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Pancreatic Neoplasms: HELP
Articles by Waki Hosoda
Based on 20 articles published since 2010
(Why 20 articles?)
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Between 2010 and 2020, W. Hosoda wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Molecular Genetics of Pancreatic Neoplasms. 2016

Hosoda, Waki / Wood, Laura D. ·Department of Pathology, Johns Hopkins University, CRB-II 362, 1550 Orleans Street, Baltimore, MD 21231, USA. · Department of Pathology, Johns Hopkins University, CRB-II 345, 1550 Orleans Street, Baltimore, MD 21231, USA. Electronic address: ldelong1@jhmi.edu. ·Surg Pathol Clin · Pubmed #27926367.

ABSTRACT: Pancreatic neoplasms have a wide range of histologic types with distinct clinical outcomes. Recent advances in high-throughput sequencing technologies have greatly deepened our understanding of pancreatic neoplasms. Now, the exomes of major histologic types of pancreatic neoplasms have been sequenced, and their genetic landscapes have been revealed. This article reviews the molecular changes underlying pancreatic neoplasms, with a special focus on the genetic changes that characterize the histologic types of pancreatic neoplasms. Emphasis is also made on the molecular features of key genes that have the potential for therapeutic targets.

2 Article Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. 2019

Fischer, Catherine G / Beleva Guthrie, Violeta / Braxton, Alicia M / Zheng, Lily / Wang, Pei / Song, Qianqian / Griffin, James F / Chianchiano, Peter E / Hosoda, Waki / Niknafs, Noushin / Springer, Simeon / Dal Molin, Marco / Masica, David / Scharpf, Robert B / Thompson, Elizabeth D / He, Jin / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Lennon, Anne Marie / Jiao, Yuchen / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: karchin@jhu.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. ·Gastroenterology · Pubmed #31175866.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

3 Article Surgery for Pancreatic Neuroendocrine Tumor G3 and Carcinoma G3 Should be Considered Separately. 2019

Yoshida, Tsukasa / Hijioka, Susumu / Hosoda, Waki / Ueno, Makoto / Furukawa, Masayuki / Kobayashi, Noritoshi / Ikeda, Masafumi / Ito, Tetsuhide / Kodama, Yuzo / Morizane, Chigusa / Notohara, Kenji / Taguchi, Hiroki / Kitano, Masayuki / Yane, Kei / Tsuchiya, Yoshiaki / Komoto, Izumi / Tanaka, Hiroki / Tsuji, Akihito / Hashigo, Syunpei / Mine, Tetsuya / Kanno, Atsushi / Murohisa, Go / Miyabe, Katsuyuki / Takagi, Tadayuki / Matayoshi, Nobutaka / Sakaguchi, Masafumi / Ishii, Hiroshi / Kojima, Yasushi / Matsuo, Keitaro / Yoshitomi, Hideyuki / Nakamori, Shoji / Yanagimoto, Hiroaki / Yatabe, Yasushi / Furuse, Junji / Mizuno, Nobumasa. ·Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Gastroenterology, Kizawa Memorial Hospital, Minokamo, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. shijioka@ncc.go.jp. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. shijioka@ncc.go.jp. · Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, Fukuoka, Japan. · Department of Oncology, Yokohama City University Hospital, Yokohama, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan. · Department of Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. · Department of Gastroenterology and Hepatology, Kinki University, Faculty of Medicine, Sayama, Japan. · Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan. · Department of Digestive Surgery, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan. · Department of Gastroenterology, Suzuka General Hospital, Suzuka, Japan. · Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan. · Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. · Department of Gastroenterology, Tokai University School of Medicine, Isehara, Japan. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Department of Gastroenterology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan. · Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. · Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan. · Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Gastroenterology, Saiseikai Kumamoto Hospital, Kumamoto, Japan. · Department of Gastroenterology, Shikoku Cancer Center, Matsuyama, Japan. · Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. · Department of Gastroenterology, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan. · Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. · Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan. · Department of Hepato-biliary-Pancreatic Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. · Department of Surgery, Kansai Medical University Hospital, Maikata, Japan. · Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan. ·Ann Surg Oncol · Pubmed #30863939.

