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Pancreatic Neoplasms: HELP
Articles by Kohei Nakata
Based on 37 articles published since 2010
(Why 37 articles?)
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Between 2010 and 2020, Kohei Nakata wrote the following 37 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review High-risk lesions in the remnant pancreas: fate of the remnant pancreas after pancreatic resection for pancreatic cancer and intraductal papillary mucinous neoplasms. 2019

Miyasaka, Yoshihiro / Ohtsuka, Takao / Matsuda, Ryota / Mori, Yasuhisa / Nakata, Kohei / 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. · Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. mnaka@surg1.med.kyushu-u.ac.jp. ·Surg Today · Pubmed #31346809.

ABSTRACT: Progress in diagnostic modalities, surgical procedures, and multidisciplinary treatment for pancreatic diseases has increased the number of long-term survivors after pancreatic resection. Several reports have focused on high-risk lesions (HRLs), including high-grade pancreatic intraepithelial neoplasia (PanIN), pancreatic ductal adenocarcinoma, high-grade intraductal papillary mucinous neoplasm (IPMN), and IPMN with an associated invasive carcinoma, in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The etiology of HRLs in the remnant pancreas is thought to be either isolated local recurrence of the initial lesion in the remnant pancreas or a newly developed primary lesion. Although it is difficult to distinguish between local recurrence and a new primary lesion, comparison of genetic alterations between two lesions may help with this distinction. Early detection of HRLs in the remnant pancreas may improve the prognosis of patients, and several investigators have proposed predictive factors for HRLs in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The reported short- and long-term outcomes of surgical resection of HRLs in the remnant pancreas are relatively favorable. Life-long surveillance of the remnant pancreas is recommended after partial pancreatic resection for pancreatic cancer or IPMN.

2 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.

3 Article Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5. 2020

Ando, Yohei / Ohuchida, Kenoki / Otsubo, Yoshiki / Kibe, Shin / Takesue, Shin / Abe, Toshiya / Iwamoto, Chika / Shindo, Koji / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Oda, Yoshinao / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · 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. · Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·PLoS One · Pubmed #31999765.

ABSTRACT: BACKGROUND: Necroptosis is a form of programmed cell death that is accompanied by release of intracellular contents, and reportedly contributes to various diseases. Here, we investigate the significance of necroptosis in pancreatic cancer. METHODS: We used immunohistochemistry and western blot analysis to evaluate expression of the key mediators of necroptosis-receptor-interacting serine/threonine protein kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL)-in human pancreatic cancer. We also tested the effects of conditioned media (CM) from necroptotic cells on pancreatic cancer cells in Transwell migration and Matrigel invasion assays. Protein array analysis was used to investigate possible mediators derived from necroptotic cells. RESULTS: RIP3 and MLKL are highly expressed in human pancreatic cancer tissues compared with normal pancreas. MLKL expression was particularly intense at the tumor invasion front. CM derived from necroptotic cells promoted cancer cell migration and invasion, but not CM derived from apoptotic cells. C-X-C motif chemokine 5 (CXCL5) was upregulated in CM derived from necroptotic cells compared with CM derived from control or apoptotic cells. Moreover, expression of the receptor for CXCL5, C-X-C-motif chemokine receptor-2 (CXCR2), was upregulated in pancreatic cancer cells. Inhibition of CXCR2 suppressed cancer cell migratory and invasive behavior enhanced by necroptosis. CONCLUSION: These findings indicate that necroptosis at the pancreatic cancer invasion front can promote cancer cell migration and invasion via the CXCL5-CXCR2 axis.

4 Article S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer. 2019

Nakayama, Hiromichi / Ohuchida, Kenoki / Yonenaga, Akiko / Sagara, Akiko / Ando, Yohei / Kibe, Shin / Takesue, Shin / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Okumura, Takashi / Shido, Koji / Miyoshi, Kei / Nakata, Kohei / Moriyama, Taiki / Miyasaka, Yoshihiro / Inoue, Shigetaka / Ohtsuka, Takao / Mizumoto, Kazuhiro / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Int J Oncol · Pubmed #31180531.

