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Pancreatic Neoplasms: HELP
Articles by Koji Shindo
Based on 36 articles published since 2010
(Why 36 articles?)
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Between 2010 and 2020, Koji Shindo wrote the following 36 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas. 2019

Ohtsuka, Takao / Tomosugi, Takahiro / Kimura, Ryuichiro / Nakamura, So / Miyasaka, Yoshihiro / Nakata, Kohei / Mori, Yasuhisa / Morita, Makiko / Torata, Nobuhiro / Shindo, Koji / Ohuchida, Kenoki / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. takao-o@surg1.med.kyushu-u.ac.jp. · Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka, Japan. takao-o@surg1.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ·Surg Today · Pubmed #30879148.

ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is characterized by cystic dilation of the pancreatic duct, caused by mucin hypersecretion, with slow progression via the adenoma-carcinoma sequence mechanism. Mutation of GNAS at codon 201 is found exclusively in IPMNs, occurring at a rate of 41-75%. Recent advances in molecular biological techniques have demonstrated that GNAS mutation might play a role in the transformation of IPMNs after the appearance of neoplastic cells, rather than in the tumorigenesis of IPMNs. GNAS mutation is observed frequently in the intestinal subtype of IPMNs with MUC2 expression, and less frequently in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC). Research has focused on assessing GNAS mutation status in clinical practice using various samples. In this review, we discuss the clinical application of GNAS mutation assessment to differentiate invasive IPMNs from concomitant PDAC, examine the clonality of recurrent IPMNs in the remnant pancreas using resected specimens, and differentiate pancreatic cystic lesions using cystic fluid collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), duodenal fluid, and serum liquid biopsy samples.

2 Clinical Trial Mutations in the pancreatic secretory enzymes 2018

Tamura, Koji / Yu, Jun / Hata, Tatsuo / Suenaga, Masaya / Shindo, Koji / Abe, Toshiya / MacGregor-Das, Anne / Borges, Michael / Wolfgang, Christopher L / Weiss, Matthew J / He, Jin / Canto, Marcia Irene / Petersen, Gloria M / Gallinger, Steven / Syngal, Sapna / Brand, Randall E / Rustgi, Anil / Olson, Sara H / Stoffel, Elena / Cote, Michele L / Zogopoulos, George / Potash, James B / Goes, Fernando S / McCombie, Richard W / Zandi, Peter P / Pirooznia, Mehdi / Kramer, Melissa / Parla, Jennifer / Eshleman, James R / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Health Sciences Research, Mayo Clinic, Rochester, MN 55905. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. · Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. · The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9. · The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. · InGenious Targeting Laboratory, Ronkonkoma, NY 11779. · Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #29669919.

ABSTRACT: To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of

3 Article Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis. 2019

Yan, Zilong / Ohuchida, Kenoki / Fei, Shuang / Zheng, Biao / Guan, Weiyu / Feng, Haimin / Kibe, Shin / Ando, Yohei / Koikawa, Kazuhiro / Abe, Toshiya / Iwamoto, Chika / Shindo, Koji / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of General Surgery, Shenzhen University General Hospital, Shenzhen, China. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Cancer Center of Kyushu University Hospital, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. mnaka@surg1.med.kyushu-u.ac.jp. ·J Exp Clin Cancer Res · Pubmed #31133044.

ABSTRACT: BACKGROUND: Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer-stromal interaction. METHODS: Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor. RESULTS: Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer-stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model. CONCLUSIONS: These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis.

4 Article CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis. 2019

Yan, Zilong / Ohuchida, Kenoki / Zheng, Biao / Okumura, Takashi / Takesue, Shin / Nakayama, Hiromichi / Iwamoto, Chika / Shindo, Koji / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenoki@surg1.med.kyushu-u.ac.jp. · Department of General Surgery, Shenzhen University General Hospital, Shenzhen, China. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Cancer Center, Kyushu University Hospital, Fukuoka, Japan. · Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·J Cancer Res Clin Oncol · Pubmed #30770989.

