Publications by authors named "Yuko Kusakabe"

59 Publications

Feasibility of a Single Pigtail Stent Made by Cutting a Nasobiliary Drainage Tube in Endoscopic Transpapillary Gallbladder Stenting for Acute Cholecystitis.

Cureus 2022 May 17;14(5):e25072. Epub 2022 May 17.

Gastroenterology, Chiba University, Chiba, JPN.

Background and objective In this study, we aimed to evaluate the efficacy and safety of a single pigtail stent made by cutting a nasobiliary drainage tube (NBD stent) by comparing the clinical outcomes of using an NBD stent and those of using a ready-made double pigtail stent (RDP stent) in endoscopic gallbladder stenting (EGBS) for acute cholecystitis. Materials and methods This was a single-center retrospective study involving 20 cases that had technical success with EGBS for acute cholecystitis; the patients were divided into two groups: those using NBD stent (NBD group) and those using RDP stent (RDP group). The baseline characteristics and clinical outcomes were compared between the two groups. Results There were 13 patients in the NBD group and seven in the RDP group. The rates of clinical success (NBD group: 92% vs. RDP group: 100%, p=0.45) did not differ significantly between the groups. Regarding adverse events, gallbladder perforation occurred in one case in the NBD group; however, no other adverse events occurred in either group (NBD group: 7.7% vs. RDP group: 0%, p=0.45). The stent patency periods did not differ significantly between the groups [NBD group: 43 (12-64) days vs. RDP group: 97 (58-215) days, p=0.17]. The stent patency period in cases of long-term stent placement after EGBS was 1,381 days and 1,579 days in the NBD group and 305 days in the RDP group, respectively. Conclusion NBD stents are considered as effective as RDP stents in EGBS for acute cholecystitis. They are highly versatile and can be used for both bridging to surgery and long-term stent placement.
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http://dx.doi.org/10.7759/cureus.25072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202489PMC
May 2022

Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring Mutation in Early Clinical Experience.

J Cancer 2022 16;13(8):2656-2661. Epub 2022 May 16.

Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of locus. A total of eight patients (24.2%) exhibited at least one mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT was comparable to those patients with WT . These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by mutation.
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http://dx.doi.org/10.7150/jca.71494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174847PMC
May 2022

Liver cirrhosis is a risk factor for poor prognosis of acute cholangitis caused by choledocholithiasis.

Ann Hepatol 2022 May-Jun;27(3):100696. Epub 2022 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8677, Japan. Electronic address:

Introduction And Objectives: Acute cholangitis, which is characterized by biliary infection and acute liver injury, may impact cirrhosis prognosis. However, the prognosis itself remains unclear.

Materials And Methods: This multicenter retrospective cohort study compared the mortality and liver function change between patients with and without cirrhosis who underwent endoscopic treatment for acute cholangitis caused by choledocholithiasis between January 2004 and December 2019.

Results: We analyzed 699 patients, 44 of whom had cirrhosis. The cirrhotic group had a significantly higher 30-day mortality rate than the noncirrhotic group (14% vs. 1%; P < 0.001). The cirrhotic group also had significantly lower total bilirubin and albumin recovery. However, all patients with cirrhosis who survived achieved total-bilirubin recovery, and 91% achieved albumin recovery within 90 days. In multivariable Cox regression analysis, the independent risk factors for total-bilirubin recovery included cirrhosis (hazard ratio, 0.37; 95%CI, 0.24‒0.58; P < 0.001) and high total-bilirubin level (0.46; 95%CI, 0.34‒0.60; P < 0.001), whereas those for albumin recovery were cirrhosis (0.51; 95%CI, 0.33‒0.79; P = 0.002), high age (0.62; 95%CI, 0.47‒0.82; P < 0.001), organ dysfunction (0.62; 95%CI, 0.39‒0.96; P = 0.03), low albumin level (0.57; 95%CI, 0.36‒0.91; P = 0.02), and high C-reactive protein level (0.73; 95%CI, 0.56‒0.95; P = 0.02).

Conclusions: Patients with cirrhosis complicated with acute cholangitis had poor prognosis. Recovery of liver function after endoscopic treatment was slow; nevertheless, most patients who survived could recover within 90 days.
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http://dx.doi.org/10.1016/j.aohep.2022.100696DOI Listing
May 2022

EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma.

Sci Rep 2021 11 1;11(1):21396. Epub 2021 Nov 1.

Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2H3K27me3 cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
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http://dx.doi.org/10.1038/s41598-021-00889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560765PMC
November 2021

Diagnostic value of IMP3 and p53 immunohistochemical staining in EUS-guided fine-needle aspiration for solid pancreatic tumors.

