Publications by authors named "Takamasa Oono"

47 Publications

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113.

Sci Rep 2021 Jun 18;11(1):12885. Epub 2021 Jun 18.

Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
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http://dx.doi.org/10.1038/s41598-021-92166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213853PMC
June 2021

Successful endoscopic retrieval of an embedded biliary stent using an intra-stent balloon inflation technique assisted by direct per-oral cholangioscopy.

Dig Endosc 2021 Jul 15;33(5):e97-e99. Epub 2021 Apr 15.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1111/den.13981DOI Listing
July 2021

High glucose promotes mineralization via bone morphogenetic protein 4-Smad signals in early stage of osteoblast differentiation.

Diabetol Int 2021 Apr 30;12(2):171-180. Epub 2020 Aug 30.

Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane 693-8501 Japan.

Diabetes mellitus is associated with bone fragility. Although osteoblast maturation is disturbed in patients with diabetes mellitus, the involvement of high glucose (HG) in different stages of osteoblast maturation is unclear. We used MC3T3-E1 cells, a murine osteoblastic cell line. The cells were incubated in high glucose medium (16.5 and 27.5 mM) with three different time courses: throughout 21 days, only first 7 days (early stage) and only last 7 days (late stage). Mineralization assay showed that HG throughout 21 days increased mineralization compared with control (5.5 mM). In the time course experiment, HG increased mRNA expression of , osteocalcin (), runt-related transcription factor 2 and osterix on days 3 and 5. By contrast, long-term treatment with HG (14 and 21 days) decreased expression of these osteoblastic markers. HG only during early stage enhanced mineralization, while HG only during late stage had no effects. HG increased the expression of bone morphogenetic protein (BMP) 4 and enhanced phosphorylation of Smad1/5/8. Treatment with a BMP receptor antagonist LDN193189 prevented the HG-induced mineralization during early stage of osteoblast differentiation, indicating that HG in the early stage promotes mineralization by BMP4. In conclusion, the study demonstrates that continuous HG treatment might enhance early osteoblast differentiation but disturbs osteoblast maturation, and that BMP-4-Smad signal might be involved in the HG-induced differentiation and mineralization of osteoblasts.
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http://dx.doi.org/10.1007/s13340-020-00463-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943678PMC
April 2021

Discriminant equation using mucosally expressed cytokines and transcription factor for making definite diagnosis of inflammatory bowel disease unclassified.

BMC Gastroenterol 2021 Feb 16;21(1):73. Epub 2021 Feb 16.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: The pathological conditions of UC and CD involved in inflammatory bowel disease-unclassified (IBD-U), UC with primary sclerosing cholangitis (PSC-UC), and UC with autoimmune pancreatitis type 2 (AIP-UC) remain unclear. Therefore, it is difficult to decide the appropriate treatments for these subtypes of UC. Our aim was to examine whether the discriminant equation using the mucosally expressed mediators designed as our previous study for IBD, could characterize IBD-U, PSC-UC, or AIP-UC.

Methods: A total of 56 patients including UC (n = 24), CD (n = 15), IBD-U (n = 10), PSC-UC (n = 4), and AIP-UC (n = 3), along with 9 control patients were enrolled in this study. Mucosally expressed inflammatory mediators related to Th1, Th2, Th17, and Treg were measured using quantitative PCR in endoscopic biopsies from the inflamed intestines of the patients. The IBD-U, PSC-UC or AIP-UC were characterized using discriminant analysis and principle component analysis.

Results: Through discriminant analyses, combinations of 3 to 7 inflammatory mediators were used to discriminate between UC and CD. Moreover, the identified 3 markers could diagnose patients with IBD-U as UC or CD with high accuracy. The distribution graph of inflammatory mediators using the principal component analysis revealed that PSC-UC and AIP-UC exhibited CD-like and UC-like features, respectively.

Conclusions: The discriminant equation using mucosally expressed mediators of IL-13, IL-21 and T-bet can be used as a universal diagnostic tool not only for IBD-U but also to assess pathological conditions in PSC-UC and AIP-UC.
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http://dx.doi.org/10.1186/s12876-021-01656-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885231PMC
February 2021

Efficacy of Early Endoscopic Ultrasound-Guided Transluminal Drainage for Postoperative Pancreatic Fistula.