ABSTRACT: PURPOSE: This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer. METHODS: We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin-CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model. RESULTS: CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK-MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model. CONCLUSIONS: CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.

5 Article Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms. 2019

Skaro, Michael / Nanda, Neha / Gauthier, Christian / Felsenstein, Matthäus / Jiang, Zhengdong / Qiu, Miaozhen / Shindo, Koji / Yu, Jun / Hutchings, Danielle / Javed, Ammar A / Beckman, Ross / He, Jin / Wolfgang, Christopher L / Thompson, Elizabeth / Hruban, Ralph H / Klein, Alison P / Goggins, Michael / Wood, Laura D / Roberts, Nicholas J. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medical Oncology, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: nrobert8@jhmi.edu. ·Gastroenterology · Pubmed #30716324.

ABSTRACT: BACKGROUND & AIMS: Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS: We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS: We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS: In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.

6 Article Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion. 2019

Kibe, Shin / Ohuchida, Kenoki / Ando, Yohei / Takesue, Shin / Nakayama, Hiromichi / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Okumura, Takashi / Iwamoto, Chika / Shindo, Koji / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Shimamoto, Masaya / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kenoki@surg1.med.kyushu-u.ac.jp. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Endoscopic Diagnostics and Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Kyushu University Hospital Cancer Center, Fukuoka, Japan. · Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: mnaka@surg1.med.kyushu-u.ac.jp. ·Cancer Lett · Pubmed #30590101.

ABSTRACT: The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.

7 Article Genetic assessment of recurrent pancreatic high-risk lesions in the remnant pancreas: Metachronous multifocal lesion or local recurrence? 2019

Gotoh, Yoshitaka / Ohtsuka, Takao / Nakamura, So / Shindo, Koji / Ohuchida, Kenoki / Miyasaka, Yoshihiro / Mori, Yasuhisa / Mochidome, Naoki / Oda, Yoshinao / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: takao-o@surg1.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Surgery · Pubmed #30497813.

ABSTRACT: BACKGROUND: It is difficult to determine whether a second high-risk lesion, including pancreatic ductal adenocarcinoma or high-grade pancreatic intraepithelial neoplasm, is a metachronous multifocal lesion or represents local recurrence after resection of the first high-risk lesion. This study attempts to clarify the characteristics of second high-risk lesions in the remnant pancreas using genetic analyses. METHODS: Clinicopathologic data were collected from 12 patients who underwent pancreatectomy for a second high-risk lesion in the remnant pancreas. We performed mutational and immunohistochemical analyses of 4 major genes-KRAS, TP53, CDKN2A, and SMAD4-associated with pancreatic ductal adenocarcinoma progression, as well as targeted next-generation sequencing. RESULTS: Mutations in the four genes in the second high-risk lesion were consistent with the first lesion in four patients but were inconsistent in the remaining eight patients, and thus we considered that the latter eight patients likely had metachronous multifocal high-risk lesions and the other four patients had local recurrence. The estimated cumulative recurrence rate after resection of the second high-risk lesion was greater in the local recurrence group compared with the metachronous multifocal group, and the estimated cumulative disease-specific survival rate was greater in the metachronous multifocal group. Targeted next-generation sequencing demonstrated that the second lesions in the metachronous multifocal high-risk lesion group showed differences in founder mutations compared with the first lesion. In the local recurrence group, the founder mutations in the second lesion were common with those in the first lesion. CONCLUSION: Genetic assessment might help discriminate metachronous multifocal high-risk lesions from local recurrence.

8 Article Genome-Wide Somatic Copy Number Alterations and Mutations in High-Grade Pancreatic Intraepithelial Neoplasia. 2018

Hata, Tatsuo / Suenaga, Masaya / Marchionni, Luigi / Macgregor-Das, Anne / Yu, Jun / Shindo, Koji / Tamura, Koji / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: mgoggins@jhmi.edu. ·Am J Pathol · Pubmed #29684357.

