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Pancreatic Neoplasms: HELP
Articles by Kyoko Shimizu
Based on 14 articles published since 2008
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Between 2008 and 2019, Kyoko Shimizu wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline Clinical Practice Guidelines for Pancreatic Cancer 2016 From the Japan Pancreas Society: A Synopsis. 2017

Yamaguchi, Koji / Okusaka, Takuji / Shimizu, Kyoko / Furuse, Junji / Ito, Yoshinori / Hanada, Keiji / Shimosegawa, Tooru / Okazaki, Kazuichi / Anonymous7740903. ·From the *Clinic of Fukuoka Government Building, Hamanomachi Hospital, Fukuoka; †Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital; ‡Department of Gastroenterology, Tokyo Women's Medical University; §Department of Medical Oncology, Faculty of Medicine, Kyorin University; ∥Department of Radiation Oncology, National Cancer Center Hospital, Tokyo; ¶Department of Gastroenterology, JA Onomichi General Hospital, Onomichi; #Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai; and **Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Japan. ·Pancreas · Pubmed #28426492.

ABSTRACT: OBJECTIVES: Clinical Practice Guidelines for Pancreatic Cancer based on Evidence-Based Medicine 2006 were first published by the Japan Pancreas Society, and they were revised to Clinical Practice Guidelines for Pancreatic Cancer 2009 in July 2009 and were further revised to Clinical Practice Guidelines for Pancreatic Cancer 2013 in October 2013. These guidelines were established according to evidence-based medicine. In October 2016, the Clinical Practice Guidelines for Pancreatic Cancer were newly revised in Japanese. METHODS: In the revised version, we introduced the concepts of GRADE - grading recommendations assessment, development, and evaluation approach for better understanding of the current guidelines. RESULTS: The guidelines show algorithms for the diagnosis, treatment, and chemotherapy of pancreatic cancer and address 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and palliative medicine. They include 51 clinical questions and 76 statements. There are statements corresponding to clinical questions, evidence levels, recommended strengths, and agreement rates. CONCLUSIONS: These guidelines represent the most standard clinical and practical management at this time in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2016 in Japanese, which aims to disseminate the Japanese guidelines worldwide for the introduction of Japanese clinical management of these diseases.

2 Guideline EBM-based Clinical Guidelines for Pancreatic Cancer (2013) issued by the Japan Pancreas Society: a synopsis. 2014

Yamaguchi, Koji / Okusaka, Takuji / Shimizu, Kyoko / Furuse, Junji / Ito, Yoshinori / Hanada, Keiji / Shimosegawa, Tooru / Anonymous6910805. ·Department of Advanced Treatment of Pancreatic Diseases, School of Medicine, University of Occupational and Environmental Health, Kitakyushu yamaguch@med.uoeh-u.ac.jp. · Hepatobiliary and Pancreatic Oncology Division, National Cancer Center, Tokyo. · Department of Gastroenterology, Tokyo Women's Medical University, Tokyo. · Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo. · Department of Radiation Oncology, National Cancer Center, Tokyo. · Department of Gastroenterology, JA Onomichi General Hospital, Onomichi. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. ·Jpn J Clin Oncol · Pubmed #25205672.

ABSTRACT: Clinical practice guidelines for pancreatic cancer based on evidence-based medicine (2006) were published by the Japan Pancreas Society (Committee for revision of clinical guidelines for pancreatic cancer) in March 2009 in Japanese, revised to Clinical Practice Guidelines for Pancreatic Cancer based on evidence-based medicine (2009) in July 2009 in Japanese and further revised to Clinical Practice Guidelines for Pancreatic Cancer (2013) in October 2013 in Japanese. These guidelines were established according to evidence-based medicine. A total of 629 papers were collected from among 4612 reports concerning pancreatic cancer listed in PubMed and Igakuchuo Zasshi between May 2007 and January 2011. This new set of guidelines was written by members of the Committee for the Revision of Clinical Practice Guidelines for Pancreatic Cancer in the Japan Pancreas Society. The guidelines provide an algorithm for the diagnosis (Fig. 1) and treatment (Fig. 2) of pancreatic cancer and address six subjects (Diagnosis, Surgery, Adjuvant therapy, Radiation therapy, Chemotherapy and stent therapy), with 35 clinical questions and 57 recommendations.