Sci Rep 2021 08 26;11(1):17257. Epub 2021 Aug 26.

Department of Gastroenterology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

We previously identified insulin-like growth factor-II messenger ribonucleic acid-binding protein 3 (IMP3) as a valuable marker to distinguish malignant from benign lesions in pancreatic solid masses. The aim of this prospective study was to evaluate the usefulness of IMP3 and p53 immunohistochemical staining in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples for pancreatic solid masses. The study recruited 90 consecutive patients with pancreatic masses, including 62 pancreatic ductal adenocarcinomas (PDACs), 11 benign tumors, and 17 other tumors, who underwent EUS-FNA, and conducted IMP3 and p53 immunohistochemical staining. The main outcome measurement was improved diagnostic utility using IMP3 and p53 immunohistochemical staining. IMP3 and p53 expressions were detected in 60.8% and 49.4% of malignant lesions, 69.4% and 58.1% of PDACs, and 0% of benign lesions, respectively. In PDAC and benign tumors, the use of IMP3 and/or p53 immunostaining increased the sensitivity of cytohistological analysis from 88.7 to 93.5%, although the difference was not statistically significant. The sensitivity of histological analysis combined with that of IMP3 staining was 91.9%, which was significantly greater than that of histology alone (80.6%). The use of IMP3 and p53 immunohistochemical staining did not significantly improve the sensitivity of cytohistological analysis; however, IMP3 staining may be helpful for the histological analysis of malignant pancreatic tumors.
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http://dx.doi.org/10.1038/s41598-021-96492-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390649PMC
August 2021

Diagnostic value of peroral cholangioscopy in addition to computed tomography for indeterminate biliary strictures.

Surg Endosc 2022 05 9;36(5):3408-3417. Epub 2021 Aug 9.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba-City, Chiba, 260-8670, Japan.

Background: Peroral cholangioscopy (POCS) has been used to overcome the difficulty in diagnosing indeterminate biliary stricture or tumor spread. However, the value of adding POCS to computed tomography (CT) remains unclear. Our aim was to evaluate the diagnostic value of adding POCS to CT for indeterminate biliary stricture and tumor spread by interpretation of images focusing on the high diagnostic accuracy of visual findings in POCS.

Methods: We retrospectively identified 52 patients with biliary stricture who underwent endoscopic retrograde cholangiography (ERC) at our institution between January 2013 and December 2018. Two teams, each composed of an expert endoscopist and surgeon, performed the interpretation independently, referring to the CT findings of the radiologist. The CT + ERC + POCS images (POCS group) were evaluated 4 weeks after the evaluation of CT + ERC images (CT group). A 5-point scale (1: definitely benign to 5: definitely malignant) was used to determine the confident diagnosis rate, which was defined as an evaluation value of 1 or 5. Tumor spread was also evaluated.

Results: In the evaluation of 45 malignant diagnoses, the score was significantly closer to 5 in the POCS group than in the CT group in both teams (P < 0.001). The confident diagnosis rate was significantly higher for the POCS group (92% and 73%) than for the CT group (25% and 12%) in teams 1 and 2, respectively (P < 0.001). We found no significant difference in diagnostic accuracy for tumor spread between the groups.

Conclusion: Visual POCS findings confirmed the diagnosis of biliary strictures. POCS was useful in cases of indefinite diagnosis of biliary strictures by CT.
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http://dx.doi.org/10.1007/s00464-021-08661-1DOI Listing
May 2022

Analysis of circulating cell-free DNA after endoscopic ultrasound-guided fine needle aspiration in pancreatic ductal adenocarcinoma.

Pancreatology 2021 Apr 15. Epub 2021 Apr 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background/objectives: Recently, increase in cell-free DNA (cfDNA) concentration or newly detected KRAS mutation after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy were reported to be related to the occurrence of new distant metastasis. In this study, we investigated whether cfDNA concentration increased with the release of tumor components into the blood after EUS-FNA and whether its increase was related to prognosis.

Methods: Sixty-eight patients underwent EUS-FNA and were pathologically confirmed as having pancreatic ductal adenocarcinoma (PDAC). We measured plasma cfDNA concentration and the copy number of KRAS mutation in 68 patients and circulating tumor cells in 8 before and after EUS-FNA.

Results: The average cfDNA concentration after EUS-FNA (672.5 ± 919.6 ng/mL) was significantly higher than that before EUS-FNA (527.7 ± 827.3 ng/mL) (P < 0.001). KRAS mutation in plasma was detected in 8 patients (11.8%), however a significant increase in cfDNA concentration after EUS-FNA was not related to the change in KRAS-mutant copy number. Minimal increase in circulating tumor cells was observed in 3 of 8 patients. New distant metastasis was observed within 286 days to initial metastasis detection in 6 of 12 patients with ≥2-fold increase in cfDNA concentration and 26 of 56 patients with <2-fold increase within 185 days. In 32 patients who underwent surgery, ≥2-fold increase in cfDNA did not affect early recurrence.