ABSTRACT: To obtain a better understanding of the genetic alterations of high-grade pancreatic intraepithelial neoplasia (HG-PanIN), we performed whole-genome copy number analysis by using single nucleotide polymorphism microarrays and targeted next-generation sequencing of 11 microdissected HG-PanIN and two low-grade PanIN lesions associated with HG-PanIN. HG-PanIN mutation profiles were compared with those of their associated invasive pancreatic ductal adenocarcinoma. All PanIN lesions harbored somatic KRAS mutations. The most common copy number losses in the HG-PanIN were at the CDKN2A (9p21), TP53 (17p13), and SMAD4 (18q21) loci. Chromosomal losses in HG-PanIN were also found at 6p25-p24, 6q11-q27, 12q24, and 17q23-q24. Biallelic inactivation of CDKN2A and TP53 was detected in five of eight and in three of eight evaluable PanIN lesions, respectively. None of the HG-PanIN lesions had SMAD4 mutations or homozygous deletion. Copy number gains were noted at the MYC (8q24) and CCNE1 (19q12) loci and at 1q25-q31. Four HG-PanINs and one low-grade PanIN harbored chromothripsis-like regions. Five of seven pancreatic ductal adenocarcinomas evaluated had additional mutations that were not found in their associated HG-PanIN. HG-PanIN harbors widespread copy number alterations and commonly shows evidence of biallelic inactivation of CDKN2A and TP53 but not SMAD4. Chromothripsis events contribute to the copy number alterations of HG-PanIN.

9 Article Pancreatic Juice Mutation Concentrations Can Help Predict the Grade of Dysplasia in Patients Undergoing Pancreatic Surveillance. 2018

Suenaga, Masaya / Yu, Jun / Shindo, Koji / Tamura, Koji / Almario, Jose Alejandro / Zaykoski, Christopher / Witmer, P Dane / Fesharakizadeh, Shahriar / Borges, Michael / Lennon, Anne-Marie / Shin, Eun-Ji / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Center for Inherited Disease Research (CIDR), Baltimore, Maryland. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. mgoggins@jhmi.edu. ·Clin Cancer Res · Pubmed #29301828.

ABSTRACT:

10 Article IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth. 2017

Ayars, Michael / O'Sullivan, Eileen / Macgregor-Das, Anne / Shindo, Koji / Kim, Haeryoung / Borges, Michael / Yu, Jun / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · 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. ·Oncotarget · Pubmed #29137350.

ABSTRACT: Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA-sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (

11 Article Lack of association between the pancreatitis risk allele CEL-HYB and pancreatic cancer. 2017

Shindo, Koji / Yu, Jun / Suenaga, Masaya / Fesharakizadeh, Shahriar / Tamura, Koji / Almario, Jose Alejandro Navarro / Brant, Aaron / Borges, Michael / Siddiqui, Abdulrehman / Datta, Lisa / Wolfgang, Christopher L / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, 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. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland, USA. ·Oncotarget · Pubmed #28881607.

ABSTRACT: CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (

12 Article Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. 2017

Shindo, Koji / Yu, Jun / Suenaga, Masaya / Fesharakizadeh, Shahriar / Cho, Christy / Macgregor-Das, Anne / Siddiqui, Abdulrehman / Witmer, P Dane / Tamura, Koji / Song, Tae Jun / Navarro Almario, Jose Alejandro / Brant, Aaron / Borges, Michael / Ford, Madeline / Barkley, Thomas / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison P / Goggins, Michael. ·All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD. ·J Clin Oncol · Pubmed #28767289.

ABSTRACT: Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

13 Article SLC2A1/GLUT1 expression in mural nodules of intraductal papillary mucinous neoplasm of the pancreas. 2017

Oda, Yasunori / Aishima, Shinichi / Shindo, Koji / Fujino, Minoru / Mizuuchi, Yusuke / Hattori, Masami / Miyazaki, Tetsuyuki / Tanaka, Masao / Oda, Yoshinao. ·Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: saish@surgpath.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Hum Pathol · Pubmed #28412205.