3 Clinical Trial Efficacy of oral administered superfine dispersed lentinan for advanced pancreatic cancer. 2009

Shimizu, Kyoko / Watanabe, Shinya / Watanabe, Seiji / Matsuda, Kenji / Suga, Tetsuya / Nakazawa, Saburo / Shiratori, Keiko. ·Department of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. ·Hepatogastroenterology · Pubmed #19453066.

ABSTRACT: BACKGROUND/AIMS: Recently, complementary alternative medicine is actively performed for cancer therapy. Superfine dispersed lentinan (beta-1,3-glucan)--an oral effective form--was recently developed and available. We investigated the effectiveness of superfine dispersed lentinan in advanced pancreatic cancer patients in a multi-center study. METHODOLOGY: Twenty-nine patients with unresectable and recurrent pancreatic cancer were enrolled, and adverse events and quality of life scores were assessed. Survival times were evaluated according to results of a 3-year follow-up survey. RESULTS: Although a diarrhea of grade-1 adverse event dependent on the test article (3.4%) was observed, the symptom was remitted without any treatment. This indicates that test article was free of anything harmful. Median survival time was 12.1 months (95% confidence interval: 7.3-25.7 months) in 25 eligible patients. Five (20%) out of 25 patients were alive for 3 years. There was a significant correlation between the quality of life scores after the superfine dispersed lentinan treatment and survival times. CONCLUSIONS: A superfine dispersed lentinan is deemed safe and effective for advanced pancreatic patients' survival and improvement of quality of life. And the assessment of quality of life status after the administration of superfine dispersed lentinan is a promising prognostic predictor.

4 Article Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma. 2017

Basturk, Olca / Berger, Michael F / Yamaguchi, Hiroshi / Adsay, Volkan / Askan, Gokce / Bhanot, Umesh K / Zehir, Ahmet / Carneiro, Fatima / Hong, Seung-Mo / Zamboni, Giuseppe / Dikoglu, Esra / Jobanputra, Vaidehi / Wrzeszczynski, Kazimierz O / Balci, Serdar / Allen, Peter / Ikari, Naoki / Takeuchi, Shoko / Akagawa, Hiroyuki / Kanno, Atsushi / Shimosegawa, Tooru / Morikawa, Takanori / Motoi, Fuyuhiko / Unno, Michiaki / Higuchi, Ryota / Yamamoto, Masakazu / Shimizu, Kyoko / Furukawa, Toru / Klimstra, David S. ·Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Tokyo Medical University, Tokyo, Japan. · Department of Pathology, Emory University, Atlanta, GA, USA. · Department of Pathology, Centro Hospitalar São João/Faculty of Medicine of Porto University and Institute for Research and Innovation in Health/Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. · Department of Pathology, University of Verona, Ospedale S.C.-Don Calabria-Negrar, Verona, Italy. · New York Genome Center, Molecular Diagnostics, New York, NY, USA. · Department of Pathology, Colombia University Medical Center, New York, NY, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. · Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. ·Mod Pathol · Pubmed #28776573.

ABSTRACT: Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

5 Article Germline mutations in Japanese familial pancreatic cancer patients. 2016

Takai, Erina / Yachida, Shinichi / Shimizu, Kyoko / Furuse, Junji / Kubo, Emi / Ohmoto, Akihiro / Suzuki, Masami / Hruban, Ralph H / Okusaka, Takuji / Morizane, Chigusa / Furukawa, Toru. ·Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. · Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. ·Oncotarget · Pubmed #27732944.