Can J Gastroenterol Hepatol 2021 25;2021:6691705. Epub 2021 Jan 25.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Endoscopic ultrasound-guided transluminal drainage (EUS-TD) is generally performed 4 weeks after disease onset for evacuating pancreatic fluid collections. However, the optimal timing for conducting the procedure in those diagnosed with postoperative pancreatic fistula (POPF) has not been established. We aimed to elucidate the efficacy and safety of early EUS-TD procedures for treating POPF.

Methods: We retrospectively reviewed patients diagnosed with POPF who underwent EUS-TD in the Kyushu University Hospital between 2008 and 2019. Clinical features were comparatively analyzed between the two patient groups who underwent either early (≤15 days postoperatively) or late (>15 days postoperatively) EUS-TD. Factors prolonging hospital stay were also analyzed using Cox proportional hazard models.

Results: Thirty patients (median age, 64.5 years) were enrolled. The most common initial operation was distal pancreatectomy with splenectomy (60.0%). Median size of POPF was 69.5 (range, 38-145) mm, and median time interval between surgery and EUS-TD was 17.5 (range, 3-232) days. Totally, 47% patients underwent early EUS-TD. Rates of technical success, clinical success, and complications were 100%, 97%, and 6.9%, respectively. No recurrence of POPF occurred during a median follow-up period of 14 months. Clinical characteristics and outcomes were comparable between the early and late drainage patient groups, except for the rates of infection and nonencapsulation of POPF, which were significantly higher in the early drainage group. Performing simultaneous internal and external drainage (hazard ratio (HR): 0.31; 95% confidence interval (CI): 0.11-0.93, =0.04) and conducting ≥2 treatment sessions (HR: 0.26; 95% CI: 0.08-0.84, =0.02) were significantly associated with prolonged hospitalization after EUS-TD.

Conclusions: EUS-TD is a safe and effective method for managing POPF, regardless of when it is performed in the postoperative period. Once infected POPF occurs, clinicians should not hesitate to perform EUS-TD even within 15 days of the initial operation.
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http://dx.doi.org/10.1155/2021/6691705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850853PMC
August 2021

Endoscopic tamponade using a fully covered self-expandable metallic stent for massive biliary bleeding from a pseudoaneurysm rupture during metallic stent removal.

VideoGIE 2021 Jan 30;6(1):24-26. Epub 2020 Sep 30.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1016/j.vgie.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804991PMC
January 2021

Collision of a pancreatic ductal adenocarcinoma and a pancreatic neuroendocrine tumor associated with multiple endocrine neoplasm type 1.

Clin J Gastroenterol 2021 Feb 20;14(1):358-363. Epub 2020 Sep 20.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka City, Fukuoka, Japan.

A 54-year-old man with pancreatic head tumor had undergone pancreaticoduodenectomy and was diagnosed with pancreatic neuroendocrine tumor (P-NET) associated with sporadic multiple endocrine neoplasm type 1. Five years after the resection, P-NET recurred and liver metastases were observed. He was treated with a somatostatin analog. Eleven years after the resection, computed tomography revealed a new pancreatic hypodense and hypovascular mass adjacent to the P-NET that was diagnosed as pancreatic adenocarcinoma via endoscopic ultrasound-guided fine-needle aspiration. He underwent a total remnant pancreatectomy. Pathological examination showed that the lesion was constituted by a pancreatic ductal adenocarcinoma (PDAC) and a neuroendocrine tumor. Additionally, the invasive ductal carcinoma collided with the neuroendocrine tumor. Both PDAC and P-NET cells were observed in the collision area. We could observe the onset of PDAC during the treatment of P-NET. Moreover, we are the first to report the case of a collision of pancreatic endocrine and exocrine tumors diagnosed preoperatively.
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http://dx.doi.org/10.1007/s12328-020-01234-0DOI Listing
February 2021

Colonic varices: a rare complication of pancreatic cancer.

