Publications by authors named "Shin Yasui"

105 Publications

Current status of diagnosis and therapy for intraductal papillary neoplasm of the bile duct.

World J Gastroenterol 2021 Apr;27(15):1569-1577

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Bile duct epithelial tumours showing papillary neoplasm in the bile duct lumen are present in the intrahepatic and extrahepatic bile ducts. Clinicopathological images of these tumours are distinctive and diverse, including histological images with a low to high grade dysplasia, infiltrating and noninfiltrating characteristics, excessive mucus production, and similarity to intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The World Health Organization Classification of Tumours of the Digestive System in 2010 named these features, intraductal papillary neoplasm of the bile duct (IPNB), as precancerous lesion of biliary carcinoma. IPNB is currently classified into type 1 that is similar to IPMN, and type 2 that is not similar to IPMN. Many of IPNB spreads superficially, and diagnosis with cholangioscopy is considered mandatory to identify accurate localization and progression. Prognosis of IPNB is said to be better than normal bile duct cancer.
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http://dx.doi.org/10.3748/wjg.v27.i15.1569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058653PMC
April 2021

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

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

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

Sci Rep 2021 Mar 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

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

Liver Cancer 2020 Sep 22;9(5):596-612. Epub 2020 Jul 22.

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

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden.

Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs.

Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC.

Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC.

Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.
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http://dx.doi.org/10.1159/000508809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548915PMC
September 2020

Role of Autoimmunity in Patients Transplanted for Acute Liver Failure of Unknown Origin: A Clinical and Graft Biopsy Analysis.

Liver Transpl 2021 02 22;27(2):309-310. Epub 2020 Nov 22.

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

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http://dx.doi.org/10.1002/lt.25917DOI Listing
February 2021

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

Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation?

Liver Transpl 2019 09 19;25(9):1455-1456. Epub 2019 Jul 19.

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

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http://dx.doi.org/10.1002/lt.25590DOI Listing
September 2019

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

Letter to the Editor: Ductular Reaction in Acute Onset Autoimmune Hepatitis.

Hepatology 2019 08;70(2):756-757

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

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http://dx.doi.org/10.1002/hep.30621DOI Listing
August 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

Letter: acute liver failure of indeterminate aetiology.

Aliment Pharmacol Ther 2018 11;48(9):1024-1025

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

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http://dx.doi.org/10.1111/apt.14931DOI Listing
November 2018

High recovery rate of consciousness by high-volume filtrate hemodiafiltration for fulminant hepatitis.

Hepatol Res 2019 Feb 9;49(2):224-231. Epub 2018 Nov 9.

Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.

Aim: An artificial liver support (ALS) system sustaining patients with acute liver failure (ALF) in good condition until recovery of the native liver or performance of liver transplantation (LT), is essential for the improvement of the poor prognosis of ALF despite the lack of survival benefit. We aimed to investigate the efficacy of various ALS systems for fulminant hepatitis (FH) carried out in our liver unit so far, focusing on the restoration of consciousness from hepatic encephalopathy.

Methods: One hundred and ten consecutive adult Japanese patients with FH admitted to Chiba University Hospital (Chiba, Japan) between 1988 and 2016 who received ALS were analyzed.

Results: Recovery rate of consciousness improved with the increased dialysate flow rate and filtrate rate: 37.5% by plasma exchange (PE), 51.9% by PE + continuous hemodiafiltration (CHDF), 57.7% by slow PE (sPE) + high-flow CHDF (HFCHDF) (Q  = 300 mL/min), 88.6% by HFCHDF (Q  = 500 mL/min) (+ sPE), and 92.9% by on-line HDF (OLHDF) (+ sPE). All patients except one, who could not be fully treated because of circulatory failure, recovered consciousness by OLHDF, including those whose liver function were completely abolished. Superiority of HFCHDF (Q  = 500 mL/min) and OLHDF was also shown in patients who died without LT or received LT.

Conclusions: More effective ALS should be recognized considering the extremely high recovery rate of consciousness. In particular, OLHDF with predilution reduces the cost of substitution fluid by supplying an unlimited amount of dialysate as substitution fluid prepared using an on-line system, and simplifies the procedure for the management.
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http://dx.doi.org/10.1111/hepr.13255DOI Listing
February 2019

Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection.

Hepatol Int 2018 Nov 21;12(6):523-530. Epub 2018 Sep 21.

Department of Gastroenterology, Yamanashi Central Hospital, Kofu, Yamanashi, Japan.

Background: Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear.

Methods: We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy.

Results: Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1 year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging "dysplastic nodule".