ABSTRACT: Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2, PALB2, ATM, or MLH1. These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.

6 Article Clinicophysiological outcomes after total pancreatectomy. 2016

Suzuki, Shuji / Miura, Junnosuke / Shimizu, Kyoko / Tokushige, Katsutoshi / Uchigata, Yasuko / Yamamoto, Masakazu. ·a Department of Gastroenterological Surgery , Tokyo Women's Medical University , Tokyo , Japan. · b Department of Gastroenterological Surgery , Ibaraki Medical Center, Tokyo Medical University , Ibaraki , Japan. · c Diabetes Center , Tokyo Women's Medical University , Tokyo , Japan. · d Department of Gastroenterology , Tokyo Women's Medical University , Tokyo , Japan. ·Scand J Gastroenterol · Pubmed #27461044.

ABSTRACT: PURPOSE: Total pancreatectomy (TP) for pancreatic neoplasms is associated with high morbidity and mortality rates. However, with recent advances in surgical techniques and improved postoperative management, the number of cases with clinical indications for TP is increasing. Here, we evaluated the clinical outcomes post-TP. MATERIALS AND METHODS: Patients (n = 41) who underwent TP between 2004 and 2011 at Tokyo Women's Medical University were retrospectively examined. Pre- and postoperative clinicophysiological data were collected up to 12 months post-TP and then analyzed. RESULTS: Only glycated hemoglobin (HbA1c), percentage of lymphocytes and hepatic Hounsfield unit level on computed tomography (CT) were significantly different between the preoperative state and at 12 months post-TP, while other clinicophysiological parameters remained unchanged. The quantity of the pancreatic enzyme administered significantly influenced glycemic control at 12 months post-TP (p < 0.05). CONCLUSIONS: All clinicophysiological parameters except for HbA1c were temporarily decreased after TP but normalized by 12 months. Thus, TP is a feasible surgical approach to treating pancreatic neoplasms with the potential to spread across the entire pancreas when adequately supplemented by synthetic insulin and pancreatic enzymes.

7 Article Original Scientific Reports: Clinicopathological Findings of Remnant Pancreatic Cancers in Survivors Following Curative Resections of Pancreatic Cancers. 2016

Suzuki, Shuji / Furukawa, Toru / Oshima, Nana / Izumo, Wataru / Shimizu, Kyoko / Yamamoto, Masakazu. ·Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, 3-20-1 Chuo, Amimachi, Inashikigun, Ibaraki, 300-0395, Japan. ssuzuki@tokyo-med.ac.jp. · Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo, Japan. ssuzuki@tokyo-med.ac.jp. · Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. ·World J Surg · Pubmed #26589594.

ABSTRACT: BACKGROUND: This retrospective study aimed to evaluate clinicopathological findings of remnant pancreatic cancers in survivors of invasive ductal adenocarcinomas of the pancreas (PDAC). METHODS: A group of 23 patients out of 826 who had curative resections for PDAC between 1980 and 2011 was identified and treated for metachronous pancreatic cancer. RESULTS: The following tubular adenocarcinomas were found at the first surgery: 3 well differentiated, 17 moderately differentiated, 1 papillary, and 1 poorly differentiated. Treatments for the remnant pancreas consisted of remnant pancreatectomy in 12 patients, chemotherapy in 6, and the best supportive care in 5. The mean time to treatment was 74.2 months. The 12 patients who received remnant resections had 10 PDACs and 2 intraductal papillary mucinous carcinomas. The median survival time was 31.6 months, and 8 patients are still alive. CONCLUSIONS: Long-term survivors after curative resection for pancreatic cancer should receive follow-up for remnant pancreatic cancer, and aggressive resection should be considered for more favorable prognosis of PDAC.

8 Article [Tumor marker of pancreatic tumor]. 2015

Ajihara, Takahiro / Shimizu, Kyoko / Shiratori, Keiko. · ·Nihon Rinsho · Pubmed #25856984.