Clin J Gastroenterol 2020 Dec 8;13(6):1355-1359. Epub 2020 Sep 8.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

A 55-year-old man was diagnosed with pancreatic cancer of the uncus and received chemotherapy (modified FOLFIRINOX). Ten months later, he was admitted to our hospital with massive lower gastrointestinal bleeding. Contrast-enhanced CT showed ascending colon varices caused by the occlusion of the superior mesenteric vein (SMV) due to pancreatic cancer invasion. Colonoscopy revealed tortuous varices with red spots in the ascending colon. The patient received blood transfusions and was discharged; however, he was hospitalized for recurrent massive lower gastrointestinal bleeding 3 months later. During this readmission, we performed the transileocolic vein obliteration method due to SMV stenosis and the absence of an obvious shunt. He experienced an uneventful post-operative recovery, and contrast-enhanced CT after 2 months revealed no recurrence of colonic varices. Ectopic varices are portosystemic venous collaterals resulting from portal hypertension occurring in any locations other than the esophagogastric region. Colonic varices have rarely been reported before. Patients with pancreatic cancer may present with gastrointestinal bleeding caused by tumor bleeding or esophagogastric varices; however, ectopic varices such as colon varices, a rare complication of pancreatic cancer, should be considered in patients with obscure gastrointestinal bleeding.
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http://dx.doi.org/10.1007/s12328-020-01225-1DOI Listing
December 2020

Successful endoscopic removal of a fully covered self-expandable metallic stent that fractured above a benign distal bile duct stricture.

Endoscopy 2021 Jan 19;53(1):E11-E12. Epub 2020 May 19.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1055/a-1167-7861DOI Listing
January 2021

Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years.

Pancreatology 2020 Jun 20;20(4):709-715. Epub 2020 Apr 20.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background/objectives: This single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification.

Methods: We enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed.

Results: The number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p < 0.01).

Conclusions: We demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.
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http://dx.doi.org/10.1016/j.pan.2020.04.003DOI Listing
June 2020

Endoscopic removal of a lumen-apposing metal stent that migrated into the walled-off necrosis during the first drainage procedure.

Endoscopy 2020 02 9;52(2):E51-E52. Epub 2019 Sep 9.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1055/a-0992-8900DOI Listing
February 2020

CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors.

Cancer Med 2019 07 25;8(8):3748-3760. Epub 2019 May 25.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Although the postoperative recurrence rate for pancreatic neuroendocrine tumors (PNETs) is reported to be 13.5%-30%, the paucity of valuable biomarkers to predict recurrence poses a problem for the early detection of relapse. Hence, this study aimed to identify new biomarkers to predict the recurrence of PNETs. We performed RNA sequencing (RNA-Seq) on RNA isolated from frozen primary tumors sampled from all localized G1/G2 PNETs resected curatively from 1998 to 2015 in our institution. We calculated differentially expressed genes (DEGs) in tumor with and without recurrence (≥3 years) for the propensity-matched cohort. Gene ontology analysis for the identified DEGs was also performed. Furthermore, we evaluated the expression levels of candidate genes as recurrence predictors via immunostaining. Comparison of transcriptional levels in tumors with and without recurrence identified 166 DEGs. Up- and downregulated genes with high significance in these tumors were mainly related to extracellular organization and cell adhesion, respectively. We observed the top three upregulated genes, C-type lectin domain family 3 member A (CLEC3A), matrix metalloproteinase-7 (MMP7), and lipocalin2 (LCN2) immunohistochemically and compared their levels in recurrent and nonrecurrent tumors. Significantly higher recurrence rate was shown in patients with positive expression of CLEC3A (P = 0.028), MMP7 (P = 0.003), and LCN2 (P = 0.040) than that with negative expression. We identified CLEC3A, MMP7, and LCN2 known to be associated with the phosphatidylinositol-3-kinase/Akt pathway, as potential novel markers to predict the postoperative recurrence of PNETs.
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http://dx.doi.org/10.1002/cam4.2232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639196PMC
July 2019

[Fulminant type 1 diabetes mellitus following acute pancreatitis and hypoglycemia with sequential imaging of the pancreas using computed tomography: a case report].

Nihon Shokakibyo Gakkai Zasshi 2019;116(2):161-167

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University.