ABSTRACT: In intraductal papillary mucinous neoplasms (IPMNs), the presence of a mural nodule showing a papillary or nodular proliferation of tumor cells in the dilated pancreatic duct is an indication for resection of IPMN. Solute carrier family 2, facilitated glucose transporter member 1, known as glucose transporter type 1 (SLC2A1/GLUT1) mediates cellular glucose uptake in many carcinomas and is correlated with increased

14 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.

15 Article Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. 2017

Yu, Jun / Sadakari, Yoshihiko / Shindo, Koji / Suenaga, Masaya / Brant, Aaron / Almario, Jose Alejandro Navarro / Borges, Michael / Barkley, Thomas / Fesharakizadeh, Shahriar / Ford, Madeline / Hruban, Ralph H / Shin, Eun Ji / Lennon, Anne Marie / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, 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. · Department of Oncology, 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. ·Gut · Pubmed #27432539.

ABSTRACT: OBJECTIVE: Secretin-stimulated pancreatic juice contains DNA shed from cells lining the pancreatic ducts. Genetic analysis of this fluid may form a test to detect pancreatic ductal neoplasia. DESIGN: We employed digital next-generation sequencing ('digital NGS') to detect low-abundance mutations in secretin-stimulated juice samples collected from the duodenum of subjects enrolled in Cancer of the Pancreas Screening studies at Johns Hopkins Hospital. For each juice sample, digital NGS necessitated 96 NGS reactions sequencing nine genes. The study population included 115 subjects (53 discovery, 62 validation) (1) with pancreatic ductal adenocarcinoma (PDAC), (2) intraductal papillary mucinous neoplasm (IPMN), (3) controls with non-suspicious pancreata. RESULTS: Cases with PDAC and IPMN were more likely to have mutant DNA detected in pancreatic juice than controls (both p<0.0001); mutant DNA concentrations were higher in patients with PDAC than IPMN (p=0.003) or controls (p<0.001). CONCLUSIONS: The detection in pancreatic juice of mutations important for the progression of low-grade dysplasia to high-grade dysplasia and invasive pancreatic cancer may improve the management of patients undergoing pancreatic screening and surveillance.

16 Article Obstructive Sleep Apnea and Pathological Characteristics of Resected Pancreatic Ductal Adenocarcinoma. 2016

Dal Molin, Marco / Brant, Aaron / Blackford, Amanda L / Griffin, James F / Shindo, Koji / Barkley, Thomas / Rezaee, Neda / Hruban, Ralph H / Wolfgang, Christopher L / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. ·PLoS One · Pubmed #27732623.

ABSTRACT: BACKGROUND: Prospective studies have identified obstructive sleep apnea (OSA) as a risk factor for increased overall cancer incidence and mortality. The potential role of OSA in the risk or progression of specific cancers is not well known. We hypothesized that pathological differences in pancreatic cancers from OSA cases compared to non-OSA cases would implicate OSA in pancreatic cancer progression. METHODS: We reviewed the medical records of 1031 patients who underwent surgical resection without neoadjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2003 and 2014 and compared the TNM classification of their cancer and their overall survival by patient OSA status. RESULTS: OSA cases were significantly more likely than non-OSA cases to have lymph node-negative tumors (37.7% vs. 21.8%, p = 0.004). Differences in the prevalence of nodal involvement of OSA vs. non-OSA cases were not associated with differences in other pathological characteristics such as tumor size, tumor location, resection margin status, vascular or perineural invasion, or other comorbidities more common to OSA cases (BMI, smoking, diabetes). A logistic regression model found that a diagnosis of OSA was an independent predictor of lymph node status (hazard ratio, 0.051, p = 0.038). Patients with OSA had similar overall survival compared to those without OSA (HR, 0.89, (0.65-1.24), p = 0.41). CONCLUSION: The observed pathological differences between OSA-associated and non-OSA-associated pancreatic cancers supports the hypothesis that OSA can influence the pathologic features of pancreatic ductal adenocarcinoma.