ABSTRACT: -- No abstract --

9 Article Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas. 2015

Furukawa, Toru / Sakamoto, Hitomi / Takeuchi, Shoko / Ameri, Mitra / Kuboki, Yuko / Yamamoto, Toshiyuki / Hatori, Takashi / Yamamoto, Masakazu / Sugiyama, Masanori / Ohike, Nobuyuki / Yamaguchi, Hiroshi / Shimizu, Michio / Shibata, Noriyuki / Shimizu, Kyoko / Shiratori, Keiko. ·1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan. · 1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Surgery, Kyorin University School of Medicine, Mitaka, Japan. · Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. · 1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Surgery, Kyorin University School of Medicine, Mitaka, Japan. · Department of Pathology, Showa University School of Medicine, Tokyo, Japan. · Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Japan. · Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. ·Sci Rep · Pubmed #25743105.

ABSTRACT: Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy.

10 Article Molecular biomarkers for progression of intraductal papillary mucinous neoplasm of the pancreas. 2015

Kuboki, Yuko / Shimizu, Kyoko / Hatori, Takashi / Yamamoto, Masakazu / Shibata, Noriyuki / Shiratori, Keiko / Furukawa, Toru. ·From the *Institute for Integrated Medical Sciences, †Department of Gastroenterology, ‡Department of Gastroenterological Surgery, Institute of Gastroenterology, §Department of Pathology, and ∥Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan. ·Pancreas · Pubmed #25423558.

ABSTRACT: OBJECTIVES: We aimed to identify molecular biomarkers for assessing the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN). METHODS: We retrospectively investigated molecular aberrations and their associations with clinicopathological features in 172 IPMNs. RESULTS: GNAS and KRAS mutations were detected in 48% and 56% of IPMNs, respectively. No mutations of EGFR, PIK3CA GNAO1, GNAQ, or GNAI2 were observed. Significant associations were observed between IPMN morphological types and GNAS mutations, KRAS mutations, the expression of phosphorylated MAPK (pMAPK), AKT, and phosphorylated AKT (pAKT), nuclear accumulation of β-catenin, SMAD4 loss, and TP53 overexpression; histological grades and the expression of EGFR, pMAPK, AKT, and pAKT, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression; invasive phenotypes and KRAS mutations, the nuclear β-catenin, and SMAD4 loss; and prognosis and SMAD4 loss and TP53 overexpression. Multivariate analysis to compare prognostic impacts of multiple molecular features revealed that TP53 overexpression was an independent prognostic factor (P = 0.030; hazard ratio, 5.533). CONCLUSIONS: These results indicate that mutations in GNAS and KRAS, the expression of EGFR and pMAPK, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression may be relevant for assessing the clinical course of IPMN, including its progression into different morphological types, invasion, and prognosis.

11 Article Clinicopathological significance of somatic RNF43 mutation and aberrant expression of ring finger protein 43 in intraductal papillary mucinous neoplasms of the pancreas. 2015

Sakamoto, Hitomi / Kuboki, Yuko / Hatori, Takashi / Yamamoto, Masakazu / Sugiyama, Masanori / Shibata, Noriyuki / Shimizu, Kyoko / Shiratori, Keiko / Furukawa, Toru. ·1] Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan [2] Department of Surgery, Kyorin University School of Medicine, Mitaka, Japan. · Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterological Surgery, Tokyo Women's Medical University, Tokyo, Japan. · Department of Surgery, Kyorin University School of Medicine, Mitaka, Japan. · Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. · Department of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. ·Mod Pathol · Pubmed #25081753.