We herein report a rare case of fulminant type 1 diabetes mellitus (FT1DM) following acute pancreatitis and hypoglycemia, in which the pancreas was evaluated by serial computed tomography (CT). A 30-year-old male presented to a local hospital with a two-day history of abdominal pain and was diagnosed with acute pancreatitis based on elevated serum amylase and peripancreatic fluid collection on CT images. The patient developed sudden hypoglycemia (plasma glucose, 45mg/dL;serum C-peptide, 3.4ng/mL) the next day and hyperglycemia (plasma glucose, 250-480mg/dL) on admission day four. CT revealed a low attenuation area extending from the pancreatic head to the pancreatic tail. On admission day eight, he was referred to our hospital and diagnosed with FT1DM after he developed ketoacidosis immediately after hospitalization, with a plasma glucose level of 442mg/dL, hemoglobin A1c concentration of 5.7% and undetectable urinary C-peptide with a serum C-peptide level of 0.1ng/mL before and after intravenous glucagon loading. CT imaging revealed dramatic improvement at the time, and no pancreatic islets were detected in the pancreatic biopsy specimens.
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http://dx.doi.org/10.11405/nisshoshi.116.161DOI Listing
June 2019

Relapse patterns and predictors of IgG4-related diseases involved with autoimmune pancreatitis: A single-center retrospective study of 115 patients.

J Dig Dis 2019 Mar;20(3):152-158

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: Autoimmune pancreatitis is an autoimmune disorder accompanied by clinicopathological manifestations that have been established as immunoglobulin (IgG)4-related diseases (IgG4-RD). Other IgG4-RD are often involved with autoimmune pancreatitis. They sometimes relapse despite a favorable response to steroid therapy. This study aimed to clarify the patterns and risk factors for extrapancreatic relapse.

Methods: We reviewed the data of 115 patients diagnosed with definite autoimmune pancreatitis type 1 and followed up for > 1 year. We analyzed two items: the timing and pattern of extrapancreatic relapse, and risk factors for relapse with three common manifestations: IgG4-related sclerosing cholangitis (SC), IgG4-related dacryoadenitis and sialadenitis (DS), and IgG4-related retroperitoneal fibrosis (RF).

Results: Remission was achieved in all patients, except one. The extrapancreatic relapse rates were 11.0%, 19.7%, and 40% within 3, 5, and 10 years, respectively. Of 26 patients with extrapancreatic relapse, nine (34.6%) relapsed with a new IgG4-RD. Based on multivariate analysis, the interval between symptom onset and steroid initiation, and the presence of RF at onset were significant risk factors for relapse with SC and RF, respectively.

Conclusions: Our results indicate that they may be various extrapancreatic relapse patterns especially in autoimmune pancreatitis with other organ involvement. Patients with a delayed initiation of steroids or RF at onset should be carefully followed up as high-risk groups for SC and RF relapse.
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http://dx.doi.org/10.1111/1751-2980.12708DOI Listing
March 2019

A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats.

Pancreatology 2014 May-Jun;14(3):201-10. Epub 2014 Mar 15.

Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.

Background: ONO-1301, a novel sustained-release prostacyclin agonist, has an anti-fibrotic effect on the lungs, heart, and kidneys that is partly associated with the induction of hepatocyte growth factor (HGF). This study examined the anti-fibrotic effect of ONO-1301 on chronic pancreatitis (CP) progression.

Methods: CP was induced in rats in vivo by dibutyltin dichloride (DBTC). Seven days after DBTC injection (day 7), a slow-release form of ONO-1301 (10 mg/kg; ONO-1301-treated group) or vehicle (DBTC-treated group) was injected. On days 14 and 28, we evaluated the histopathological CP score and mRNA expressions of HGF, cytokines, and collagen in the pancreas by real-time RT-PCR. In vitro, monocytes and pancreatic stellate cells (PSCs) were isolated from normal rat spleen and pancreas, respectively. The cytokine and collagen expressions of monocytes and PSCs were detected by real-time RT-PCR, and PSCs proliferation was examined by BrdU assay.

Results: Histopathological CP scores in vivo improved in the ONO-1301-treated group compared to the DBTC-treated group, particularly inflammatory cell infiltration on day 14 and interstitial fibrosis on day 28. HGF mRNA increased significantly after ONO-1301 administration, whereas IL-1β, TNF-α, TGF-β, MCP-1, and collagen mRNA decreased significantly. Cytokine expression in monocytes was suppressed in vitro not only by HGF, but also ONO-1301 alone. However, neither ONO-1301 nor HGF affected the proliferation, or cytokine or collagen expression of PSCs.

Conclusions: ONO-1301 suppresses pancreatic fibrosis in the DBTC-induced CP model by inhibiting monocyte activity not only with induction of HGF but also by ONO-1301 itself.
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http://dx.doi.org/10.1016/j.pan.2014.02.009DOI Listing
July 2015

Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist.