17 Article Predictive Factors for the Metachronous Development of High-risk Lesions in the Remnant Pancreas After Partial Pancreatectomy for Intraductal Papillary Mucinous Neoplasm. 2016

Miyasaka, Yoshihiro / Ohtsuka, Takao / Tamura, Koji / Mori, Yasuhisa / Shindo, Koji / Yamada, Daisuke / Takahata, Shunichi / Ishigami, Kousei / Ito, Tetsuhide / Tokunaga, Shoji / Oda, Yoshinao / Mizumoto, Kazuhiro / Nakamura, Masafumi / Tanaka, Masao. ·*Departments of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan†Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan‡Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan§Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan||The Medical Information Center and Cancer Center, Kyushu University Hospital, Fukuoka, Japan. ·Ann Surg · Pubmed #26334637.

ABSTRACT: OBJECTIVE: To identify factors predicting the development of high-risk lesions in the remnant pancreas after surgery for intraductal papillary mucinous neoplasm (IPMN). BACKGROUND: IPMN has unique features, including multifocality, adenoma-carcinoma sequence, and the development of distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. Careful attention should, therefore, be paid to the metachronous occurrence of high-risk lesions, including high-grade dysplasia or invasive carcinoma (HGD/INV) of IPMN and concomitant PDAC in the remnant pancreas after partial pancreatectomy for IPMN. METHODS: Clinicopathologic and surveillance data for 195 patients who underwent partial pancreatectomy for IPMN were reviewed retrospectively. RESULTS: Thirteen patients exhibited metachronous development of high-risk lesions including 6 HGD/INV and 7 concomitant PDACs in the remnant pancreas. The 5- and 10-year cumulative incidences of metachronous high-risk lesions in the remnant pancreas were 7.8% and 11.8%, respectively. Twelve of 13 patients had high-risk lesions at the time of initial surgery, and 10 of the 13 IPMNs were located in the distal pancreas. The IPMN subtypes initially resected were gastric in 6 patients, intestinal in 5, and pancreatobililary in the remaining 2. Univariate and multiple regression analyses identified pathologic results of HGD/INV and IPMN located in the distal pancreas as independent predictive factors for metachronous HGD/INV of IPMN, and the pancreatobiliary subtype of IPMN and presence of concomitant PDAC for metachronous PDAC. CONCLUSIONS: Patients undergoing partial pancreatectomy for IPMN are at high risk of developing lesions requiring surgery in the remnant pancreas, and close, long-term surveillance should be considered in these patients.

18 Article Significance of expression of glucagon-like peptide 1 receptor in pancreatic cancer. 2015

Cases, Ana Ines / Ohtsuka, Takao / Kimura, Hideyo / Zheng, Biao / Shindo, Koji / Oda, Yoshinao / Mizumoto, Kazuhiro / Nakamura, Masafumi / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Higashi‑ku, Fukuoka 812‑8582, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi‑ku, Fukuoka 812-8582, Japan. ·Oncol Rep · Pubmed #26238361.

ABSTRACT: Glucagon-like peptide 1 (GLP-1) induces insulin secretion and proliferation of pancreatic β-cells, and inhibits their apoptosis through the GLP-1 receptor (GLP-1R), thus providing a foundation for using GLP-1-based therapies for the treatment of type 2 diabetes. However, doubts have emerged regarding the drug safety of these therapies. We investigated the potential role of GLP-1R in pancreatic ductal adenocarcinoma (PDAC). GLP-1R expression was semi-quantitatively evaluated by immunohistochemistry in 48 PDAC samples, and its correlations with clinicopathological features were investigated. CFPAC-1 cells were used for GLP-1R knockdown to evaluate its effects on cell proliferation, migration and invasion. GLP-1R expression was positive in 23 tumors and negative in 25 tumors. No correlations were found between GLP-1R expression status and clinicopathological characteristics. Furthermore, GLP-1R expression status did not affect the patient prognosis (P=0.74). The majority of lymph node metastases (11 of 15 samples examined; 73%) were positive for GLP-1R expression. Immunoreactivity for GLP-1R was also noted in sites of perineural and lymphovascular invasion. GLP-1R knockdown significantly reduced the proliferation, migration and invasion of CFPAC-1 cells (P<0.05). In conclusion, although GLP-1R is not an independent prognostic factor in PDAC patients, it appears to have some implications for PDAC metastatic ability.