ABSTRACT: Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.

5 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.

6 Article Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer Potentially Improves Survival and Facilitates Surgery. 2019

Miyasaka, Yoshihiro / Ohtsuka, Takao / Kimura, Ryuichiro / Matsuda, Ryota / Mori, Yasuhisa / Nakata, Kohei / Kakihara, Daisuke / Fujimori, Nao / Ohno, Takamasa / 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. · Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. mnaka@surg1.med.kyushu-u.ac.jp. ·Ann Surg Oncol · Pubmed #30868514.

ABSTRACT: BACKGROUND: Accumulation of evidence suggests that neoadjuvant chemotherapy improves the outcomes of borderline resectable pancreatic cancer (BRPC). Gemcitabine plus nab-paclitaxel (GnP) has been widely accepted as systemic chemotherapy for unresectable pancreatic cancer and reportedly results in remarkable tumor shrinkage. This study was performed to evaluate the safety and efficacy of neoadjuvant chemotherapy using neoadjuvant GnP for BRPC. METHODS: The medical records of 57 patients who underwent treatment of BRPC from 2010 to 2017 were retrospectively reviewed. The patient characteristics and short- and intermediate-term outcomes were compared between the GnP and upfront surgery (UFS) groups. RESULTS: The GnP group comprised 31 patients and the UFS group comprised 26 patients. The patient characteristics were comparable with the exception of a higher prevalence of arterial involvement in the GnP group. Twenty-seven of the 31 patients (87%) in the GnP group and all 26 patients in the UFS group underwent resection. The GnP group showed a significantly shorter operation time (429 vs. 509.5 min, p = 0.0068), less blood loss (760 vs. 1324 ml, p = 0.0115), and a higher R0 resection rate (100% vs. 77%, p = 0.0100) than the UFS group. Postoperative complications and hospital stay were comparable between the two groups, and no treatment-related mortality occurred in either group. Both the disease-free survival and overall survival times were significantly longer in the GnP group (p = 0.0018 and p = 0.0024, respectively). CONCLUSIONS: Neoadjuvant GnP is a safe and effective treatment strategy for BRPC. It potentially improves patients' prognosis and facilitates surgical procedures.

7 Article Pancreatic Juice Exosomal MicroRNAs as Biomarkers for Detection of Pancreatic Ductal Adenocarcinoma. 2019

Nakamura, So / Sadakari, Yoshihiko / Ohtsuka, Takao / Okayama, Takafumi / Nakashima, Yohei / Gotoh, Yoshitaka / Saeki, Kiyoshi / Mori, Yasuhisa / Nakata, Kohei / Miyasaka, Yoshihiro / Onishi, Hideya / Oda, Yoshinao / Goggins, Michael / 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. · Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Departments of Pathology, Medicine, and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. mnaka@surg1.med.kyushu-u.ac.jp. ·Ann Surg Oncol · Pubmed #30820789.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm because of difficulties in early detection. Several studies have recently suggested that exosomes may have potential as novel biomarkers. This study aimed to isolate exosomes from pancreatic juice and to investigate whether exosomal microRNAs (ex-miRs) could be used as biomarkers for PDAC. METHODS: Pancreatic juice was collected from patients with PDAC and chronic pancreatitis (CP) by endoscopic retrograde pancreatography. Exosomes were extracted by ultracentrifugation. The presence of exosomes was confirmed by electron microscopy and Western blotting using anti-CD63, -CD81, and -TSG101 antibodies. Relative levels of ex-miR-21 and ex-miR-155 were quantified and compared between PDAC and CP patients. RESULTS: A total of 35 pancreatic juice samples (27 PDAC and 8 CP) were collected. Relative levels of both ex-miR-21 and ex-miR-155 were significantly higher in PDAC patients compared with CP patients (p < 0.001 and p = 0.008, respectively). By contrast, no significant difference was apparent in relative levels of miR-21 and miR-155 in whole pancreatic juice from PDAC patients compared with CP patients (p = 0.08 and p = 0.61, respectively). Ex-miR-21 and ex-miR-155 levels discriminated PDAC patients from CP patients with area under the curve values of 0.90 and 0.89, respectively. The accuracies of ex-miR-21 levels, ex-miR-155 levels, and pancreatic juice cytology were 83%, 89%, and 74%, respectively. When combining the results of ex-miR profiling with pancreatic juice cytology, the accuracy was improved to 91%. CONCLUSIONS: We successfully extracted exosomes from pancreatic juice. Ex-miRs, including ex-miR-21 and ex-miR-155, in pancreatic juice may be developed as biomarkers for PDAC.