Conclusions: SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging "dysplastic nodule" was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of "dysplastic nodule" by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed.
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http://dx.doi.org/10.1007/s12072-018-9895-5DOI Listing
November 2018

Five Cases of Interstitial Pneumonitis Due to Gemcitabine and Nab-Paclitaxel Combination Treatment in Pancreatic Cancer Patients.

Pancreas 2018 08;47(7):e42-e43

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

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http://dx.doi.org/10.1097/MPA.0000000000001088DOI Listing
August 2018

Risk factors of ineffective drainage in uncovered self-expandable metal stenting for unresectable malignant hilar biliary strictures.

Oncotarget 2018 Jun 15;9(46):28185-28194. Epub 2018 Jun 15.

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

Aim: In this study, we assessed the factors contributing to ineffective drainage in the initial transpapillary uncovered self-expandable metal stent (USEMS) placements in patients with unresectable malignant hilar biliary strictures (UMHBSs) (Bismuth type II or higher).

Methods: This was a retrospective, single-center study. A total of 97 patients with UMHBSs who underwent technically successful initial USEMS placements using endoscopic retrograde cholangiopancreatography (ERCP) were classified into the effective drainage group (n = 73) or the ineffective drainage group (n = 24). We then compared group characteristics, clinical outcomes, and drained liver volumes. Drained liver volume was measured by using computed tomography volumetry. The definition of effective biliary drainage was a 50% decrease in the serum total bilirubin level or normalization of the level within 14 days of stent placement.

Results: Univariate analysis showed that ineffective drainage was associated with the pre-ERCP serum total bilirubin level ( = 0.0075), pre-ERCP serum albumin level ( = 0.042), comorbid liver cirrhosis ( = 0.010), drained liver volume ( = 0.0010), and single stenting ( = 0.022). Multivariate analysis identified comorbid liver cirrhosis (adjusted odds ratio [OR], 5.79; 95% confidence interval [CI], 1.30-25.85; = 0.022) and drained liver volume < 50% (adjusted OR, 5.50; 95% CI, 1.50-20.25; = 0.010) as independent risk factors of ineffective drainage.

Conclusion: Comorbid liver cirrhosis and a drained liver volume < 50% contributed significantly to ineffective drainage in the initial transpapillary USEMS placements for UMHBSs.
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http://dx.doi.org/10.18632/oncotarget.25598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021331PMC
June 2018

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

A Role of Renal Replacement Therapy for Acute Liver Failure.

Hepatology 2018 09;68(3):1204

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

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http://dx.doi.org/10.1002/hep.30081DOI Listing
September 2018

Successful retreatment with grazoprevir and elbasvir for patients infected with hepatitis C virus genotype 1b, who discontinued prior treatment with NS5A inhibitor-including regimens due to adverse events.

Oncotarget 2018 Mar 23;9(22):16263-16270. Epub 2018 Mar 23.

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

Background: Sustained virologic response (SVR) by interferon and interferon-free treatment can results in the reduction of advanced liver fibrosis and the occurrence of hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). Recent interferon-free treatment for HCV shortens the duration of treatment and leads to higher SVR rates, without any serious adverse events. However, it is important to retreat patients who have had treatment-failure with HCV non-structural protein 5A (NS5A) inhibitor-including regimens. Combination of sofosbuvir and ledipasvir only leads to approximately 100% SVR rates in HCV genotype (GT1b), NS5A inhibitor-naïve patients in Japan. This combination is not an indication for severe renal disease or heart disease, and these patients should be treated or retreated with a different regimen.

Case Summary: Retreatment with HCV non-structural protein 3/4A inhibitor, grazoprevir, and HCV NS5A inhibitor, elbasvir, successfully eradicated HCV RNA in three patients with HCV genotype 1b infection who discontinued prior interferon-free treatments including HCV NS5A inhibitors due to adverse events within 2 weeks.

Conclusion: Retreatment with the 12-week combination regimen of grazoprevir and elbasvir is effective for HCV GT1b patients who discontinue the HCV NS5A inhibitor-including regimens within 2 weeks. The treatment response may be related to the short duration of initial treatment, which did not produce treatment-emergent RASs.
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http://dx.doi.org/10.18632/oncotarget.24620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882333PMC
March 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

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis.

Oncotarget 2018 Feb 3;9(14):11631-11637. Epub 2018 Feb 3.

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

Background: Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases.

Results: All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment.

Conclusions: Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments.

Methods: Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.
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http://dx.doi.org/10.18632/oncotarget.24391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837765PMC
February 2018

Long-term observation of acute-onset autoimmune hepatitis presenting clinically and radiologically as acute hepatitis.