ABSTRACT: BACKGROUND: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. METHODS: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). RESULTS: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. CONCLUSION: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

4 Article Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. 2019

Kuboki, Yuko / Fischer, Catherine G / Beleva Guthrie, Violeta / Huang, Wenjie / Yu, Jun / Chianchiano, Peter / Hosoda, Waki / Zhang, Hao / Zheng, Lily / Shao, Xiaoshan / Thompson, Elizabeth D / Waters, Kevin / Poling, Justin / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #30430578.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next-generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

5 Article IPMNs with co-occurring invasive cancers: neighbours but not always relatives. 2018

Felsenstein, Matthäus / Noë, Michaël / Masica, David L / Hosoda, Waki / Chianchiano, Peter / Fischer, Catherine G / Lionheart, Gemma / Brosens, Lodewijk A A / Pea, Antonio / Yu, Jun / Gemenetzis, Georgios / Groot, Vincent P / Makary, Martin A / He, Jin / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Goggins, Michael G / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #29500184.

ABSTRACT: OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

6 Article Rb Loss and 2017

Hijioka, Susumu / Hosoda, Waki / Matsuo, Keitaro / Ueno, Makoto / Furukawa, Masayuki / Yoshitomi, Hideyuki / Kobayashi, Noritoshi / Ikeda, Masafumi / Ito, Tetsuhide / Nakamori, Shoji / Ishii, Hiroshi / Kodama, Yuzo / Morizane, Chigusa / Okusaka, Takuji / Yanagimoto, Hiroaki / Notohara, Kenji / Taguchi, Hiroki / Kitano, Masayuki / Yane, Kei / Maguchi, Hiroyuki / Tsuchiya, Yoshiaki / Komoto, Izumi / Tanaka, Hiroki / Tsuji, Akihito / Hashigo, Syunpei / Kawaguchi, Yoshiaki / Mine, Tetsuya / Kanno, Atsushi / Murohisa, Go / Miyabe, Katsuyuki / Takagi, Tadayuki / Matayoshi, Nobutaka / Yoshida, Tsukasa / Hara, Kazuo / Imamura, Masayuki / Furuse, Junji / Yatabe, Yasushi / Mizuno, Nobumasa. ·Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. rizasusu@aichi-cc.jp. · Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan. · Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. · Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, Fukuoka, Japan. · Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. · Department of Oncology, Yokohama City University Hospital, Yokohama, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Hepato-Biliary-Pancreatic Surgery, Osaka National Hospital, Osaka, Japan. · Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. · Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Surgery, Kansai Medical University, Hirakata, Japan. · Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan. · Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. · Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Sayama, Japan. · Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan. · Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan. · Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan. · Department of Gastroenterology, Suzuka General Hospital, Suzuka, Japan. · Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan. · Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. · Department of Gastroenterology, Tokai University School of Medicine, Isehara, Japan. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Department of Gastroenterology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan. · Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. · Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan. · Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Neuroendocrine Tumor Center, Kansai Electric Power Hospital, Osaka, Japan. · Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan. ·Clin Cancer Res · Pubmed #28455360.

ABSTRACT:

7 Article Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. 2017

Hosoda, Waki / Chianchiano, Peter / Griffin, James F / Pittman, Meredith E / Brosens, Lodewijk Aa / Noë, Michaël / Yu, Jun / Shindo, Koji / Suenaga, Masaya / Rezaee, Neda / Yonescu, Raluca / Ning, Yi / Albores-Saavedra, Jorge / Yoshizawa, Naohiko / Harada, Kenichi / Yoshizawa, Akihiko / Hanada, Keiji / Yonehara, Shuji / Shimizu, Michio / Uehara, Takeshi / Samra, Jaswinder S / Gill, Anthony J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico. · The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. · Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. · Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. · Center for Gastroendoscopy, Onomichi General Hospital, Onomichi, Japan. · Department of Pathology, Onomichi General Hospital, Onomich, Japan. · Diagnostic Pathology Center, Hakujikai Memorial Hospital, Tokyo, Japan. · Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and Discipline of Surgery, University of Sydney, Sydney, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, Australia. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·J Pathol · Pubmed #28188630.

ABSTRACT: High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

8 Article Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis. 2016

Hackeng, Wenzel M / Brosens, Lodewijk A A / Poruk, Katherine E / Noë, Michaël / Hosoda, Waki / Poling, Justin S / Rizzo, Anthony / Campbell-Thompson, Martha / Atkinson, Mark A / Konukiewitz, Björn / Klöppel, Günter / Heaphy, Christopher M / Meeker, Alan K / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, Technical University Munich, 81675 Munich, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu. ·Hum Pathol · Pubmed #27342911.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.