8 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.

9 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.

10 Article Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors. 2019

Nakashima, Yohei / Ohtsuka, Takao / Nakamura, So / Mori, Yasuhisa / Nakata, Kohei / Miyasaka, Yoshihiro / Ishigami, Kosei / Matsuda, Ryota / 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: takao-o@surg1.med.kyushu-u.ac.jp. · Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 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. Electronic address: mnaka@surg1.med.kyushu-u.ac.jp. ·Pancreatology · Pubmed #30497875.

ABSTRACT: BACKGROUND/OBJECTIVES: The biological features of cystic pancreatic neuroendocrine tumors (PNETs) remain unclear. The aim of this study was to clarify the clinicopathological characteristics of non-functioning PNETs (NF-PNETs) with a cystic component. METHODS: The medical records of 75 patients with NF-PNETs who had undergone resection in our institution were retrospectively reviewed. Clinicopathological factors were compared between PNETs with and without a cystic component. Expression of somatostatin 2 receptor (SSTR-2) was also analyzed. RESULTS: Cystic PNETs were diagnosed in 14 patients (19%). The proportion of men was significantly higher for cystic than solid PNETs (79% vs. 44%, P < 0.05) and cystic PNETs were significantly larger than solid PNETs (25 mm vs. 17 mm, P < 0.01). However, there were no significant differences in the prevalence of lymph node metastases (14% vs. 10%, P = 0.64), hepatic metastasis (7% vs. 3%, P = 0.54), or disease-free survival rate (both 86%, P = 0.29) between PNETs with and without a cystic component. SSTR-2 expression was more frequently observed in PNETs with a cystic component than in those without (100% vs. 70%, P < 0.01). CONCLUSIONS: Although cystic PNETs were larger upon diagnosis than solid PNETs in this study, prognosis after surgical resection did not differ significantly between these types of PNET. Somatostatin receptor scintigraphy and somatostatin analogues may be more useful for diagnosing and treating cystic PNETs, respectively.

11 Article Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix. 2019

Okumura, Takashi / Ohuchida, Kenoki / Kibe, Shin / Iwamoto, Chika / Ando, Yohei / Takesue, Shin / Nakayama, Hiromichi / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Sada, Masafumi / Horioka, Kohei / Mochidome, Naoki / Arita, Makoto / 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, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Materials Science and Engineering, Faculty of Engineering, Kyushu University, Fukuoka, Japan. ·Int J Cancer · Pubmed #30152542.

ABSTRACT: Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

12 Article Prognostic Value of Preoperative Nutritional and Immunological Factors in Patients with Pancreatic Ductal Adenocarcinoma. 2018

Abe, Toshiya / Nakata, Kohei / Kibe, Shin / Mori, Yasuhisa / Miyasaka, Yoshihiro / Ohuchida, Kenoki / Ohtsuka, Takao / Oda, Yoshinao / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 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. mnaka@surg1.med.kyushu-u.ac.jp. ·Ann Surg Oncol · Pubmed #30225838.