Hepatol Int 2018 Mar 15;12(2):191-199. Epub 2018 Feb 15.

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

Background: There is yet no gold standard for the diagnosis of acute-onset autoimmune hepatitis (A-AIH), especially histologically acute AIH. As a result, long-term observation of A-AIH has been difficult and the nature is not well known. We retrospectively analyzed the clinicopathological features of A-AIH over a long prospective follow-up period.

Methods: Clinical, biochemical, immunological and pathological features of 30 patients (21 female, mean age 55.1 ± 13.1 years) with non-severe A-AIH "without signs of clinical and radiological chronicity" admitted to a community hospital between 2001 and 2015 who were prospectively followed for more than 2 years were analyzed retrospectively.

Results: Liver histology of 45% showed acute and 55% chronic hepatitis. Mean age was older, prothrombin time activity was higher, AIH scores before treatment were lower in histologically acute hepatitis than histologically chronic hepatitis significantly. Liver fibrosis was not coarse, but delicate with severe activity in most patients showing chronic hepatitis defined by our strict criteria. Median (range) follow-up period was 6.9 (2.1-16.2) years. Six (20%) patients experienced episode of relapses. All were alive at the last follow-up point. Corticosteroid was continued at 2.5-5 mg/day until the study end point without serious side effects in most patients. Serial change of alanine aminotransferase levels, immunoglobulin G levels and anti-nuclear antibody titers did not show statistical difference between histologically acute and chronic hepatitis.

Conclusion: Rapid progression of fibrosis could occur in A-AIH. Treatment response and long-term prognosis were good, and not different between patients with histologically acute and chronic hepatitis.
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http://dx.doi.org/10.1007/s12072-018-9848-zDOI Listing
March 2018

Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature.

Oncotarget 2018 Jan 29;9(4):5509-5513. Epub 2017 Dec 29.

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

Background: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ∼70% SVR rates.

Case Summary: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment.

Conclusion: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment.
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http://dx.doi.org/10.18632/oncotarget.23768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797068PMC
January 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

Early Combination Therapy with Corticosteroid and Nucleoside Analogue Induces Rapid Resolution of Inflammation in Acute Liver Failure due to Transient Hepatitis B Virus Infection.

Intern Med 2018 Jun 11;57(11):1543-1552. Epub 2018 Jan 11.

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

Objective Patients with acute hepatitis B sometimes develop acute liver failure (ALF), which has a poor prognosis. The efficacy of nucleoside analogue (NA) monotherapy for ALF due to transient hepatitis B virus infection (HBV-ALF) remains controversial. Further investigations are necessary in nations with a shortage of donor livers for liver transplantation. In the present study, we aimed to clarify the efficacy of combination therapy with corticosteroid (CS) and NA in the treatment HBV-ALF. Patients We examined the clinical and biochemical features of 19 patients with HBV-ALF who were treated in the early stage of the disease between 2000 and 2015. Results Fourteen patients received CS and NA (CS + NA group) and 5 received NA monotherapy (NA group). Eleven patients (58%) survived and 8 (42%) died. The survival rates in the CS + NA and NA groups were 64% and 40%, respectively (p=0.60). The mean alanine aminotransferase (ALT) levels declined significantly at week 2 in both groups. The mean PT activities improved significantly at weeks 1 and 2 in the CS + NA group (p<0.05) but not in the NA group. None of the surviving patients developed persistent infection. Conclusion Combination therapy with CS and NA induces the rapid resolution of inflammation leading to a rapid recovery of the liver function. When it is administered at a sufficiently early stage, it would have a survival benefit and prevent persistent infection in HBV-ALF.
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http://dx.doi.org/10.2169/internalmedicine.9670-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028684PMC
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

Association of Genotype with Hepatic Steatosis in Chronic Hepatitis C Patients Treated with Peginterferon and Ribavirin Combination Therapy.

Int J Med Sci 2017 4;14(11):1088-1093. Epub 2017 Sep 4.

Department of Molecular Virology, Graduate School of Medicine, Chiba University, Japan.

Background: Genetic variation near the interferon lambda 3 () is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis.

Aims: We examined whether this genetic variation is associated with host lipids and treatment response.

Methods: A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis.

Results: Forty patients (40%) had liver steatosis before therapy. Patients with minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, genotype was the most significant predictor, as per multivariate analysis.

Conclusions: Our results confirmed that genotype is associated with hepatic steatosis as well as IFN response.
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http://dx.doi.org/10.7150/ijms.20171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666539PMC
June 2018