Publications by authors named "Koji Sawada"

58 Publications

A Successful Case of Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab with Multisystem Immune-related Adverse Events.

Intern Med 2022 Apr 30. Epub 2022 Apr 30.

Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.

A 63-year-old man with hepatitis C was treated with atezolizumab plus bevacizumab for unresectable diffuse hepatocellular carcinoma (HCC). After four cycles of atezolizumab plus bevacizumab, the diffuse HCC markedly shrank; however, he complained of general fatigue, loss of appetite, and slight loss of muscle strength in the lower legs. He was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD), hypothyroidism, and myopathy, suggesting multisystem immune-related adverse events (irAEs). After administration of hydrocortisone, the clinical symptoms rapidly disappeared. Patients with multisystem irAEs can have favorable outcomes; thus, to continue immune-checkpoint inhibitors therapy, a correct diagnosis and management of multisystem irAEs are important.
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http://dx.doi.org/10.2169/internalmedicine.9393-22DOI Listing
April 2022

Submarine volcanic eruption of esophageal varices induced by failed variceal ligation and identified by the gel immersion method.

Dig Endosc 2022 May 29;34(4):e85-e86. Epub 2022 Mar 29.

Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan.

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http://dx.doi.org/10.1111/den.14281DOI Listing
May 2022

The treatment choices and outcome of hepatocellular carcinoma in hemophilic patients with human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection due to contaminated blood products in Japan.

J Gastrointest Oncol 2021 Dec;12(6):2952-2959

Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Background: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection through unheated blood product for hemophilia caused in early 1980s has been significantly serious problem in Japan. After the development of HIV treatment in 1990s, HCV-related hepatocellular carcinoma (HCC) has been one of the most significant problem in these population. Treatment choices for HCC might be limited in hemophilia patients because of their bleeding tendency. The aim of this study was to elucidate the treatment choices and outcome of HCC in hemophilic patients coinfected with HIV/HCV due to contaminated blood products.

Methods: We asked 444 Japanese centers that specialize in treating HIV patients for participation, whether they have HIV/HCV coinfected cases with HCC, and the patient characteristics, treatments for HCC and survival after treatments were retrospectively reviewed according to each institutional medical records.

Results: Of 444 centers, 139 centers (31%) responded to the first query, and 8 centers (1.8%) ultimately provided 26 cases of HCC in coinfected hemophilic patients, diagnosed between December 1999 and December 2017. All 26 were male hemophilic patients, with a median age at HCC diagnosis of 49 (range, 34-73) years. Thirteen cases (50%) were HCV-RNA positive, and 14 cases (54%) had a solitary tumor. Even in the cases of Child-Pugh grade A, only 1 case underwent resection, and 18 cases (69%) did not receive the standard treatment recommended by the Japanese Society of Hepatology.

Conclusions: Hemophilic HCC patients with HIV/HCV coinfection may not routinely receive standard treatment due to their bleeding tendency and several complications related to HIV/HCV coinfection.
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http://dx.doi.org/10.21037/jgo-21-157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748074PMC
December 2021

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

Clin Gastroenterol Hepatol 2022 Jan 17. Epub 2022 Jan 17.

Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.

Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.

Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.

Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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http://dx.doi.org/10.1016/j.cgh.2022.01.002DOI Listing
January 2022

Treatment of hepatocellular carcinoma with autologous platelets encapsulating sorafenib or lenvatinib: A novel therapy exploiting tumor-platelet interactions.

Int J Cancer 2022 05 29;150(10):1640-1653. Epub 2021 Dec 29.

Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.

Hepatocellular carcinoma (HCC) activates platelets through the action of adjacent sinusoidal cells. Activated platelets bind to tumor-associated endothelial cells and release growth factors that promote tumor progression. We hypothesized that platelets encapsulated with tumor inhibitors would function as drug carriers for tumor therapy. We propose a therapeutic strategy for HCC using autologous platelets encapsulating multiple tyrosine kinase inhibitors in a rat chemically induced HCC model. Sorafenib or lenvatinib was encapsulated in platelets isolated from tumor-bearing rats in vitro. The rats were divided into groups that received repeated intravenous injections (twice a week for 10 weeks) of the following materials: placebo, sorafenib (SOR), lenvatinib (LEN), autologous platelets, autologous platelets encapsulating sorafenib (SOR-PLT) and autologous platelets encapsulating lenvatinib (LEN-PLT). The therapeutic effect was then analyzed by ultrasonography (US) and histopathological analysis. Histopathological and US analysis demonstrated extensive tumor necrosis in the tumor tissue of SOR-PLT or LEN-PLT, but not in other experimental groups. By liquid chromatography-mass spectrometry, more abundant sorafenib was detected in tumor tissues after SOR-PLT administration than in surrounding normal tissues, but no such difference in sorafenib level was observed with SOR administration. Therefore, the use of autologous platelets encapsulating drugs might be a novel therapeutic strategy for HCC.
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http://dx.doi.org/10.1002/ijc.33915DOI Listing
May 2022

Endoscopic findings of hepatocellular carcinoma invading the duodenum.