19 Article TM4SF1 as a prognostic marker of pancreatic ductal adenocarcinoma is involved in migration and invasion of cancer cells. 2015

Zheng, Biao / Ohuchida, Kenoki / Cui, Lin / Zhao, Ming / Shindo, Koji / Fujiwara, Kenji / Manabe, Tatsuya / Torata, Nobuhiro / Moriyama, Taiki / Miyasaka, Yoshihiro / Ohtsuka, Takao / Takahata, Shunichi / Mizumoto, Kazuhiro / Oda, Yoshinao / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Int J Oncol · Pubmed #26035794.

ABSTRACT: The cell surface protein Transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors, and its expression on tumor cells is implicated in cancer cell metastasis and patient prognosis. The role of TM4SF1 in malignant tumors remains poorly understood, particularly in pancreatic cancer. We performed immunohistochemical staining to analyze the expression of TM4SF1 in resected pancreatic tissues and investigated the correlation between TM4SF1 expression and prognosis. The function of TM4SF1 in the invasion and migration of pancreatic cancer cells was analyzed in vitro using an RNA interference technique. In pancreatic cancer tissues, TM4SF1 expression was detected in cancer cells, and patients with high tumor levels of TM4SF1 showed longer survival times than those with low TM4SF1 levels (P=0.0332). In vitro, reduced TM4SF1 expression enhanced the migration (P<0.05) and invasion (P<0.05) of pancreatic cancer cells partially via decreased E-cadherin expression. TM4SF1 protein levels were also reduced after TGF-β1-induced epithelial-mesenchymal transition (EMT).TM4SF1 expression is associated with better prognosis in pancreatic cancer. Loss of TM4SF1 contributes to the invasion and migration of pancreatic cancer cells.

20 Article Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial-mesenchymal transition. 2015

Mizuuchi, Yusuke / Aishima, Shinichi / Ohuchida, Kenoki / Shindo, Koji / Fujino, Minoru / Hattori, Masami / Miyazaki, Tetsuyuki / Mizumoto, Kazuhiro / Tanaka, Masao / Oda, Yoshinao. ·1] Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [2] Reserch Fellow of Japan Society for the Promotion of Science, Tokyo, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Kyushu University Hospital Cancer Center, Fukuoka, Japan. ·Lab Invest · Pubmed #25418581.

ABSTRACT: Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.

21 Article Prediction of Pancreatic Fistula by Preoperatively Assessable Factors; Retrospective Review of Unified Operations by Single Surgeon. 2014

Nakamura, Masafumi / Shindo, Koji / Ideno, Noboru / Ueda, Junji / Takahata, Shunichi / Nakashima, Hiroshi / Ohtsuka, Takao / Shimizu, Shuji / Oda, Yoshinao / Tanaka, Masao. · ·Hepatogastroenterology · Pubmed #26176082.

ABSTRACT: BACKGROUND/AIMS: This retrospective study was conducted to find preoperatively assessable risk factors for postoperative pancreatic fistula (POPF) in patients undergoing laparoscopic distal pancreatectomy (LDP) using a slow compression method with a stapler, which we call pen-firing compression (PFC). METHODOLOGY: Fifty-two patients underwent LDP, of whom 42 underwent PFC for pancreatic division using a stapler. The relationship between preoperatively assessable factors and the incidence of clinical POPF was statistically analyzed. RESULTS: Overall rate of POPF was 7.1% in 42 patients. Univariate analysis showed that greater BMI (p = 0.004) and thicker pancreatic stump (0.0022) were significant risk factors for POPF. BMI and stump thickness remained significant (P < 0.0001, P < 0.0001) by multivariate analysis. Cutoff points estimated by ROC curve were 27 kg/m2 for BMI and 27 mm for stump thickness. CONCLUSIONS: High BMI value and thick pancreatic stump are significant risk factors for POPF after LDP. Alternative treatment of the pancreatic stump may prevent POPF in high-risk patients.