ABSTRACT: Mutations in RNF43, which encodes the ubiquitin E3 ligase ring finger protein 43, were recently found in intraductal papillary mucinous neoplasms of the pancreas. We evaluated somatic mutations of RNF43 and the expression of ring finger protein 43 as well as their associations with the molecular and clinicopathological features in 176 surgically resected intraductal papillary mucinous neoplasms. Frozen tissues were available for 57 cases and were used for next-generation sequencing analysis of the entire coding exons of RNF43. Formalin-fixed and paraffin-embedded tissues from all 176 cases were used for the immunohistochemical analysis of the expression of ring finger protein 43. Mutations detected with the next-generation sequencing analysis were validated by using Sanger sequencing. Statistical analysis was used to evaluate the associations between RNF43 aberrations and molecular and clinicopathological features including GNAS mutations, KRAS mutations, loss of SMA and MAD4 homologue expression, tumor protein 53 overexpression, tumor grade, histological type, mural nodule detection, macroscopic type, stage, recurrence, and survival. Somatic RNF43 mutations were found in 8 (14%) of the 57 examined cases, and included 5 frameshift mutations (p.F69fs, p.S264fs, p.L311fs, p.R363fs, and p.V490fs), 1 non-sense mutation (p.Q153X), and 2 missense mutations (p.I164N and p.P310A). The expression of ring finger protein 43 was downregulated in 52 (29.5%) of the 176 examined cases. RNF43 mutations were significantly associated with the downregulated expression of ring finger protein 43 (P=0.011), GNAS mutation (P=0.020), and mural nodule detection (P=0.038). The expression of ring finger protein 43 was not associated with any clinicopathological features except RNF43 mutation. These results indicate that RNF43 mutation might cause downregulation of the expression of ring finger protein 43 and play a crucial role and associate synergistically with GNAS mutation during development of intraductal papillary mucinous neoplasm of the pancreas.

12 Article The discrete nature and distinguishing molecular features of pancreatic intraductal tubulopapillary neoplasms and intraductal papillary mucinous neoplasms of the gastric type, pyloric gland variant. 2013

Yamaguchi, Hiroshi / Kuboki, Yuko / Hatori, Takashi / Yamamoto, Masakazu / Shimizu, Kyoko / Shiratori, Keiko / Shibata, Noriyuki / Shimizu, Michio / Furukawa, Toru. ·Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan; Department of Pathology, Saitama International Medical Center, Saitama Medical University, Hidaka, Japan. ·J Pathol · Pubmed #23893889.

ABSTRACT: Intraductal tubulopapillary neoplasms (ITPNs) are composed of tubulopapillary glands with high-grade dysplasia in the pancreatic duct. Intraductal papillary mucinous neoplasms of the gastric type, pyloric gland variant (IPMN-PGs) are composed of tubular glands mimicking pyloric glands with low-grade dysplasia and were formerly called intraductal tubular adenomas. Because of their apparent common tubular morphology, IPMN-PGs and ITPNs could be associated. While the former might progress to the latter, this has not been fully assessed. In this study, we compared the molecular features of ITPNs and IPMN-PGs to determine their association using formalin-fixed, paraffin-embedded tissues of 14 ITPNs and 15 IPMN-PGs. Somatic mutations in PIK3CA, GNAS, KRAS, and BRAF were determined by Sanger sequencing. Expression of phosphorylated AKT was examined by immunohistochemistry. Somatic PIK3CA mutations were found in 3 of 14 ITPNs (21.4%) but in none of the IPMN-PGs (p = 0.0996). In contrast, GNAS mutations were found in none of the ITPNs but in 9 of 15 IPMN-PGs (60.0%; p < 0.001). KRAS mutations were detected in 1 of 14 ITPNs (7.1%) and 12 of 15 IPMN-PGs (80.0%; p < 0.001). BRAF mutation was found in one ITPN but in none of the IPMN-PGs. Phosphorylated AKT expression in ITPNs was significantly more evident than that in IPMN-PGs (p = 0.0401). These results indicate that ITPNs and IPMN-PGs are molecularly distinct, suggesting that IPMN-PG does not progress to ITPN. Furthermore, the molecular features of IPMN-PGs are confirmed to be identical to those of IPMNs reported elsewhere. These results validate the current World Health Organization system that classifies pancreatic intraductal neoplasms into IPMN and ITPN and confirm that IPMN-PG is not a benign counterpart of ITPN. The term 'intraductal tubular adenoma' should be eliminated and replaced with IPMN-PG.