Conclusions: The increase in cfDNA concentration after EUS-FNA was not caused by tumor cell components released into blood vessels. Hence, the risk of seeding via the blood stream after EUS-FNA may need not be considered.
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http://dx.doi.org/10.1016/j.pan.2021.04.001DOI Listing
April 2021

Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma.

J Cancer 2021 5;12(9):2694-2701. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is typically accompanied by abundant arterial blood flow. Although angiogenic growth factors such as Angiopoietin 2 (Ang2) play a central role in tumor angiogenesis in HCC, the role of serum Ang2 as a biomarker in HCC remains unclear. In this study, we aimed to investigate the potential of Ang2 as a diagnostic and prognostic biomarker in HCC using a sandwich enzyme-linked immunosorbent assay (ELISA). The median Ang2 levels in controls (n=20), chronic liver disease patients (n=98), and HCC patients (n=275) were 1.58, 2.33, and 3.53 ng/mL, respectively. The optimal cut-off value of Ang2 was determined as 3.5 ng/mL by receiver operating curve analysis. The sensitivity, specificity, and accuracy of Ang2 for HCC detection were 50.9, 83.7, and 59.5%, respectively. Spearman's rank correlation coefficient analysis demonstrated only a weak correlation between Ang2 serum levels and alpha-fetoprotein (AFP) or des-gamma-carboxy prothrombin (DCP) serum levels. The diagnostic value of Ang2 was comparable to those of other existing markers. In addition, 24 out of 73 patients with normal AFP and DCP levels (32.9%) demonstrated abnormally high Ang2 levels (≥3.5 ng/mL). Although no significant difference in overall survival was found between Ang2 and Ang2 patients with curative ablation therapy, recurrence-free survival (RFS) in Ang2 patients was observed to be significantly shorter than those in Ang2 patients. Multivariate analysis demonstrated that high serum Ang2 levels (≥3.5 ng/mL) and the presence of multiple tumors were poor prognostic factors. In conclusion, our findings indicate that serum Ang2 is a potential novel biomarker for both diagnosis and prognosis in HCC.
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http://dx.doi.org/10.7150/jca.56436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040723PMC
March 2021

Percutaneous Two-Dimensional Shear Wave Elastography for Diagnosis of Pancreatic Tumor.

Diagnostics (Basel) 2021 Mar 11;11(3). Epub 2021 Mar 11.

Department of Gastroenterology, Chiba University Graduate School of Medicine, 1-8-1 Inohan, Chuo-ku Chiba City 260-8670, Japan.

Background: To investigate the efficacy of two-dimensional shear wave elastography (2D-SWE) for the diagnosis of pancreatic mass lesions.

Methods: This ethics committee-approved cross-sectional study included 52 patients with histologically-proven pancreatic tumors (pancreatic ductal adenocarcinoma (PDAC), 36; tumor-forming pancreatitis (TFP), 15; neuroendocrine tumor, 1) and 33 control subjects. The 2D-SWE was performed for the tumor/non-tumor tissues, and SWE-mapping patterns and propagation quality were assessed.

Results: Three mapping patterns were detected based on the size and distribution of the coloring areas. Pattern A (whole coloring) was detected in all non-tumor tissues and TFP, whereas pattern C (multiple small coloring spots) was detected in PDAC only. Pattern B (partial coloring with smaller spots) was detected in other lesions. The specificity and positive predictive value of pattern A for non-PDAC and those of pattern C for PDAC were 100%. The SWE value was higher in tumor lesions than in the non-tumor tissues (38.1 vs. 9.8 kPa; < 0.001) in patients with PDAC. The SWE value in the non-tumor lesion was higher in patients with PDAC than in control (9.8 vs. 7.5 kPa; < 0.001).

Conclusions: 2D-SWE may play a role as a novel diagnostic tool for PDAC to detect a specific mapping pattern with quantitative assessment.
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http://dx.doi.org/10.3390/diagnostics11030498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001884PMC
March 2021

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2021 04 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 03 5;11(1):5303. Epub 2021 Mar 5.

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

Relationships between the response of the sweet taste receptor, salivation toward sweeteners, and sweetness intensity.

Food Sci Nutr 2021 Feb 15;9(2):719-727. Epub 2020 Dec 15.

Food Research Institute National Agriculture and Food Research Organization (NARO) Tsukuba Japan.