22 Article CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells. 2014

Fujiwara, Kenji / Ohuchida, Kenoki / Sada, Masafumi / Horioka, Kohei / Ulrich, Charles D / Shindo, Koji / Ohtsuka, Takao / Takahata, Shunichi / Mizumoto, Kazuhiro / Oda, Yoshinao / Tanaka, Masao. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Kyushu University Hospital Cancer Center, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·PLoS One · Pubmed #25221999.

ABSTRACT: BACKGROUND: CD166, also known as activated leukocyte cell adhesion molecule (ALCAM), is expressed by various cells in several tissues including cancer. However, the role of CD166 in malignant tumors is controversial, especially in pancreatic cancer. This study aimed to clarify the role and significance of CD166 expression in pancreatic cancer. METHODS: We performed immunohistochemistry and flow cytometry to analyze the expression of CD166 in surgical pancreatic tissues and pancreatic cancer cell lines. The differences between isolated CD166+ and CD166- pancreatic cancer cells were analyzed by invasion and migration assays, and in mouse xenograft models. We also performed quantitative RT-PCR and microarray analyses to evaluate the expression levels of CD166 and related genes in cultured cells. RESULTS: Immunohistochemistry revealed high expression of CD166 in pancreatic cancer tissues (12.2%; 12/98) compared with that in normal pancreas controls (0%; 0/17) (p = 0.0435). Flow cytometry indicated that CD166 was expressed in 33.8-70.2% of cells in surgical pancreatic tissues and 0-99.5% of pancreatic cancer cell lines. Invasion and migration assays demonstrated that CD166- pancreatic cancer cells showed stronger invasive and migratory activities than those of CD166+ cancer cells (p<0.05). On the other hand, CD166+ Panc-1 cells showed a significantly stronger colony formation activity than that of CD166- Panc-1 cells (p<0.05). In vivo analysis revealed that CD166+ cells elicited significantly greater tumor growth than that of CD166- cells (p<0.05) in both subcutaneous and orthotopic mouse tumor models. mRNA expression of the epithelial-mesenchymal transition activator Zeb1 was over-expressed in CD166- cells (p<0.001). Microarray analysis showed that TSPAN8 and BST2 were over-expressed in CD166+ cells, while BMP7 and Col6A1 were over-expressed in CD166- cells. CONCLUSIONS: CD166+ pancreatic cancer cells are strongly tumorigenic, while CD166- pancreatic cancer cells exhibit comparatively stronger invasive and migratory activities. These findings suggest that CD166 expression is related to different functions in pancreatic cancer cells.

23 Article "High-risk stigmata" of the 2012 international consensus guidelines correlate with the malignant grade of branch duct intraductal papillary mucinous neoplasms of the pancreas. 2014

Aso, Teppei / Ohtsuka, Takao / Matsunaga, Taketo / Kimura, Hideyo / Watanabe, Yusuke / Tamura, Koji / Ideno, Noboru / Osoegawa, Takashi / Takahata, Shunnichi / Shindo, Koji / Ushijima, Yasuhiro / Aishima, Shinichi / Oda, Yoshinao / Ito, Tetsuhide / Mizumoto, Kazuhiro / Tanaka, Masao. ·From the Departments of *Surgery and Oncology, †Medicine and Bioregulatory Science, ‡Anatomic Pathology, and §Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Pancreas · Pubmed #25036910.

ABSTRACT: OBJECTIVES: The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas stratified patients into 2 clinical categories, "high-risk stigmata" and "worrisome features," and recommended different therapeutic strategies for these groups. The aim of this study was to elucidate the significance of these categories in terms of predicting malignant IPMNs. METHODS: The medical records of 100 consecutive patients who underwent pancreatectomy for IPMNs were retrospectively reviewed. Seventy patients with branch duct IPMNs (BD-IPMNs) were stratified into 3 groups. The relationships between the number of predictive factors and histopathologic grade were investigated. RESULTS: The prevalence rates of malignant IPMN, invasive carcinoma, and lymph node metastasis in the high-risk group were 80%, 55%, and 20%, respectively, with these percentages significantly increasing in a stepwise manner according to the number of predictive factors. In contrast, there was no significant correlation between the number of worrisome features and grade of malignancy in patients stratified as having worrisome BD-IPMNs. CONCLUSIONS: The number of high-risk stigmata correlated significantly with the grade of malignancy of BD-IPMNs. The presence of at least 1 high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomy with lymphadenectomy.