9 Article Risk factors for postoperative recurrence of intraductal papillary mucinous neoplasms of the pancreas based on a long-term follow-up study: proposals for follow-up strategies. 2015

Yogi, Tatsuji / Hijioka, Susumu / Imaoka, Hiroshi / Mizuno, Nobumasa / Hara, Kazuo / Tajika, Masahiro / Tanaka, Tsutomu / Ishihara, Makoto / Shimizu, Yasuhiro / Hosoda, Waki / Yatabe, Yasushi / Niwa, Yasumasa / Yoshimura, Kenichi / Bhatia, Vikram / Fujita, Jiro / Yamao, Kenji. ·Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases (First Department of Internal Medicine), Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. · Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Gastrointestinal Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan. · Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan. · Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India. ·J Hepatobiliary Pancreat Sci · Pubmed #26148131.

ABSTRACT: BACKGROUND: The aim of this study was to examine the associations between postoperative clinicopathological features of intraductal papillary mucinous neoplasm (IPMN) and recurrence over a long follow-up period. METHODS: We retrospectively assessed 153 IPMN patients who underwent resection. RESULTS: The resected tumors showed low/intermediate-grade dysplasia (LGD/IGD), high-grade dysplasia (HGD), T1a (stromal invasion ≤5 mm), and invasive intraductal papillary mucinous carcinoma (IPMC), in 54.9%, 22.2%, 4.6%, and 18.3% of patients, respectively. The median follow-up period after surgery was 46.4 (6.0-216.3) months, with an overall recurrence rate of 17.0%; the recurrence rates by histological type were 6.0%, 5.9%, 42.9%, and 57.1% for LGD/IGD, HGD, T1a, and invasive IPMC, respectively. Multivariate analysis revealed that recurrences related with tumor location, mural nodule size, presence of invasive cancer, lymph node metastasis, IPMN in the remnant pancreas, and main pancreatic duct dilatation after surgery. Recurrence occurred within the remnant pancreas in all LGD-T1a patients and as extrapancreatic metastasis in all patients with invasive IPMC. Of the total recurrences, 15.4% occurred over 5 years postoperatively. CONCLUSIONS: The postoperative follow-up protocol for patients with LGD-T1a should be similar to non-resected IPMN, and that for invasive IPMC should be the same as for pancreatic ductal adenocarcinoma patients.

10 Article GNAS mutation is a frequent event in pancreatic intraductal papillary mucinous neoplasms and associated adenocarcinomas. 2015

Hosoda, Waki / Sasaki, Eiichi / Murakami, Yoshiko / Yamao, Kenji / Shimizu, Yasuhiro / Yatabe, Yasushi. ·Department of Pathology and Molecular Diagnostics, Aichi Cancer Centre Hospital, Kanokoden 1-1, Chikusa-ku, Nagoya, 464-8681, Japan. ·Virchows Arch · Pubmed #25796395.

ABSTRACT: In contrast to pancreatic ductal adenocarcinomas (PDAs), intraductal papillary mucinous neoplasms (IPMNs) frequently harbour GNAS mutations. To characterise GNAS-mutated pancreatic carcinomas, we examined mutations of GNAS and KRAS in 290 pancreatic adenocarcinomas and 77 pancreatic intraepithelial neoplasias (PanINs). In 64 % (39/61) of IPMNs and 37 % (11/30) of IPMN-associated adenocarcinomas, a GNAS mutation was found. GNAS mutations were frequent (78 %, 7/9) in mucinous carcinomas, with or without associated IPMN. In contrast, GNAS mutations were rarely observed in PDAs (1 %, 1/88) and PanINs (3 %, 2/77), and not at all in mucinous cystic neoplasms (MCNs) (0/10), neuroendocrine neoplasms (0/52), acinar cell neoplasms (0/16), serous cystadenomas (0/10), and solid-pseudopapillary neoplasms (0/14). We found GNAS mutations in 55/91 IPMNs with or without associated invasive carcinoma, solely in intestinal-type (78 %, 21/27) and gastric-type (62 %, 34/55) IPMNs. Of the IPMN-associated adenocarcinomas, mucinous-subtype tumours harboured GNAS mutations more frequently (83 %, 5/6) than tubular-subtype tumours (25 %, 6/24) (p = 0.02). We separately analysed GNAS in the adenocarcinoma and the IPMN component in the IPMN-associated adenocarcinomas. In all mucinous-subtype tumours, the two components exhibited identical genotypes. In contrast, the two components in 8 of 24 tubular-subtype tumours exhibited different genotypes, indicating intratumour heterogeneity. In conclusion, mucinous carcinomas with or without associated IPMN as well as IPMNs frequently harbour a GNAS mutation, reinforcing the notion that these constitute a spectrum of pancreatic tumours. Clinically and pathologically, these tumours are associated, but GNAS mutation sheds further light on this spectrum.