Sweeteners are widely used in food products, and their sweetness potency is usually evaluated by comparing it with that of sucrose. This, however, has led to confusion as some sweeteners are evaluated based on their maximum value of sweet taste response, while others are evaluated by their threshold value. Here, we aimed to develop a novel nonverbal sweetness evaluation system through the sweet taste signal transduction by comparing the responses of the sweet taste receptor, salivation, taste intensity, and preference among six sweeteners. The hT1r2/hT1r3 sweet taste receptor responses represented the input signal of the sweet taste signal transduction, while salivation, sweet taste intensity, and participants' preferences represented the output signals by the gustatory-salivary reflex, primary gustatory cortex area, and the secondary gustatory cortex, respectively. Our results showed that the sweet taste receptor, sweet intensity, and salivary secretion responses were concentration-dependent and expressed exponentially. Moreover, the results comparing coefficients showed 15-35 times more sensitivity between the response of hT1r2/hT1r3 and the salivation or the sweet taste intensity in non-nutrient sweeteners. The preference graph curve was not exponential, suggesting that the sweetener preference was not related to the sweet taste receptor, salivation, or sweet taste intensity. These results may suggest that the sweet taste signal of the non-nutritive sweeteners might be maintained by taste reception by hT1r2/hT1r3 to taste recognition in the primary gustatory area and that receptor responses and salivation could be used as indicators of sweetness intensity.
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http://dx.doi.org/10.1002/fsn3.2036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866590PMC
February 2021

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

Diverse transitions in diabetes status during the clinical course of patients with resectable pancreatic cancer.

Jpn J Clin Oncol 2020 Dec;50(12):1403-1411

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objective: Pancreatic cancer and diabetes status have complex bilateral interactions; therefore, understanding their clinical features is essential for the clinical management of pancreatic cancer patients. We aimed to evaluate the diabetes status before diagnosis, after resection and until the time of recurrence in patients with resectable pancreatic cancer and to clarify the correlations among the clinical course of pancreatic cancer, operative procedure and diabetes status.

Methods: Between 2011 and 2016, we retrospectively identified 189 pancreatic cancer patients who underwent pancreatoduodenectomy or distal pancreatectomy at our institution. The entire clinical course of each patient was retrieved from the medical records, and the diabetes status in the longest possible duration was assessed.

Results: Among 115 pancreatic cancer patients who had normal glucose tolerance at the time of resection, 22 (19.1%) developed type 2 diabetes after resection. In a multivariate analysis, distal pancreatectomy was strongly associated with the development of postoperative diabetes. On the other hand, 74 pancreatic cancer patients had already been diagnosed with type 2 diabetes at the time of resection. During the follow-up period, 15 patients were noted to have diabetes resolution after resection; interestingly, the majority of these patients had newly diagnosed diabetes, which was defined as the diagnosis of diabetes within 3 months before resection. Moreover, newly diagnosed diabetes was an independent factor for diabetes resolution after resection.

Conclusions: In pancreatic cancer patients who underwent pancreatectomy, distal pancreatectomy was correlated with postoperative diabetes, and newly diagnosed diabetes had a high probability of resolution after resection.
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http://dx.doi.org/10.1093/jjco/hyaa136DOI Listing
December 2020

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Int J Med Sci 2020 15;17(7):874-880. Epub 2020 Mar 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. : A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. : Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. : A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.
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http://dx.doi.org/10.7150/ijms.41454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163362PMC
February 2021

Endoscopic Ultrasound Criteria for Arterial Invasion in Pancreatic Cancer of the Body and Tail.

Pancreas 2020 04;49(4):561-567

From the Departments of Gastroenterology.

Objectives: We aimed to determine the difference in endoscopic ultrasonography (EUS) images between portal vein (PV) and arterial invasion of pancreatic cancer and to develop criteria for arterial involvement.

Methods: We reviewed EUS data of consecutive patients who underwent distal pancreatectomy from December 2010 to May 2017. We categorized the tumor-vessel relationship into 4 and 5 types, respectively, for the PV and arteries: (a) clear separation between tumor and vessel; (b) tumor border at vessel, echo-rich vessel wall uninterrupted; (c) echo-rich vessel wall interrupted; (d) vessel contour irregularity; and (e) arterial wall thickening or echogenic band surrounding the artery. We compared EUS outcomes with surgical and pathological results.

Results: Overall, 56 patients underwent distal pancreatectomy, of whom 22 received en bloc celiac axis resection. The pathological invasion rates of PVs and arteries were 46.2% and 0% in (c), and 72.5% and 42.4% in (d) (P = 0.046, P = 0.016), respectively. The overall sensitivity and specificity were 92.1% and 83.2%, respectively, for diagnosing venous invasion and 70.0% and 84.4%, respectively, for arterial invasion.