24 Article Podoplanin expression in the cyst wall correlates with the progression of intraductal papillary mucinous neoplasm. 2014

Shindo, Koji / Aishima, Shinichi / Ohuchida, Kenoki / Fujino, Minoru / Mizuuchi, Yusuke / Hattori, Masami / Ohtsuka, Takao / Tokunaga, Shoji / Mizumoto, Kazuhiro / Tanaka, Masao / Oda, Yoshinao. ·Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582, Japan. ·Virchows Arch · Pubmed #24990300.

ABSTRACT: A thickened, enhanced cyst wall on imaging examinations is one of the "worrisome features" described in the consensus guidelines for management of intraductal papillary mucinous neoplasm of the pancreas (IPMN). Podoplanin (PDPN) expression by cancer-associated fibroblasts is known to be an indicator of poor prognosis in some types of cancer. We performed immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in IPMN lesions and determined the pathological wall thickness by measuring the thinnest and thickest α-SMA-positive parts of the wall of the largest cyst in each case, and the mean of these two values was recorded as the wall thickness. The thickness of the pathological wall increased with progression from IPMN with low-grade dysplasia to IPMN with an invasive carcinoma. The pathological wall was thicker in IPMN with main duct involvement, nongastric-type IPMN, and IPMN with mural nodules. We also stained for PDPN and assessed the thickness of cyst wall staining as for α-SMA. The thickness of the PDPN-positive cyst wall varied in a pattern similar to the thickness of the α-SMA-positive pathological cyst wall. PDPN-positive stromal fibroblasts in the invasive component of IPMN-IC were evaluated as a ratio to α-SMA-positive fibroblasts. A high ratio (>50 %) of PDPN-positive stromal fibroblasts was a predictor of poor outcome. PDPN expression in the cyst wall correlates with the progression of IPMN. PDPN may be a significant prognostic marker of IPMN-IC.

25 Article Pancreatic intraepithelial neoplasia in the background of invasive ductal carcinoma of the pancreas as a prognostic factor. 2014

Oda, Yasunori / Aishima, Shinichi / Morimatsu, Katsuya / Shindo, Koji / Fujino, Minoru / Mizuuchi, Yusuke / Hattori, Masami / Miyazaki, Tetsuyuki / Tanaka, Masao / Oda, Yoshinao. ·Department of Anatomical Pathology, Kyushu University, Fukuoka, Japan. ·Histopathology · Pubmed #24931343.

ABSTRACT: AIMS: Of the recognized precursor lesions of pancreatic adenocarcinoma, pancreatic intraepithelial neoplasia (PanIN) is the most common form. However, little is known about the relationship between the grade of PanIN and prognosis for patients with invasive ductal carcinoma. METHODS AND RESULTS: In 124 patients with invasive ductal carcinoma, we examined the grade and number of PanIN lesions in all slides of resected pancreas. The prevalence rates of PanIN-1A, PanIN-1B, PanIN-2 and PanIN-3 were 86%, 84%, 57% and 30%, respectively. We allocated PanIN-2 and PanIN-3 cases into a PanIN-high group, and cases showing PanIN-1A, PanIN-1B or absence of PanIN into a PanIN-low group. In clinicopathological analysis, PanIN-high status was significantly correlated with the number of PanIN lesions (P < 0.0001). Disease-free and overall survival were statistically better in the PanIN-high group than in the PanIN-low group (P = 0.0005 and P = 0.0003). Univariate and multivariate analyses revealed that tumour size and PanIN-low status were statistically significant factors for a poorer prognosis (P = 0.042 and P = 0.007). CONCLUSIONS: In a pathological examination, it is important to evaluate the grade and number of PanINs in assessing the prognosis of pancreatic cancer.

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