Pancreas 2014 Jul;43(5):708-19

From the *Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan; †Department of Cell Biology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; and ‡Department of Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan.

Objectives: Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1), in acute/chronic pancreatitis; however, the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues and the effects of CX3CL1 on activated PSCs.

Methods: CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues was evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated PSCs were examined with real-time polymerase chain reaction, BrdU (5-bromo-2-deoxyuridine) assays, and Western blotting.

Results: In normal pancreas, acinar cells expressed CX3CR1 within granule-like formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal, and activated PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1 did not induce inflammatory genes expression in activated PSCs, but induced proliferation.

Conclusions: CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis, and the CX3CR1s are activated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSC proliferation in pancreatitis where CX3CL1 levels are elevated.
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http://dx.doi.org/10.1097/MPA.0000000000000109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315317PMC
July 2014

PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.

Lab Invest 2014 Jan 11;94(1):63-78. Epub 2013 Nov 11.

Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.

There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.
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http://dx.doi.org/10.1038/labinvest.2013.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879597PMC
January 2014

Large area of walled-off pancreatic necrosis successfully treated by endoscopic necrosectomy using a grasping-type scissors forceps.

Dig Endosc 2014 May 7;26(3):474-7. Epub 2013 Jun 7.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka.

Endoscopic necrosectomy (EN) for walled-off pancreatic necrosis (WOPN) is less invasive than surgical treatment and has become the first choice for pancreatic abscess. EN is usually carried out with several devices including snares, baskets, and grasping forceps. Occasionally, we have encountered cases in which EN has not been satisfactorily carried out, and there is pressure for further innovation in EN. Here, we describe a case of a large area of WOPN that was successfully treated by EN with endoscopic submucosal dissection and associated techniques, which facilitated removal of necrotic tissues. A 60-year-old man was referred to our hospital for WOPN as a complication of necrotizing pancreatitis. As a result of his complicating conditions including ischemic heart disease, uncontrollable arrhythmia, chronic renal failure, and persistent pleural effusion, he was deemed a poor surgical candidate. Although EN with conventional devices was carried out for five sessions, we could not remove the dense and massive necrotic tissues. At the sixth EN session, the Clutch Cutter device (Fujifilm, Tokyo, Japan) was used to remove the necrotic tissues, without major complications. This is believed to be the first report of EN using the Clutch Cutter for successful treatment of WOPN.
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http://dx.doi.org/10.1111/den.12134DOI Listing
May 2014

Endoscopic approach through the minor papilla for the management of pancreatic diseases.

World J Gastrointest Endosc 2013 Mar;5(3):81-8

Nao Fujimori, Hisato Igarashi, Akira Asou, Lingaku Lee, Takamasa Oono, Taichi Nakamura, Yusuke Niina, Masayuki Hijioka, Masahiko Uchida, Kazuhiro Kotoh, Kazuhiko Nakamura, Tetsuhide Ito, Ryoichi Takayanagi, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.

Aim: To clarify the efficacy and safety of an endoscopic approach through the minor papilla for the management of pancreatic diseases.

Methods: This study included 44 endoscopic retrograde cholangiopancreatography (ERCP) procedures performed in 34 patients using a minor papilla approach between April 2007 and March 2012. We retrospectively evaluated the clinical profiles of the patients, the endoscopic interventions, short-term outcomes, and complications.

Results: Of 44 ERCPs, 26 were diagnostic ERCP, and 18 were therapeutic ERCP. The most common cause of difficult access to the main pancreatic duct through the major papilla was pancreas divisum followed by distortion of Wirsung's duct. The overall success rate of minor papilla cannulation was 80% (35/44), which was significantly improved by wire-guided cannulation (P = 0.04). Endoscopic minor papillotomy (EMP) was performed in 17 of 34 patients (50%) using a needle-knife (13/17) or a pull-type papillotome (4/17). EMP with pancreatic stent placement, which was the main therapeutic option for patients with chronic pancreatitis, recurrent acute pancreatitis, and pancreatic pseudocyst, resulted in short-term clinical improvement in 83% of patients. Mild post-ERCP pancreatitis occurred as an early complication in 2 cases (4.5%).

Conclusion: The endoscopic minor papilla approach is technically feasible, safe, and effective when the procedure is performed in a high-volume referral center by experienced endoscopists.
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http://dx.doi.org/10.4253/wjge.v5.i3.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600553PMC
March 2013

Gastric gastrointestinal stromal tumor smaller than 20 mm with liver metastasis.