Conclusions: Different EUS criteria may be necessary for diagnosing arterial and portal venous invasions. Criterion (d) might be appropriate for diagnosing arterial invasion.
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http://dx.doi.org/10.1097/MPA.0000000000001523DOI Listing
April 2020

Serum fibroblast growth factor 19 serves as a potential novel biomarker for hepatocellular carcinoma.

BMC Cancer 2019 Nov 12;19(1):1088. Epub 2019 Nov 12.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA).

Methods: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined.

Results: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment.

Conclusion: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.
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http://dx.doi.org/10.1186/s12885-019-6322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849282PMC
November 2019

Differential scanning fluorimetric analysis of the amino-acid binding to taste receptor using a model receptor protein, the ligand-binding domain of fish T1r2a/T1r3.

PLoS One 2019 4;14(10):e0218909. Epub 2019 Oct 4.

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Okayama, Japan.

Taste receptor type 1 (T1r) is responsible for the perception of essential nutrients, such as sugars and amino acids, and evoking sweet and umami (savory) taste sensations. T1r receptors recognize many of the taste substances at their extracellular ligand-binding domains (LBDs). In order to detect a wide array of taste substances in the environment, T1r receptors often possess broad ligand specificities. However, the entire ranges of chemical spaces and their binding characteristics to any T1rLBDs have not been extensively analyzed. In this study, we exploited the differential scanning fluorimetry (DSF) to medaka T1r2a/T1r3LBD, a current sole T1rLBD heterodimer amenable for recombinant preparation, and analyzed their thermal stabilization by adding various amino acids. The assay showed that the agonist amino acids induced thermal stabilization and shifted the melting temperatures (Tm) of the protein. An agreement between the DSF results and the previous biophysical assay was observed, suggesting that DSF can detect ligand binding at the orthosteric-binding site in T1r2a/T1r3LBD. The assay further demonstrated that most of the tested l-amino acids, but no d-amino acid, induced Tm shifts of T1r2a/T1r3LBD, indicating the broad l-amino acid specificities of the proteins probably with several different manners of recognition. The Tm shifts by each amino acid also showed a fair correlation with the responses exhibited by the full-length receptor, verifying the broad amino-acid binding profiles at the orthosteric site in LBD observed by DSF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218909PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777825PMC
March 2020

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Invest New Drugs 2020 02 6;38(1):172-180. Epub 2019 Jun 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.
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http://dx.doi.org/10.1007/s10637-019-00801-8DOI Listing
February 2020

Diffusion-Weighted Magnetic Resonance Imaging and 18-Fluorodeoxglucose Positron Emission Tomography With Computed Tomography for Evaluating Malignancy of Branch Duct and Mixed Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Pancreas 2019 May/Jun;48(5):e43-e45

Department of Gastroenterology, Graduate School of Medicine, Chiba UniversityChiba, Japan. Department of Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan Diagnostic Imaging Center, Sannou Hospital Medical Center, Chiba, Japan Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1097/MPA.0000000000001316DOI Listing
February 2020

Genome-Wide Mapping of Bivalent Histone Modifications in Hepatic Stem/Progenitor Cells.

Stem Cells Int 2019 1;2019:9789240. Epub 2019 Apr 1.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

The "bivalent domain," a distinctive histone modification signature, is characterized by repressive trimethylation of histone H3 at lysine 27 (H3K27me3) and active trimethylation of histone H3 at lysine 4 (H3K4me3) marks. Maintenance and dynamic resolution of these histone marks play important roles in regulating differentiation processes in various stem cell systems. However, little is known regarding their roles in hepatic stem/progenitor cells. In the present study, we conducted the chromatin immunoprecipitation (ChIP) assay followed by high-throughput DNA sequencing (ChIP-seq) analyses in purified delta-like 1 protein (Dlk) hepatic stem/progenitor cells and successfully identified 562 genes exhibiting bivalent domains within 2 kb of the transcription start site. Gene ontology analysis revealed that these genes were enriched in developmental functions and differentiation processes. Microarray analyses indicated that many of these genes exhibited derepression after differentiation toward hepatocyte and cholangiocyte lineages. Among these, 72 genes, including and , were significantly upregulated after differentiation toward hepatocyte or cholangiocyte lineages. Knockdown of in Dlk cells suppressed colony propagation and resulted in increased numbers of albumin/cytokeratin 7 progenitor cells in colonies. These findings implicate that derepression of expression is required to induce normal differentiation processes. In conclusion, combined ChIP-seq and microarray analyses successfully identified bivalent genes. Functional analyses of these genes will help elucidate the epigenetic machinery underlying the terminal differentiation of hepatic stem/progenitor cells.
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http://dx.doi.org/10.1155/2019/9789240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466853PMC
April 2019

Clinical characteristics and outcomes of primary sclerosing cholangitis and ulcerative colitis in Japanese patients.