11 Article Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? 2015

Hijioka, Susumu / Hosoda, Waki / Mizuno, Nobumasa / Hara, Kazuo / Imaoka, Hiroshi / Bhatia, Vikram / Mekky, Mohamed A / Tajika, Masahiro / Tanaka, Tsutomu / Ishihara, Makoto / Yogi, Tatsuji / Tsutumi, Hideharu / Fujiyoshi, Toshihisa / Sato, Takamitsu / Hieda, Nobuhiro / Yoshida, Tsukasa / Okuno, Nozomi / Shimizu, Yasuhiro / Yatabe, Yasushi / Niwa, Yasumasa / Yamao, Kenji. ·Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan, rizasusu@aichi-cc.jp. ·J Gastroenterol · Pubmed #25142799.

ABSTRACT: BACKGROUND: The WHO classified pancreatic neuroendocrine neoplasms in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to the Ki67 labeling index (LI). However, the clinical behavior of NEC is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs. METHODS: We retrospectively evaluated the clinicopathological characteristics, KRAS mutation status, treatment response, and the overall survival of eleven pNEC patients diagnosed between 2001 and 2014 according to the WHO 2010. We subclassified WHO-NECs into well-differentiated NEC (WDNEC) and poorly differentiated NEC (PDNEC). The latter was further subdivided into large-cell and small-cell subtypes. RESULTS: The median Ki67 LI was 69.1% (range 40-95%). Eleven WHO-NECs were subclassified into 4 WDNECs and 7 PDNECs. The latter was further separated into 3 large-cell and 4 small-cell subtypes. Comparisons of WDNEC vs. PDNEC revealed the following traits: hypervascularity on CT, 50% (2/4) vs. 0% (0/7) (P = 0.109); median Ki67 LI, 46.3% (40-53%) vs. 85% (54-95%) (P = 0.001); Rb immunopositivity, 100% (4/4) vs. 14% (1/7) (P = 0.015); KRAS mutations, 0% (0/4) vs. 86% (6/7) (P = 0.015); response rates to platinum-based chemotherapy, 0% (0/2) vs. 100% (4/4) (P = 0.067), and median survival, 227 vs. 186 days (P = 0.227). CONCLUSIONS: The WHO-NEC category may be composed of heterogeneous disease entities, namely WDNEC and PDNEC. These subgroups tended to exhibit differing profiles of Ki67 LI, Rb immunopositivity and KRAS mutation, and distinct response to chemotherapy. Further studies for the reevaluation of the current WHO 2010 classification are warranted.

12 Article Combination of cyst fluid CEA and CA 125 is an accurate diagnostic tool for differentiating mucinous cystic neoplasms from intraductal papillary mucinous neoplasms. 2014

Nagashio, Yoshikuni / Hijioka, Susumu / Mizuno, Nobumasa / Hara, Kazuo / Imaoka, Hiroshi / Bhatia, Vikram / Niwa, Yasumasa / Tajika, Masahiro / Tanaka, Tsutomu / Ishihara, Makoto / Shimizu, Yasuhiro / Hosoda, Waki / Yatabe, Yasushi / Yamao, Kenji. ·Department of Gasroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. · Department of Medical Hepatology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi 110070, India. · Department of Endoscopy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. · Department of Gastrointestinal Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. · Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. · Department of Gasroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Electronic address: kyamao@aichi-cc.jp. ·Pancreatology · Pubmed #25458668.

ABSTRACT: BACKGROUND/OBJECTIVES: Despite advances in imaging techniques, diagnosis and management of pancreatic cystic lesions still remains challenging. The objective of this study was to determine the utility of cyst fluid analysis (CEA, CA 19-9, CA 125, amylase, and cytology) in categorizing pancreatic cystic lesions, and in differentiating malignant from benign cystic lesions. METHODS: A retrospective analysis of 68 patients with histologically and clinically confirmed cystic lesions was performed. Cyst fluid was obtained by surgical resection (n = 45) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) (n = 23). Cyst fluid tumor markers and amylase were measured and compared between the cyst types. RESULTS: Receiver operating characteristic (ROC) curve analysis of the tumor markers demonstrated that cyst fluid CEA provided the greatest area under ROC curve (AUC) (0.884) for differentiating mucinous versus non-mucinous cystic lesions. When a CEA cutoff value was set at 67.3 ng/ml, the sensitivity, specificity and accuracy for diagnosing mucinous cysts were 89.2%, 77.8%, and 84.4%, respectively. The combination of cyst fluid CEA content >67.3 ng/ml and cyst fluid CA 125 content >10.0 U/ml segregated 77.8% (14/18) of mucinous cystic neoplasms (MCNs) from other cyst subtypes. On the other hand, no fluid marker was useful for differentiating malignant versus benign cystic lesions. Although cytology (accuracy 83.3%) more accurately diagnosed malignant cysts than CEA (accuracy 65.6%), it lacked sensitivity (35.3%). CONCLUSIONS: Our results demonstrate that cyst fluid CEA can be a helpful marker in differentiating mucinous from non-mucinous, but not malignant from benign cystic lesions. A combined CEA and CA 125 approach may help segregate MCNs from IPMNs.