Clin J Gastroenterol 2013 Feb 9;6(1):29-32. Epub 2013 Jan 9.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

There have been no reports of gastric gastrointestinal stromal tumors (GISTs) <20 mm with distant metastasis. We report a case of a 15-mm gastric GIST with liver metastasis 1 year after surgical resection of the primary lesion. A 35-year-old man underwent routine esophagogastroduodenoscopy in July 2009. A submucosal tumor (SMT) <20 mm was incidentally detected at the posterior wall of the gastric body. Endoscopic ultrasound (EUS) indicated that it was a gastrointestinal mesenchymal tumor, including GIST, leiomyoma or schwannoma. He did not accept regular follow-up for this gastric SMT, therefore local laparoscopic excision was carried out in October 2009. The final pathological diagnosis after surgery was GIST, 15 mm in size, and a mitotic rate of 7/50 high-power fields, which did not indicate a high metastatic risk. The patient was followed up regularly without adjuvant chemotherapy. At 1 year after surgery, a space-occupying lesion ~15 mm was detected in the left lobe of the liver by abdominal ultrasound, where no mass lesion had been observed before surgery. To make a definite diagnosis of the hepatic mass lesion, EUS-guided fine-needle aspiration was performed, which demonstrated a metastatic liver tumor from a gastric GIST. Although this was a rare case, we should keep in mind that gastric GISTs do have a chance of malignant behavior, even if <20 mm.
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http://dx.doi.org/10.1007/s12328-012-0351-0DOI Listing
February 2013

Retroperitoneal fibrosis associated with immunoglobulin G4-related disease.

World J Gastroenterol 2013 Jan;19(1):35-41

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs. Retroperitoneal fibrosis can be of 2 types: idiopathic and secondary. The recently advocated concept and diagnostic criteria of immunoglobulin G4 (IgG4)-related disease, derived from research on autoimmune pancreatitis (AIP), has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease. We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease; however, the actual prevalence is unclear. Conversely, some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease. Because retroperitoneal fibrosis has no specific symptoms, diagnosis is primarily based on diagnostic imaging (computed tomography and magnetic resonance imaging), which is also useful in evaluating the effect of therapy. Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP. Thus, the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis. High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease. The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause. For patients with concurrent AIP, i.e., IgG4-related retroperitoneal fibrosis, the starting dose of steroid is usually 30-40 mg/d. The response to steroid therapy is generally favorable. In most cases, the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment. However, the epidemiology, treatment for recurring retroperitoneal fibrosis, and long-term prognosis are still largely unknown. Further analysis of such cases and research are necessary.
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http://dx.doi.org/10.3748/wjg.v19.i1.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545227PMC
January 2013

[Pancreatic diabetes].

Nihon Rinsho 2012 Jul;70 Suppl 5:161-4

Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University.

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July 2012

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells.

Lab Invest 2013 Jan 12;93(1):41-53. Epub 2012 Nov 12.

Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.

The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP.
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http://dx.doi.org/10.1038/labinvest.2012.156DOI Listing
January 2013

The current strategy for managing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1.

Gut Liver 2012 Jul 19;6(3):287-94. Epub 2012 Jan 19.

Department of Medicine and Bioregulatory Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited autosomal dominant disease presenting with pancreatic neuroendocrine tumors (pNETs), parathyroid tumors, or pituitary tumors. Using the PubMed database, we reviewed the literature on information regarding the proper diagnosis and treatment of MEN1-associated pNET. Many cases of MEN1-associated pNET are functioning pNETs. Gastrinomas and insulinomas tend to occur frequently in the duodenum and pancreas, respectively. In addition to diagnostic imaging, the selective arterial secretagogue injection test (SASI test) is useful for localizing functioning pNET. The standard treatment is surgical resection. However, in the case of a functioning pNET, the tumor should first be accurately located using the SASI test before an appropriate surgical method is selected. In cases of a MEN1-associated non-functioning pNET that exceeds 2 cm in diameter, the incidence of distant metastasis is significantly increased, and surgery is recommended. In cases of unresectable pNET, a somatostatin analog has been shown to demonstrate antitumor effects and is considered to be a promising treatment. In addition, molecular-targeted drugs have recently been found to be effective in phase III clinical trials.
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http://dx.doi.org/10.5009/gnl.2012.6.3.287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404164PMC
July 2012

[Current status and problems in the diagnostic criteria for autoimmune pancreatitis].