PLoS One 2018 20;13(12):e0209352. Epub 2018 Dec 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: In Western countries, most patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). The number of patients with UC in East Asia has increased markedly over the past two decades. However, current clinical features of PSC and of PSC associated with UC (PSC-UC) have not yet been clarified in East Asia, particularly in Japan. We aimed to reveal the clinical courses and associations with UC in Japanese patients with PSC from the mutual viewpoint of PSC and UC.

Methods: We retrospectively retrieved medical records of patients with PSC (69) and UC (1242) who were diagnosed at Chiba University Hospital between June 1991 and August 2017.

Results: In the present cohort, 37 patients had PSC-UC; the cumulative risks of PSC in patients with UC and of UC in patients with PSC were 3.0% and 53.6%, respectively. We confirmed similar distinctive results by a Japanese nationwide survey, noting that younger patients with PSC had a notably high possibility of association with UC. From the viewpoint of the UC cohort, the occurrence of right-sided disease was significantly higher in patients with PSC-UC than in those with UC (16.2% vs. 4.2%, P = 0.003). Pancolitis was more commonly observed in PSC-UC, and proctits/left-sided colitis was less commonly found in patients with UC. The number of patients with young-onset PSC-UC may be increasing similar to an increase in patients with UC in Japan.

Conclusions: In our cohort, the comorbidity rate of PSC-UC was higher than that obtained in previous reports. The incidence of PSC-UC and UC may increase in the future in East Asia, particularly in Japan.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301618PMC
May 2019

Epigenetic dysregulation in hepatocellular carcinoma: an up-to-date review.

Hepatol Res 2019 Jan 19;49(1):3-13. Epub 2018 Oct 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Due to the advances made in research based on next generation sequencers, it is now possible to detect and analyze epigenetic abnormalities associated with cancer. DNA methylation, various histone modifications, chromatin remodeling, and non-coding RNA-associated gene silencing are considered to be transcriptional regulatory mechanisms associated with gene expression changes. The breakdown of this precise regulatory system is involved in the transition to cancer. The important role of epigenetic regulation can be observed from the high rate of genetic mutations and abnormal gene expression leading to a breakdown in epigenetic gene expression regulation seen in hepatocellular carcinoma (HCC). Based on an understanding of epigenomic abnormalities associated with pathological conditions, these findings will lead the way to diagnosis and treatment. In particular, in addition to the fact that there are few choices in terms of extant drug therapies aimed at HCC, there are limits to their antitumor effects. The clinical application of epigenetic therapeutic agents for HCC has only just begun, and future developments are expected.
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http://dx.doi.org/10.1111/hepr.13250DOI Listing
January 2019

Usefulness of the 2-Devices-in-1-Channel Method in Case of Difficult Selective Biliary Cannulation Due to Parapapillary Diverticulum/Diverticular Papilla.

Surg Laparosc Endosc Percutan Tech 2018 Oct;28(5):295-297

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: To investigate whether the 2-devices-in-1-channel method is useful for selective biliary cannulation in patients with parapapillary diverticulum or intradiverticular papilla, where the papilla cannot be seen from the front.

Materials And Methods: Biliary cannulation using the 2-devices-in-1-channel method was performed in 28 patients who presented difficulty due to parapapillary diverticulum or intradiverticular papilla. There were 15 men and 13 women whose mean age was 68.8 (58 to 88) years. There were 22 patients with common bile duct stones, 5 with pancreatic cancer, and 1 with gallbladder cancer.

Results: Selective biliary cannulation was successful in all 28 patients. Common bile duct stones could be removed in all 22 patients after endoscopic sphincterotomy or endoscopic balloon dilation, and all 5 patients with pancreatic cancer as well as the patient with gallbladder cancer were successfully drained. There were no procedure-related complications.

Conclusions: From these results, we consider the 2-devices-in-1-channel method is useful and safe to perform selective biliary cannulation when the papilla cannot be seen from the front due to parapapillary diverticulum, or intradiverticular papilla.
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http://dx.doi.org/10.1097/SLE.0000000000000551DOI Listing
October 2018

Transarterial chemoembolization as a substitute to radiofrequency ablation for treating Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma.