ABSTRACT: BACKGROUND: Preoperative nutritional and immunological patient factors have been found to be associated with prognostic outcomes of malignant tumors; however, the clinical significance of these factors in pancreatic ductal adenocarcinoma (PDAC) remains controversial. OBJECTIVE: The aim of this study was to evaluate the prognostic value of nutritional and immunological factors in predicting survival of patients with PDAC. METHODS: Retrospective studies of 329 patients who underwent surgical resection for PDAC and 95 patients who underwent palliative surgery were separately conducted to investigate the prognostic impact of tumor-related factors and patient-related factors, including Glasgow Prognostic Score (GPS), modified GPS, Prognostic Nutritional Index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, and lymphocyte/monocyte ratio. RESULTS: In multivariate analysis for patients with surgical resection for PDAC, PNI was an independent factor for overall survival (OS) and disease-free survival. The median OS of patients with PNI ≤ 45 was significantly shorter than that of patients with PNI > 45 (17.5 and 36.2 months, respectively; p < 0.001). In multivariate analysis for patients undergoing palliative surgery for PDAC, only NLR was an independent prognosis factor. The median OS of patients with NLR > 5 was significantly shorter than that of patients with NLR ≤ 5 (2.7 and 8.9 months, respectively; p < 0.001). CONCLUSIONS: PNI in patients with surgical resection and NLR in patients with palliative surgery for PDAC may be useful prognostic factors.

13 Article Minimally invasive preservation versus splenectomy during distal pancreatectomy: a systematic review and meta-analysis. 2018

Nakata, Kohei / Shikata, Satoru / Ohtsuka, Takao / Ukai, Tomohiko / Miyasaka, Yoshihiro / Mori, Yasuhisa / Velasquez, Vittoria Vanessa D M / Gotoh, Yoshitaka / Ban, Daisuke / Nakamura, Yoshiharu / Nagakawa, Yuichi / Tanabe, Minoru / Sahara, Yatsuka / Takaori, Kyoichi / Honda, Goro / Misawa, Takeyuki / Kawai, Manabu / Yamaue, Hiroki / Morikawa, Takanori / Kuroki, Tamotsu / Mou, Yiping / Lee, Woo-Jung / Shrikhande, Shailesh V / Tang, Chung Ngai / Conrad, Claudius / Han, Ho-Seong / Chinnusamy, Palanivelu / Asbun, Horacio J / Kooby, David A / Wakabayashi, Go / Takada, Tadahiro / Yamamoto, Masakazu / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Mie Prefectural Ichishi Hospital, Tsu-Shi, Mie, Japan. · Department of Community Medicine, Mie University School of Medicine, Tsu, Mie, Japan. · Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. · Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan. · Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan. · Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan. · Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. · Department of Surgery, Tokyo Jikei University School of Medicine, Tokyo, Japan. · Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan. · Department of Surgery, Tohoku University, Sendai, Japan. · Department of Surgery, National Hospital Nagasaki Medical Center, Nagasaki, Japan. · Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Zhejiang, China. · Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul, Korea. · Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea. · Division of Gastrointestinal Surgery and Minimal Access Surgery, GEM Hospital and Research Centre, Coimbatore, India. · Department of Surgery, Mayo Clinic, Jacksonville, FL, USA. · Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. · Department of Surgery, Ageo Central General Hospital, Ageo, Japan. · Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan. · Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan. ·J Hepatobiliary Pancreat Sci · Pubmed #29943909.

ABSTRACT: BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) has gained in popularity recently. However, there is no consensus on whether to preserve the spleen or not. In this study, we compared MIDP outcomes between spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS); as well as outcomes between splenic vessel preservation (SVP) and Warshaw's technique (WT). METHODS: A systematic search of PubMed (MEDLINE) and Cochrane Library was conducted and the reference lists of review articles were hand-searched. RESULTS: Fifteen relevant studies with 769 patients were selected for meta-analyses of DPS and SPDP, while another 15 studies with 841 patients were used for the analysis between SVP and WT. Compared with the DPS group, SPDP patients had significantly lower incidences of infectious complications (P = 0.006) and pancreatic fistula (P = 0.002), shorter operative time (P < 0.001), and less blood loss (P = 0.01). Compared with WT, SVP patients had significantly lower incidences of splenic infarction (P < 0.001) and secondary splenectomy (P = 0.003). Subanalysis for laparoscopic surgery alone had similar results. CONCLUSIONS: Based on this study, SPDP has significantly superior outcomes compared to DPS. When a spleen is preserved, SVP has better outcomes over WT for reducing splenic complications.