13 Article Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors. 2014

Hasegawa, Toshiyuki / Yamao, Kenji / Hijioka, Susumu / Bhatia, Vikram / Mizuno, Nobumasa / Hara, Kazuo / Imaoka, Hiroshi / Niwa, Yasumasa / Tajika, Masahiro / Kondo, Shinya / Tanaka, Tutomu / Shimizu, Yasuhiro / Kinoshita, Taira / Kohsaki, Takuhiro / Nishimori, Isao / Iwasaki, Shinji / Saibara, Toshiji / Hosoda, Waki / Yatabe, Yasushi. ·Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Medical Hepatology, Institute of Liver and Biliary Sciences, Delhi, India. · Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Gastrointestinal Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. · Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan. · Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan. ·Endoscopy · Pubmed #24218309.

ABSTRACT: BACKGROUND AND STUDY AIM: Malignancy in pancreatic neuroendocrine tumors (PNETs) is graded by assessing the resected specimens according to the World Health Organization (WHO) 2010 criteria. The feasibility of such grading using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens remains unclear. The aim of this study was to ascertain the optimal method of measuring the Ki-67 index in EUS-FNA specimens, using resected specimens as the criterion standard. PATIENTS AND METHODS: A total of 58 consecutive patients diagnosed with PNETs between March 1998 and May 2011 were included. The study measured intratumoral Ki-67 index heterogeneity, concordance rates of PNET grading by EUS-FNA with grade of the resected tumor, optimal method of measuring the Ki-67 index in EUS-FNA specimens, and survival analysis based on EUS-FNA specimen grading. RESULTS: Intratumoral dispersion of Ki-67 index in resected specimens was 0.033 for Grade 1 and 0.782 for Grade 2 tumors (P<0.001). Concordance rates for WHO classification between EUS-FNA and resected specimens were 74.0% using the mean Ki-67 index in EUS-FNA specimens and 77.8% using the highest Ki-67 index. The concordance rate rose to 90% when EUS-FNA samples with less than 2000 tumor cells were excluded (26% of EUS-FNA cases). The Kaplan-Meier survival curves were significantly stratified by the EUS-FNA grading of PNETs with 5-year survival rates of 100%, 58.3%, and 0%, for Grade 1, Grade 2, and neuroendocrine carcinoma (NEC) tumors, respectively. CONCLUSIONS: Grading of PNETs by the highest Ki-67 index in EUS-FNA specimens with adequate cellularity has a high concordance with grading of resected specimens, and can predict long term patient survival with high accuracy.

14 Article BCL10 as a useful marker for pancreatic acinar cell carcinoma, especially using endoscopic ultrasound cytology specimens. 2013

Hosoda, Waki / Sasaki, Eiichi / Murakami, Yoshiko / Yamao, Kenji / Shimizu, Yasuhiro / Yatabe, Yasushi. ·Department of Pathology, Aichi Cancer Center Hospital, Nagoya, Japan. ·Pathol Int · Pubmed #23530562.