Oncotarget 2018 Apr 20;9(30):21560-21568. Epub 2018 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aim: Transarterial chemoembolization (TACE) is the standard procedure for treating Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC). However, it is often carried out in the treatment of BCLC stage 0/A HCC for various reasons. This study aimed to elucidate the prognosis for BCLC stage 0/A HCC patients treated with TACE or with radiofrequency ablation (RFA).

Materials And Methods: The prognosis of 242 BCLC stage 0/A HCC patients within Milan criteria who underwent initially TACE or RFA were retrospectively analyzed using propensity score matching analysis.

Results: The analyses of baseline patient characteristics revealed that the maximum tumor size and the proportion of BCLC stage A patients were significantly higher in patients treated with TACE than in those treated with RFA (<0.001 and 0.047, respectively). After adjusting these factors using propensity score matching (1:3 matching), patients treated with TACE (n=32) and those treated with RFA (n=96) were further analyzed. The local recurrence rate was significantly higher in the TACE group than in the RFA group (<0.001). However, the overall survival (OS) in HCC patients treated with TACE was comparable to that in HCC patients treated with RFA (1 year, 93.5 vs. 95.8%; 3 years, 75.4 vs. 85.8%; 5 years, 61.8 vs. 70.7%; =0.196). Multivariate analyses followed by univariate analyses revealed that serum bilirubin level (=0.032), serum albumin level (=0.008), HBV-DNA (=0.013), and tumor number (=0.021) were independent predictors of OS.

Conclusion: TACE can substitute RFA at least in some patients with BCLC 0/A HCC.
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http://dx.doi.org/10.18632/oncotarget.25108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940395PMC
April 2018

Risk factors of adverse events in endoscopic retrograde cholangiopancreatography for patients aged ≥85 years.

Geriatr Gerontol Int 2018 Jul 24;18(7):1038-1045. Epub 2018 Mar 24.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Aim: Little is known about the factors that contribute to the occurrence of adverse events in endoscopic retrograde cholangiopancreatography (ERCP) for people aged ≥85 years and safety for the super-old. Therefore, we decided to identify these factors and to examine whether ERCP is safe in the super-old.

Methods: This was a single-center retrospective study. A total of 137 patients aged ≥85 years who underwent therapeutic ERCP at Chiba University Hospital from January 2012 to March 2017 were retrospectively reviewed.

Results: Four cases of Billroth II reconstruction and two cases of gastrectomy with Roux-en-Y reconstruction were excluded, and 131cases in total were examined in the present study. A total of 10 and 121 cases with and without adverse events, respectively, were present. Using univariate analysis, factors significantly contributing to the occurrence of adverse events in therapeutic ERCP were identified as aged ≥90 years (P = 0.0096), duodenal papilla cancer (P = 0.0012), gallbladder carcinoma (P = 0.023), and biliary metal stenting (P = 0.040). In multivariate analysis, only ≥90 years-of-age was a significant factor (P = 0.049). In addition, comparison between 25 cases of the super-old and 106 cases aged 85-89 years was carried out. In the super-old group, the average value of the American Society of Anesthesiologists physical status classification and Charlson's Comorbidity Index were significantly better than those in 85-89-year-olds (P = 0.0035 and P < 0.0001, respectively).

Conclusions: Although the super-old group had fewer comorbid diseases, they had significantly increased adverse events compared with patients aged 85-89 years. Geriatr Gerontol Int 2018; 18: 1038-1045.
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http://dx.doi.org/10.1111/ggi.13302DOI Listing
July 2018

Granular cell tumor of the pancreas diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

Clin J Gastroenterol 2018 Jun 27;11(3):193-199. Epub 2018 Jan 27.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

A 68-year-old woman was referred to our hospital for the treatment of bile duct stone, pancreatic tumor, and pancreatic cysts. First, bile duct stone was removed using endoscopic retrograde cholangiopancreatography. By abdominal contrast-enhanced computed tomography, a 12-mm diameter tumor was found in the pancreatic body. The tumor was isodense compared with the surrounding pancreatic parenchyma in the non-contrast phase and poorly enhanced in the arterial phase; it exhibited gradual enhancement from the portal vein phase to the late phase. Numerous pancreatic cysts were also observed by contrast-enhanced computed tomography. By magnetic resonance imaging, the tumor was hypointense in T1-weighted images, isointense in T2-weighted images, and hyperintense in diffusion-weighted images. By magnetic resonance cholangiopancreatography, the main pancreatic duct was not dilated, and pancreatic cysts communicated with the main pancreatic duct. The pancreatic cysts were diagnosed as branch-type intraductal papillary mucinous neoplasm. Histopathologic assessment of the specimens obtained by endoscopic ultrasound-guided fine-needle aspiration revealed the tumor as benign pancreatic granular cell tumor. The patient was followed up without surgical resection. On contrast-enhanced computed tomography at 6 months after admission, the tumor did not show any changes in diameter or characteristics.
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http://dx.doi.org/10.1007/s12328-018-0821-0DOI Listing
June 2018

Immunohistochemical analysis of IMP3 and p53 expression in endoscopic ultrasound-guided fine needle aspiration and resected specimens of pancreatic diseases.