14 Article Role of SpyGlass-DS 2018

Ohtsuka, Takao / Gotoh, Yoshitaka / Nakashima, Yohei / Okayama, Yoshifumi / Nakamura, So / Morita, Makiko / Aly, Mohammed Y F / Velasquez, Vittoria Vanessa D M / Mori, Yasuhisa / Sadakari, Yoshihiko / Nakata, Kohei / Miyasaka, Yoshihiro / Ishigami, Kousei / Fujimori, Nao / Mochidome, Naoki / Oda, Yoshinao / Shimizu, Shuji / Nakamura, Masafumi. ·Department of Surgery and Oncology, 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 Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Medicine and Bioregulatory Science, 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. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · International Medical Department, Kyushu University Hospital, 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. ·Pancreatology · Pubmed #29730245.

ABSTRACT: BACKGROUND/OBJECTIVES: It is often difficult to determine an adequate resection line during pancreatectomy for intraductal papillary mucinous neoplasm involving the main pancreatic duct during partial pancreatectomy. The aim of this study was to evaluate the usefulness of improved peroral pancreatoscopy using SpyGlass-DS METHODS: We collected and retrospectively analyzed clinicopathological data from seven consecutive patients who underwent preoperative assessment of intraductal papillary mucinous neoplasm involving the main duct using SpyGlass-DS RESULTS: Good imaging quality of the intraductal protruding lesion was obtained in all seven patients, and only one adverse event was noted wherein a patient had mild pancreatitis. Six patients underwent pancreatectomy. In one patient, masked-type concomitant pancreatic ductal adenocarcinoma and low-length dysplastic lesion was found near the surgical margin, which was not detected by preoperative imaging modalities including SpyGlass-DS CONCLUSIONS: SpyGlass-DS

15 Article Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma. 2018

Koikawa, Kazuhiro / Ohuchida, Kenoki / Ando, Yohei / Kibe, Shin / Nakayama, Hiromichi / Takesue, Shin / Endo, Sho / Abe, Toshiya / Okumura, Takashi / Iwamoto, Chika / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Hashizume, Makoto / 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 Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: mnaka@surg1.med.kyushu-u.ac.jp. ·Cancer Lett · Pubmed #29580808.

ABSTRACT: Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.

16 Article Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180. 2018

Koikawa, Kazuhiro / Ohuchida, Kenoki / Takesue, Shin / Ando, Yohei / Kibe, Shin / Nakayama, Hiromichi / Endo, Sho / Abe, Toshiya / Okumura, Takashi / Horioka, Kohei / Sada, Masafumi / Iwamoto, Chika / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Ohuchida, Riichi / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Hashizume, Makoto / 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. · Section of Fixed Prosthodontics, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan. ·Cancer Lett · Pubmed #29061505.

ABSTRACT: Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.

17 Article Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells. 2017

Endo, Sho / Nakata, Kohei / Sagara, Akiko / Koikawa, Kazuhiro / Ando, Yohei / Kibe, Shin / Takesue, Shin / Nakayama, Hiromichi / Abe, Toshiya / Okumura, Takashi / Moriyama, Taiki / Miyasaka, Yoshihiro / Ohuchida, Kenoki / Ohtsuka, Takao / Mizumoto, Kazuhiro / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: knakata@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; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: mnaka@surg1.med.kyushu-u.ac.jp. ·Pancreatology · Pubmed #28927939.

ABSTRACT: BACKGROUND: Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy. However, it has not been clarified whether autophagy induced by salinomycin treatment has a protective or cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells and whether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells. METHODS: We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigated effect on proliferation and the CD133 positive fraction using flow cytometry. In addition, we monitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining, western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was used to investigate the impact of autophagy inhibition on sensitivity to salinomycin. RESULTS: Salinomycin suppressed the proliferation of pancreatic cancer cells in a concentration dependent manner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cells in a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitive to salinomycin. CONCLUSIONS: Our data provide the first evidence indicating that autophagy induced by salinomycin have a protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin, autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment.