Nihon Shokakibyo Gakkai Zasshi 2012 Jun;109(6):888-96

Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University.

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June 2012

Cytosolic double-stranded DNA as a damage-associated molecular pattern induces the inflammatory response in rat pancreatic stellate cells: a plausible mechanism for tissue injury-associated pancreatitis.

Int J Inflam 2012 9;2012:504128. Epub 2012 Apr 9.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex) in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes.
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http://dx.doi.org/10.1155/2012/504128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328960PMC
August 2012

Relationship between pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels in IgG4-related diseases.

J Dig Dis 2012 May;13(5):274-9

Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: We aimed to investigate the relationship between the number of involved organs or regions and serum immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) levels.

Methods: The number of pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels were examined by groups in 46 patients with IgG4-related diseases at diagnosis prior to the initiation of steroid treatment: group A (one region involved, n=7), group B (two regions involved, n=11), group C (three regions involved, n=12), group D (four regions involved, n=9) and group E (five to seven regions involved, n=7).

Results: Both serum IgG and IgG4 levels increased with the number of inflamed regions. Mean serum IgG levels were 15.11, 18.65, 20.92, 23.29 and 30.98 g/L while the mean IgG4 levels were 3.99, 4.70, 4.70, 9.86 and 16.49 g/L in group A, B, C, D and E, respectively. Regression analysis also suggested that IgG4 was positively correlated with the number of regions involved. Additionally, serum IgG4 was higher in patients with multiple lesions when accompanied by sclerosing sialadenitis.

Conclusion: Patients having IgG4-related disease with high serum IgG and IgG4 levels should be systematically examined for involved lesions.
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http://dx.doi.org/10.1111/j.1751-2980.2012.00583.xDOI Listing
May 2012

Paclitaxel-based chemotherapy for advanced pancreatic cancer after gemcitabine-based therapy failure: a case series of 5 patients.

Case Rep Oncol 2011 Sep 22;4(3):534-41. Epub 2011 Nov 22.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan. igaras @ med.kyushu-u.ac.jp

Background/objectives: Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed.

Results: The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively.

Conclusion: Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.
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http://dx.doi.org/10.1159/000334704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242710PMC
September 2011

Vasoactive intestinal peptide reduces oxidative stress in pancreatic acinar cells through the inhibition of NADPH oxidase.

Peptides 2011 Oct 8;32(10):2067-76. Epub 2011 Sep 8.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.

Vasoactive intestinal peptide (VIP) attenuates experimental acute pancreatitis (AP) by inhibition of cytokine production from inflammatory cells. It has been suggested that reactive oxygen species (ROS) as well as cytokines play pivotal roles in the early pathophysiology of AP. This study aimed to clarify the effect of VIP on the oxidative condition in pancreas, especially pancreatic acinar cells (acini). Hydrogen peroxide (H(2)O(2))-induced intracellular ROS, assessed with CM-H(2)DCFDA, increased time- and dose-dependently in acini isolated from rats. Cell viability due to ROS-induced cellular damage, evaluated by MTS assay, was decreased with ≥100 μmol/L H(2)O(2). VIP significantly inhibited ROS production from acini and increased cell viability in a dose-dependent manner. Expression of antioxidants including catalase, glutathione reductase, superoxide dismutase (SOD) 1 and glutathione peroxidase was not altered by VIP except for SOD2. Furthermore, Nox1 and Nox2, major components of NADPH oxidase, were expressed in pancreatic acini, and significantly increased after H(2)O(2) treatment. Also, NADPH oxidase activity was provoked by H(2)O(2). VIP decreased NADPH oxidase activity, which was abolished by PKA inhibitor H89. These results suggested that VIP affected the mechanism of ROS production including NADPH oxidase through induction of a cAMP/PKA pathway. In conclusion, VIP reduces oxidative stress in acini through the inhibition of NADPH oxidase. These results combined with findings of our previous study suggest that VIP exerts its protective effect in pancreatic damage, not only through an inhibition of cytokine production, but also through a reduction of the injury caused by oxidative stress.
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http://dx.doi.org/10.1016/j.peptides.2011.08.027DOI Listing
October 2011
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