Pancreatology 2018 Mar 26;18(2):176-183. Epub 2017 Dec 26.

Department of Gastroenterology, Chiba University Graduate School of Medicine, Japan.

Background: Insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3) is a valuable marker that distinguishes malignant from benign lesions and predicts prognosis.

Methods: First, we evaluated IMP3 expression in 77 resected specimens of pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), and chronic pancreatitis (CP). Eleven PDAC patients preoperatively underwent endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Survival analysis of IMP3 and clinicopathological factors was performed. IMP3 and p53 expression was evaluated in another 127 EUS-FNA samples of solid pancreatic masses to compare the diagnostic value of routine and immunohistochemical staining.

Results: IMP3 expression was detected in 72.3%, 50%, 20%, and 0% of PDAC, malignant IPMN, benign IPMN, and CP, respectively. Evaluation of IMP3 expression in EUS-FNA specimens coincided with that in resected specimens in 10 of 11. IMP3 expression correlated with tumor differentiation in PDAC samples (p = .006) and with poor prognosis through univariate analysis (p = .045). Tumor differentiation and lymph node metastasis were significantly associated with poor prognosis through multivariate analysis. In EUS-FNA specimens, the sensitivity, specificity, and accuracy of cytohistological analysis were 80.8%, 100%, and 85.0%, respectively. IMP3 and p53 expression were detected in 80.8% and 44.9% of malignant and 0% and 5% of benign lesions. Combined with IMP3 immunostaining, the sensitivity, specificity and accuracy of cytohistological analysis significantly increased to 87.9%, 100%, and 90.8% (p = .016), respectively. Meanwhile, p53 staining had no impact on the results.

Conclusions: IMP3 immunohistochemical staining can improve the diagnostic accuracy of EUS-FNA for malignant pancreatic tumors.
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http://dx.doi.org/10.1016/j.pan.2017.12.010DOI Listing
March 2018

Henoch-Schönlein Purpura Complicated by Hepatocellular Carcinoma.

Intern Med 2017 Nov 25;56(22):3041-3045. Epub 2017 Sep 25.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Japan.

Although Henoch-Schönlein purpura (HSP) is known to be accompanied by malignancies, cases with hepatobiliary cancer are extremely rare. A 62-year-old man with palpable purpura rapidly extending to both lower legs was admitted to our hospital. He was undergoing follow-up for cirrhosis caused by chronic hepatitis B virus infection and hepatocellular carcinoma (HCC). He had renal dysfunction with hematuria and proteinuria and abdominal pain. Based on the clinical presentation and skin biopsy findings, he was diagnosed with HSP. The administration of steroids resulted in the rapid improvement of the patient's symptoms and he was discharged 12 days after admission.
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http://dx.doi.org/10.2169/internalmedicine.8885-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725858PMC
November 2017

Taste of breath: the temporal order of taste and smell synchronized with breathing as a determinant for taste and olfactory integration.

Sci Rep 2017 08 21;7(1):8922. Epub 2017 Aug 21.

Laboratory of Sensory Science, Food Research Institute, National Agriculture and Food Research Organization, 2-1-12, Kannondai, Tsukuba, Ibaraki, 305-8642, Japan.

Many studies have reported that subjective taste intensity is enhanced by odors which are congruent, for example a sweet taste and a vanilla odor. Some reports have suggested that subjective taste is more strongly enhanced by retronasal than by orthonasal odors; others have suggested that taste enhancements by both odor routes are identical. Differences between the two routes include the direction of airflow accompanying breath. Thus, it is possible that the order of gustatory and olfactory stimuli when breathing through either route while drinking is a determining factor for taste-odor integration. To reveal the natural relationship between taste intensity enhancement by odors and breath, synchronization of odor stimulation with the breath is necessary. Here, we examined whether the enhancement of a sweet taste is induced by a vanilla odor presented in various combinations of odor routes, immediately before and immediately after drinking. The results showed that a retronasal odor after drinking enhanced taste, but an orthonasal odor before drinking did not. The retronasal odor before drinking and the orthonasal odor after drinking did not enhance the sweet taste. These results show that congruency with the natural order of stimulus and kinetic sensation is a determining factor for odor-induced taste enhancement.
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http://dx.doi.org/10.1038/s41598-017-07285-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566545PMC
August 2017
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