13 Article Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells. 2012

Furukawa, Toru / Tanji, Etsuko / Kuboki, Yuko / Hatori, Takashi / Yamamoto, Masakazu / Shimizu, Kyoko / Shibata, Noriyuki / Shiratori, Keiko. ·Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. furukawa.toru@twmu.ac.jp ·Mol Cancer · Pubmed #23227827.

ABSTRACT: BACKGROUND: Pancreatic cancer is characterized by constitutive activation of mitogen-activated protein kinase (MAPK). Activation of MAPK is associated with the upregulation of genes implicated in the proliferation and survival of pancreatic cancer cells. We hypothesized that knockdown of these MAPK-associated molecules could produce notable anticancer phenotypes. METHODS: A RNA interference-mediated knockdown screening of 78 MAPK-associated molecules previously identified was performed to find molecules specifically associated with proliferation of pancreatic cancer cells in vitro. Expression of an identified molecule in pancreatic cancer tissues was examined by immunohistochemistry. In vivo tumorigenicity of cancer cells with stable knockdown of the molecule was assayed by using xenograft models. Flow cytometry and live cell imaging were employed to assess an association of the molecule with cell cycle. RESULTS: The knockdown screening revealed that knockdown of SON, the gene encoding SON, which is a large serine/arginine-rich protein involved in RNA processing, substantially suppressed pancreatic cancer cell proliferation and survival in vitro and tumorigenicity in vivo. SON expression was higher in ductal adenocarcinomas than in cells of normal ducts and precursor lesions in pancreatic cancer tissues. Knockdown of SON induced G2/M arrest and apoptosis in cultured cancer cells. The suppressive effect of SON knockdown on proliferation was less pronounced in cultured normal duct epithelial cells. SON formed nuclear speckles in the interphase of the cell cycle and dispersed in the cytoplasm during mitosis. Live cell imaging showed that SON diffusely dispersed in the early mitotic phase, accumulated in some foci in the cytoplasm in the late mitotic phase, and gradually reassembled into speckles after mitosis. CONCLUSION: These results indicate that SON plays a critical role in the proliferation, survival, and tumorigenicity of pancreatic cancer cells, suggesting that SON is a novel therapeutic molecular target for pancreatic cancer.

14 Article Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. 2011

Furukawa, Toru / Kuboki, Yuko / Tanji, Etsuko / Yoshida, Shoko / Hatori, Takashi / Yamamoto, Masakazu / Shibata, Noriyuki / Shimizu, Kyoko / Kamatani, Naoyuki / Shiratori, Keiko. ·Institute for Integrated Medical Sciences, Institute of Gastroenterology, Deparment of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan. furukawa.toru@twmu.ac.jp ·Sci Rep · Pubmed #22355676.

ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are known. We performed whole-exome sequencing for a primary IPMN tissue, which uncovered somatic mutations in KCNF1, DYNC1H1, PGCP, STAB1, PTPRM, PRPF8, RNASE3, SPHKAP, MLXIPL, VPS13C, PRCC, GNAS, KRAS, RBM10, RNF43, DOCK2, and CENPF. We further analyzed GNAS mutations in archival cases of 118 IPMNs and 32 pancreatic ductal adenocarcinomas (PDAs), which revealed that 48 (40.7%) of the 118 IPMNs but none of the 32 PDAs harbored GNAS mutations. G-protein alpha-subunit encoded by GNAS and its downstream targets, phosphorylated substrates of protein kinase A, were evidently expressed in IPMN; the latter was associated with neoplastic grade. These results indicate that GNAS mutations are common and specific for IPMN, and activation of G-protein signaling appears to play a pivotal role in IPMN.