18 Article Degree of desmoplasia in metastatic lymph node lesions is associated with lesion size and poor prognosis in pancreatic cancer patients. 2017

Nakayama, Hiromichi / Ohuchida, Kenoki / Yoshida, Masaki / Miyazaki, Tetsuyuki / Takesue, Shin / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Okumura, Takashi / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Shirahane, Kengo / Manabe, Tatsuya / Ohtsuka, Takao / Toma, Hiroki / Tominaga, Yohei / Nagai, Eishi / Mizumoto, Kazuhiro / Oda, Yoshinao / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. · Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. · Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Oncol Lett · Pubmed #28927058.

ABSTRACT: Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10-70%) and low (<10%). Desmoplasia was not observed in cancer-free lymph nodes. The size of metastatic lymph node lesions was additionally measured, and a significant association between metastatic lesion size and the degree of desmoplasia was observed (P<0.001). The degree of desmoplasia was additionally associated with local extranodal invasion. In the analysis of 65 pancreatic cancer patients with metastatic lymph nodes, the presence of multiple metastatic lymph nodes with moderate or high desmoplasia was significantly associated with poor survival (high, P=0.0048; moderate/high, P=0.0075). Of several clinicopathological factors, the presence of multiple metastatic lymph nodes with high or moderate desmoplasia was associated with overall survival in univariate (P=0.0098) and multivariate (P=0.0466) analyses. The degree of desmoplasia in metastatic lymph nodes is associated with lesion size, and the presence of multiple metastatic lymph nodes with desmoplasia is an independent poor prognostic factor, suggesting that the desmoplasia may have an important role in the malignant progression of lymph node metastases.

19 Article Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells. 2017

Okumura, Takashi / Ohuchida, Kenoki / Sada, Masafumi / Abe, Toshiya / Endo, Sho / Koikawa, Kazuhiro / Iwamoto, Chika / Miura, Daisuke / Mizuuchi, Yusuke / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. · Kyushu University Hospital Cancer Center, Fukuoka, Japan. · Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Oncotarget · Pubmed #28407685.

ABSTRACT: Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.

20 Article Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice. 2017

Endo, Sho / Nakata, Kohei / Ohuchida, Kenoki / Takesue, Shin / Nakayama, Hiromichi / Abe, Toshiya / Koikawa, Kazuhiro / Okumura, Takashi / Sada, Masafumi / Horioka, Kohei / Zheng, Biao / Mizuuchi, Yusuke / Iwamoto, Chika / Murata, Masaharu / Moriyama, Taiki / Miyasaka, Yoshihiro / Ohtsuka, Takao / Mizumoto, Kazuhiro / Oda, Yoshinao / Hashizume, Makoto / 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: knakata@surg1.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kenoki@surg1.med.kyushu-u.ac.jp. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, 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. ·Gastroenterology · Pubmed #28126348.

ABSTRACT: BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice. METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified. RESULTS: Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1.56). Immunoblots showed that PSCs from pancreatic tumor samples expressed higher levels of markers of autophagy than PSCs from chronic pancreatitis samples. Inhibitors of autophagy increased the number of lipid droplets of PSCs, indicating a quiescent state of PSCs, and reduced their production of ECM molecules and interleukin 6, as well as their proliferation and invasiveness in culture. PSCs exposed to autophagy inhibitors formed smaller tumors in nude mice (P = .001) and fewer liver metastases (P = .018) with less peritoneal dissemination (P = .018) compared to PSCs not exposed to autophagy inhibitors. CONCLUSIONS: Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.

21 Article Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination. 2017

Abe, Toshiya / Ohuchida, Kenoki / Koikawa, Kazuhiro / Endo, Sho / Okumura, Takashi / Sada, Masafumi / Horioka, Kohei / Zheng, Biao / Moriyama, Taiki / Nakata, Kohei / Miyasaka, Yoshihiro / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Mizumoto, Kazuhiro / Hashizume, Makoto / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. · Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Int J Oncol · Pubmed #28035373.