ABSTRACT: Acinar cell carcinomas (ACCs) of the pancreas are characterized by the histological and immunohistochemical features of acinar cell differentiation. Recently, BCL10, originally identified as a recurrent t(1;14)(p22;q32) translocation in MALT B-cell lymphoma, was found to be immunohistochemically positive in some solid tumors, including ACC. To evaluate its diagnostic efficacy, we performed BCL10 immunohistochemistry and evaluated molecular markers correlated to pancreatic tumor lineages (neuroendocrine markers and a mutation analysis of KRAS and GNAS) using samples from 126 pancreatic tumors (17 ACCs, 24 pancreatic ductal adenocarcinomas, 4 adenosquamous carcinomas, 9 intraductal papillary mucinous neoplasms, 10 mucinous cystic neoplasms, 44 neuroendocrine tumors, 9 serous cystic tumors and 10 solid-pseudopapillary neoplasms). BCL10 was exclusively expressed in normal acini. In pancreatic tumors, 14 of 17 (82%) ACCs and 2 of 4 (50%) adenosquamous carcinomas were positive, while the other subtypes were almost negative. We subsequently examined the diagnostic utility of BCL10 in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens using 57 pancreatic tumors. BLC10 correctly identified ACCs (9/13) and adenosquamous carcinomas (2/4) but none of the other subtypes (n = 41). Therefore, we suggested that BCL10 expression is a useful marker for acinar cell differentiation, particularly in the diagnosis of EUS-FNA specimens.

15 Article Predictors of malignancy in intraductal papillary mucinous neoplasm of the pancreas: analysis of 310 pancreatic resection patients at multiple high-volume centers. 2013

Shimizu, Yasuhiro / Yamaue, Hiroki / Maguchi, Hiroyuki / Yamao, Kenji / Hirono, Seiko / Osanai, Manabu / Hijioka, Susumu / Hosoda, Waki / Nakamura, Yasushi / Shinohara, Toshiya / Yanagisawa, Akio. ·Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. yshimizu@aichi-cc.jp ·Pancreas · Pubmed #23508017.

ABSTRACT: OBJECTIVES: The present study was a retrospective investigation of predictors of malignancy in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. METHODS: The subjects were 310 patients who underwent pancreatic resection at 3 high-volume centers. Preoperative laboratory and imaging findings were analyzed in logistic regression analyses. Endoscopic ultrasonography measurements were essential for the size of mural nodules, and a central review was conducted for pathological diagnosis. RESULTS: Pathological diagnosis was benign IPMN in 150 cases and malignant in 160 (noninvasive carcinoma, n = 100; invasive, n = 60). In multivariate analysis, size of mural nodules, diameter of main pancreatic duct, and cyst size of branch pancreatic duct were independent predictors of malignancy, and areas under the receiver operating characteristic curve for these 3 factors were 0.798, 0.643, and 0.601, respectively. With 7 mm taken as the cutoff value for the size of mural nodules, the diagnosis of malignant IPMN had sensitivity of 74.3% and specificity of 72.7%. Carcinoma without nodules was present in 15 patients (15/160 [9.4%]). CONCLUSIONS: The size of mural nodules measured with endoscopic ultrasonography showed high predictive ability. However, about 10% of carcinoma patients did not have nodules, and the handling of the diagnosis in such cases is a problem for the future.

16 Article Diagnostic ability and factors affecting accuracy of endoscopic ultrasound-guided fine needle aspiration for pancreatic solid lesions: Japanese large single center experience. 2013

Haba, Shin / Yamao, Kenji / Bhatia, Vikram / Mizuno, Nobumasa / Hara, Kazuo / Hijioka, Susumu / Imaoka, Hiroshi / Niwa, Yasumasa / Tajika, Masahiro / Kondo, Shinya / Tanaka, Tsutomu / Shimizu, Yasuhiro / Yatabe, Yasushi / Hosoda, Waki / Kawakami, Hiroshi / Sakamoto, Naoya. ·Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. ·J Gastroenterol · Pubmed #23090002.

ABSTRACT: BACKGROUND: Several studies have investigated the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for pancreatic lesions, but they have included only limited patient populations. This study aimed to clarify the diagnostic accuracy of EUS-FNA in a large number of pancreatic lesions, and to describe the factors that influence it. METHODS: From March 1997 to May 2010, 944 consecutive patients who had undergone EUS-FNA for pancreatic solid lesions were evaluated retrospectively. Factors affecting EUS-FNA accuracy were then analyzed. RESULTS: A total of 996 solid pancreatic lesions were sampled by EUS-FNA. The overall sampling adequacy and diagnostic accuracy of these lesions were 99.3 % (989/996) and 91.8 % (918/996), respectively. The sensitivity and specificity for differentiating malignant from benign lesions were 91.5 % (793/867) and 97.7 % (126/129), respectively. The diagnostic performance was significantly higher when both cytological and cell-block examinations were carried out than with only cytological examination. In multivariate analysis, final diagnosis, location of lesion, lesion size, availability of on-site cytopathological evaluation, and experience of EUS-FNA procedure were independent factors affecting the accuracy of EUS-FNA. On-site cytopathological evaluation and lesion size were found to be the most weighted factors affecting diagnostic accuracy. CONCLUSIONS: EUS-FNA for pancreatic solid lesions yielded a high accuracy and low complication rate. Both cytological and cell-block preparations and on-site cytopathological evaluation contributed to improve the accuracy. The diagnostic ability of EUS-FNA was less for smaller lesions, and repeated procedures may be needed if malignancy is suspected.

