nakanishi, Hiroyuki, Komiyama, Motokiyo, Fujimoto, Hiroyuki

JAPANESE JOURNAL OF CLINICAL ONCOLOGY (OXFORD UNIV PRESS) 42 ( 11 ) 1066 - 1072 2012.11

Research paper (scientific journal), ISSN 0368-2811

The aim of this study was to identify clinicopathological variables associated with the clinical outcomes of patients with lymph node metastasis-positive urothelial bladder carcinoma after radical cystectomy.
Forty-six patients who underwent radical cystectomy without preoperative chemotherapy and had histologically proven nodal metastasis were included in the study. The status of lymph nodes and primary lesion was analyzed in terms of disease-specific survival and recurrence-free survival.
The 5-year disease-specific survival and recurrence-free survival for the 46 patients overall were 41.3 and 32.2, respectively. Univariate analysis showed that pN status, the total number of involved lymph nodes, lymph node density and extranodal invasion were statistically significant variables predictive of disease-specific survival. Multivariate analysis revealed that the total number of involved lymph nodes, extranodal invasion and diameter of the metastatic lesion were statistically significant variables predictive of disease-specific survival. Interestingly, the diameter of metastatic lesions was inversely correlated with poorer survival. Patients with large (epsilon 10 mm) metastatic lesions and no extranodal invasion (expansive growth) had significantly better disease-specific survival than those with multiple small (10 mm) metastatic lesions and no extranodal invasion (highly spreading) (P 0.0156) or those with extranodal invasion (infiltrative growth) (P 0.0181).
Our data indicate that the clinical outcome of node-positive patients is not only stratified according to the tumor burden reflected in the total number of involved lymph nodes, but also affected by tumor biology including invasiveness and potential for metastasis, which is reflected in pathological characteristics such as extranodal invasion and the diameter of metastatic lesions.

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