ABSTRACT: The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.

22 Article Clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer. 2017

Abe, Toshiya / Ohuchida, Kenoki / Endo, Sho / Ookubo, Fumihiko / Mori, Yasuhisa / Nakata, Kohei / Miyasaka, Yoshihiro / Manabe, Tatsuya / Ohtsuka, Takao / Nagai, Eishi / Oda, Yoshinao / Nakamura, Masafumi. ·Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Division of Diagnostic Pathology, Graduate School of Medical Sciences, Kyushu University, 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. ·Surgery · Pubmed #27939334.

ABSTRACT: BACKGROUND: The clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer remains incompletely understood. METHODS: Peritoneal washing samples were collected from 411 consecutive patients with pancreatic ductal adenocarcinoma from 1996 to 2014. Of the 411 patients, 335 underwent macroscopically curative resection and 76 with noncurative factors did not undergo resection. We compared long-term outcomes between patients with positive cytology (cytology+) and those with negative cytology (cytology-) and investigated the importance of clinicopathologic factors. RESULTS: Of 335 patients with curative resection, 300 (89.6%) were cytology- and 35 (10.4%) were cytology+. The median overall survival of cytology+ patients was less than that of cytology- patients (16 vs 31 months, respectively; P < .0001). The median overall survival of cytology+ patients with noncurative factors was significantly worse than that of cytology+ patients with curative resection (6.9 vs 16.0 months, respectively; P = .0023). The median disease-free survival of cytology+ patients was less than that of cytology- patients (6.5 vs 16 months, respectively; P < .0001). In the multivariate analysis, cytology+ was an independent prognostic factor for overall survival and disease-free survival. CONCLUSION: Cytology+ without noncurative factors was a predictive factor for a poor prognosis. Therefore, it is important to regard patients with pancreatic cancer characterized by cytology+ as a special group that may warrant more aggressive adjuvant therapy.

23 Article Micro RNA-373 is down-regulated in pancreatic cancer and inhibits cancer cell invasion. 2014

Nakata, Kohei / Ohuchida, Kenoki / Mizumoto, Kazuhiro / Aishima, Shinichi / Oda, Yoshinao / Nagai, Eishi / Tanaka, Masao. ·Departments of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Ann Surg Oncol · Pubmed #24748127.

ABSTRACT: BACKGROUND: Micro RNAs (miRNAs) are small noncoding RNAs that have gained attention as key molecules in the malignant characteristics of cancers, and several recent investigations also have identified some miRNAs as potential key regulators to inhibit the malignant characteristics of tumors. MiRNA-373 (miR-373) has recently been reported to induce E-cadherin, which is a key regulator of epithelial-mesenchymal transition (EMT). However, the role of miR-373 in the characteristics of cancer cells is not still well known. METHODS: We investigated the expression levels of miR-373 in pancreatic cancer cell lines and its effect on the invasiveness of pancreatic cancer by using in vitro and in vivo models. We also analyzed the expression of miR-373 using formalin-fixed paraffin-embedded (n = 152) and microdissected frozen (n = 57) samples from pancreatic tissues. RESULTS: The levels of miR-373 expression were low in pancreatic cancer cell lines. In formalin-fixed paraffin-embedded and microdissected frozen samples, miR-373 expression was significantly down-regulated in pancreatic cancer compared with that in healthy pancreas (P < 0.001 and P = 0.005, respectively). We also found that reexpression of miR-373 repressed transforming growth factor-β-induced EMT, leading to inhibition of invasiveness of cancer cells. Furthermore, reexpression of miR-373 significantly inhibited peritoneal dissemination in vivo (P < 0.001). CONCLUSIONS: MiR-373 is down-regulated in pancreatic cancer, and its reexpression represses the invasiveness of pancreatic cancer cells.