17 Article Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. 2013

Ogura, Takeshi / Yamao, Kenji / Hara, Kazuo / Mizuno, Nobumasa / Hijioka, Susumu / Imaoka, Hiroshi / Sawaki, Akira / Niwa, Yasumasa / Tajika, Masahiro / Kondo, Shinya / Tanaka, Tsutomu / Shimizu, Yasuhiro / Bhatia, Vikram / Higuchi, Kazuhide / Hosoda, Waki / Yatabe, Yasushi. ·Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan. ·J Gastroenterol · Pubmed #22983505.

ABSTRACT: BACKGROUND: Although recent reports indicate that K-ras mutation status is a biomarker that acts as a prognostic factor, only a few analyses of K-ras mutation subtypes have been published. In addition, there are no reports that analyze overall survival and prognostic factors according to K-ras mutation status and subtypes in only unresectable pancreatic cancer (PC) determined from tissues obtained by endoscopic ultrasound-guided fine-needle aspiration. METHODS: We retrospectively analyzed 242 patients who were diagnosed as having unresectable PC with available histological diagnosis. Clinical data collected included sex, age, Eastern Cooperative Oncology Group performance status, carbohydrate antigen (CA) 19-9, primary tumor location, stage (local or metastatic) according to TNM staging, first-line chemotherapy, K-ras mutation status and subtypes (G12D, G12V, and G12R), and overall survival. We analyzed the negative prognostic factors for reduced overall survival in unresectable PC patients using these data. RESULTS: From multivariate analysis, CA19-9 ≥1000 U/ml (hazard ratio [HR] 1.78, 95 % confidence interval [CI] 1.28-2.46, P < 0.01), metastatic stage (HR 2.26, 95 % CI 1.58-3.24, P < 0.01), and mutant-K-ras (HR 1.76, 95 % CI 1.03-3.01, P = 0.04) were negative prognostic factors, indicating a reduced survival. Among the patients who had K-ras mutation subtypes, CA19-9 ≥1000 U/ml (HR 1.65, 95 % CI 1.12-2.37, P < 0.01), metastatic stage (HR 2.12, 95 % CI 1.44-3.14, P < 0.01), and the presence of the G12D or G12R mutations (HR 1.60, 95 % CI 1.11-2.28) were negative prognostic factors for overall survival. CONCLUSIONS: K-ras mutation status and subtypes may be associated with survival duration in pancreatic cancer patients.

18 Article Clinical impact of K-ras mutation analysis in EUS-guided FNA specimens from pancreatic masses. 2012

Ogura, Takeshi / Yamao, Kenji / Sawaki, Akira / Mizuno, Nobumasa / Hara, Kazuo / Hijioka, Susumu / Niwa, Yasumasa / Tajika, Masahiro / Kondo, Shinya / Shimizu, Yasuhiro / Bhatia, Vikram / Higuchi, Kazuhide / Hosoda, Waki / Yatabe, Yasushi. ·Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. ·Gastrointest Endosc · Pubmed #22284089.

ABSTRACT: BACKGROUND: EUS-guided FNA (EUS-FNA) is considered optimal for differentially diagnosing pancreatic masses. However, the sensitivity of EUS-FNA ranges from 65% to 95%, respectively, which requires improvement. OBJECTIVE: To evaluate clinical impact of K-ras mutation analysis in EUS-FNA specimens from pancreatic masses. DESIGN: Prospective registration, single-center study. SETTING: Tertiary referral center. PATIENTS: This study involved 394 consecutive patients with pancreatic masses (307 pancreatic ductal adenocarcinomas [PDACs], 47 pancreatic inflammatory lesions, and 40 other types of tumors) who underwent EUS-FNA and analysis of K-ras mutations. INTERVENTION: EUS-FNA, Cycleave polymerase chain reaction. MAIN OUTCOME MEASUREMENTS: Improvement of the diagnostic accuracy by K-ras mutation analysis; absence of K-ras mutations in non-PDAC masses. RESULTS: K-ras mutations were detected in 266 of 307 PDAC aspirates (87%) and in 3 of 87 non-PDAC masses (3%). K-ras mutations were detected in 18 of 39 patients (46%) who remained cytohistopathologically undiagnosed. The sensitivity, specificity, positive and negative predictive values, and accuracy of cytohistopathological and K-ras mutation analyses alone were 87%, 100%, 100%, 54%, and 89%, respectively, and, when combined, were 93%, 100%, 100%, 68%, and 94%, respectively. Adding K-ras mutation analysis to standard cytohistopathological assessment increased the sensitivity and accuracy of EUS-FNA by 6% (P < .001) and 5% (P < .001), respectively. LIMITATIONS: Single-center study. CONCLUSIONS: K-ras mutation analysis may be helpful in patients with suspected PDAC yet inconclusive EUS-FNA findings. K-ras mutations were extremely rare in pancreatic inflammation and other pancreatic tumors.