24 Article Insulin-like growth factor II messenger RNA-binding protein-3 is a valuable diagnostic and prognostic marker of intraductal papillary mucinous neoplasm. 2013

Morimatsu, Katsuya / Aishima, Shinichi / Yamamoto, Hidetaka / Hayashi, Akifumi / Nakata, Kohei / Oda, Yasunori / Shindo, Koji / Fujino, Minoru / Tanaka, Masao / Oda, Yoshinao. ·Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ·Hum Pathol · Pubmed #23597774.

ABSTRACT: Recently, various studies have shown that insulin-like growth factor II messenger RNA-binding protein-3 (IMP3) is a useful diagnostic marker for malignant lesions and a prognostic marker for poor survival in several kinds of tumors. However, the value of IMP3 as a diagnostic and prognostic marker in intraductal papillary mucinous neoplasm (IPMN) of pancreas has been unclear until now. In this study, we examined IMP3 immunohistochemical expression in 190 resection samples and 15 biopsy samples of IPMN and analyzed the value of IMP3 as a diagnostic and prognostic marker. IMP3 expression was recognized in 71.8% (28/39) of IPMNs with high-grade dysplasia and in 81.3% (26/32) of IPMNs with an associated invasive carcinoma (IPMN-IC), but it was not found in any IPMNs with low-grade dysplasia or in IPMNs with intermediate dysplasia. IMP3 expression was significantly higher in cancerous lesions (IPMN with high-grade dysplasia and IPMN-IC) than in noncancerous lesions (IPMN with low-grade dysplasia and IPMN with intermediate-grade dysplasia), with a sensitivity of 76.1% and a specificity of 100% (P < .001). We also identified a significant difference in IMP3 expression between cancerous lesions and noncancerous lesions in biopsy specimens (P = .027). In IPMN-IC, disease-specific survival was significantly shorter in the high-expression group (>50% tumor staining) than in the low-expression group (≤50% tumor staining; P = .0069). In conclusion, our findings show that IMP3 is a useful diagnostic marker for distinguishing between noncancerous and cancerous lesions and is a valuable prognostic biomarker in IPMN.

25 Article Liver-intestine cadherin expression is associated with intestinal differentiation and carcinogenesis in intraductal papillary mucinous neoplasm. 2012

Morimatsu, Katsuya / Aishima, Shinichi / Kayashima, Tadashi / Hayashi, Akifumi / Nakata, Kohei / Oda, Yasunori / Taguchi, Tomoaki / Tsuneyoshi, Masazumi / Tanaka, Masao / Oda, Yoshinao. ·Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ·Pathobiology · Pubmed #22286087.

ABSTRACT: OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMN) are classified into four phenotypes according to the WHO classification. Recently, intestinal-type IPMN has been suggested to grow with a distinct carcinogenetic pathway. Like mucin 2, oligomeric mucus/gel forming (MUC2) and caudal-related homeobox 2 (CDX2), liver-intestine cadherin (LI cadherin) is an intestine-specific marker. We aimed to investigate the roles of LI cadherin expression in IPMN. METHODS: We examined LI cadherin expression in 135 cases of IPMN by immunohistochemical staining and the quantitative real-time reverse-transcription polymerase chain reaction. RESULTS: LI cadherin protein and mRNA levels were significantly higher in intestinal-type IPMN than in nonintestinal-type IPMN (protein level, p < 0.001; mRNA level, p = 0.0312). A positive correlation was found between protein and mRNA of LI cadherin (p = 0.0037). The positivity rates of LI cadherin expression were significantly higher in CDX2-positive cases than in CDX2-negative cases (p < 0.001). In 41 intestinal-type IPMNs, LI cadherin-positive rates tended to increase gradually, from IPMN with low-grade dysplasia (IPMN-L) to IPMN with an associated invasive carcinoma (IPMN-IC) [IPMN-L vs. IPMN with high-grade dysplasia (IPMN-H); p = 0.0357, IPMN-L vs. IPMN-IC; p = 0.0230] and positively correlated with the Ki-67 labeling index (p = 0.0408), whereas this tendency was not recognized in nonintestinal-type IPMNs. CONCLUSIONS: LI cadherin is associated with an intestinal phenotype and an 'intestinal pathway' of carcinogenesis in IPMN.

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