19 Article Role of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in diagnosing metastasis to the pancreas: a tertiary center experience. 2011

Hijioka, S / Matsuo, K / Mizuno, N / Hara, K / Mekky, M A / Vikram, B / Hosoda, W / Yatabe, Y / Shimizu, Y / Kondo, S / Tajika, M / Niwa, Y / Tamada, K / Yamao, K. ·Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt. rizasusu@isis.ocn.ne.jp ·Pancreatology · Pubmed #21894056.

ABSTRACT: BACKGROUND: Metastasis to the pancreas (MP) is a rare entity that is difficult to identify by imaging alone. Few reports have described endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) findings. Herein, we try to describe the EUS and EUS-FNA characteristics of MP. METHODS: This retrospective study compared 28 patients with MP (13 males; mean age: 60.1 ± 12.6 years) and 60 control patients (30 males; 62.7 ± 11.5 years) with pancreatic ductal adenocarcinoma (PDAC). All lesions were characterized by EUS, and MP was diagnosed by EUS-FNA (n = 16), surgery (n = 6) or both (n = 6). RESULTS: Multivariate logistic regression revealed that the presence of regular borders (p = 0.004; OR: 8.81, 95% CI: 1.97-39.4), the absence of retention cysts (p = 0.045; OR: 12.5, 95% CI: 1.06-147.0), and the absence of main pancreatic duct (MPD) dilation (p = 0.003; OR: 8.18, 95% CI: 2.04-32.8) were predictors of MP rather than PDAC. The EUS-FNA sampling adequacy was 95.4% (21/22), and the correct diagnosis was obtained in 95.2% (20/21) of cases when K-ras mutation analysis and/or immunostaining were added. CONCLUSION: The presence of regular borders, the absence of retention cysts and the presence of nondilated MPD on EUS indicate MP rather than PDAC. This diagnosis can be accurately confirmed by EUS-FNA with immunostaining and/or K-ras analysis.

20 Article Diagnostic approach to pancreatic tumors with the specimens of endoscopic ultrasound-guided fine needle aspiration. 2010

Hosoda, Waki / Takagi, Tadayuki / Mizuno, Nobumasa / Shimizu, Yasuhiro / Sano, Tsuyoshi / Yamao, Kenji / Yatabe, Yasushi. ·Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan. ·Pathol Int · Pubmed #20518885.

ABSTRACT: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has enabled clinicians to histologically diagnose pancreatic tumors. However, EUS-FNA specimens often result in tiny fragmented tissues, so auxiliary utilities are necessary. Using immunostaining of CK7, CDX2, neuroendocrine markers and KRAS mutation analysis, we examined 57 FNA cell block sections and 61 surgically-resected specimens (25 invasive ductal carcinomas, 25 endocrine tumors, and 11 acinar cell tumors). In the majority of the matched pairs, the diagnoses between EUS-FNA and surgical specimens were concordant using the following criteria: neuroendocrine markers negative, CK7 positive, and mutated KRAS gene for invasive ductal carcinomas; neuroendocrine markers diffusely positive, CK7 and CDX2 negative, and wild-type KRAS gene for well-differentiated endocrine tumors; and neuroendocrine markers no more than focal positive, CK7 and CDX2 with various staining patterns, and wild-type KRAS gene for acinar cell carcinomas. Expression of CK7 and/or CDX2 in addition to KRAS mutations were occasionally seen in endocrine carcinomas, but not in well-differentiated endocrine tumors, suggesting that ductal differentiation in an endocrine tumor may be a predictor of aggressive disease. The usefulness of these markers was confirmed using 13 additional pancreatic tumors, prospectively. Although minimal in selection, these markers are helpful in making diagnosis from EUS-FNA specimens of the major pancreatic tumors.