Jpn J Clin Oncol 2021 11;51(11):1689-1690

Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.

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http://dx.doi.org/10.1093/jjco/hyab125DOI Listing
November 2021

Brain metastasis from hepatic cholangiolocellular carcinoma in a young female without chronic liver disease.

Dig Liver Dis 2021 Sep 27;53(9):1206-1207. Epub 2020 Aug 27.

Division of gastroenterology and hematology/oncology, Department of medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka Higashi, Asahikawa, Hokkaido 078-8510, Japan.

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http://dx.doi.org/10.1016/j.dld.2020.08.002DOI Listing
September 2021

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.
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http://dx.doi.org/10.3390/ijms21144939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404115PMC
July 2020

Efficacy of Granulocyte and Monocyte Adsorptive Apheresis in Patients With Inflammatory Bowel Disease Showing Lost Response to Infliximab.

J Crohns Colitis 2020 Sep;14(9):1264-1273

IBD Centre, Toho University Sakura Medical Centre, Chiba, Japan.

Background And Aims: In inflammatory bowel disease [IBD] patients, antibody-to-infliximab [ATI] generation is responsible for loss of response [LOR] and infusion reaction [IR] to infliximab. An immuno-therapeutic approach is considered an option to overcome LOR. Granulocyte/monocyte adsorptive apheresis [GMA] using an Adacolumn has been shown to have clinical efficacy together with immunomodulatory effects in IBD patients.

Methods: We developed an ATI-CAI assay utilizing a C1q immobilized plate and applied it to measure ATI in patients who were receiving infliximab, including 56 with sustained response, 76 with LOR and six with IR. Furthermore, 14 patients with LOR and two with paradoxical skin reactions who received infliximab + GMA combination therapy were analysed.

Results: Fourteen patients with LOR, seven with Crohn's disease and seven with ulcerative colitis, showed significantly improved clinical indices [p = 0.0009], and decreased ATI [p = 0.0171] and interleukin-6 [p = 0.0537] levels at week 8 following initiation of infliximab + GMA therapy. Nine patients who received combination therapy achieved remission, which was maintained to week 24 with infliximab alone. Additionally, cutaneous lesions in two patients with IR were improved. ATI-CAI assay efficiency was not influenced by infliximab concentration during the test. Pre- and post-infliximab infusion ATI levels were not different. Patients with ATI greater than the 0.153 μg/mL cut-off value were likely to experience LOR [odds ratio 3.0].

Conclusions: Patients who received infliximab + GMA therapy appeared to regain clinical response to infliximab by a decrease in ATI level. Furthermore, the concentration of infliximab in the test did not influence ATI measurement, but was associated with clinical response.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa051DOI Listing
September 2020

Efficacy of apheresis as maintenance therapy for patients with ulcerative colitis in an open-label prospective multicenter randomised controlled trial.

J Gastroenterol 2020 Apr 6;55(4):390-400. Epub 2019 Dec 6.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Background: Apheresis therapy involves the selective removal of leukocytes and is used to induce remission in ulcerative colitis (UC) patients. The aim of this study was to demonstrate the efficacy and safety of apheresis therapy for maintaining UC remission.

Methods: We conducted a multicenter, prospective, randomised-control trial of patients with remitting UC induced by granulocyte and monocyte adsorption apheresis or leukocytapheresis. Patients were randomly assigned to the apheresis group (twice per month for 12 months) or the control group (no apheresis treatment) using a 1:1 allocation ratio. The primary endpoint was the rate of cumulative clinical remission (Mayo score ≤ 2) at 12 months. The secondary endpoints were the rates of clinical remission, endoscopic remission, and complete endoscopic remission at 12 months.

Results: Between March 2013 and March 2017, 164 patients were enrolled. The cumulative remission rate at 12 months was 46.6% in the apheresis group and 36.4% in the control group (p = 0.1621). The rate of endoscopic remission at 12 months was significantly higher in the apheresis group than in the control group (42.5% vs. 25.9%) p = 0.0480). The rate of clinical remission (47.5% vs.32.1%, p = 0.0540) and complete endoscopic remission (33.8% vs.19.8%, p = 0.0513) tended to be higher in the apheresis than in the control group; however, the difference was not significant. No severe adverse events were observed in either group.

Conclusions: Apheresis was well tolerated as maintenance therapy for UC although the cumulative clinical remission rate at 12 months was comparable between the apheresis and control groups.
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http://dx.doi.org/10.1007/s00535-019-01651-0DOI Listing
April 2020

Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor.

J Gastroenterol Hepatol 2020 Jun 21;35(6):1042-1048. Epub 2019 Nov 21.

Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.

Background And Aim: Because of their survival benefits, immune checkpoint inhibitors (ICIs) are widely administered to patients with various advanced-stage malignancies. During ICI treatment, drug-induced liver injury (DILI) occasionally occurs. In particular, hepatic immune-related adverse events (irAEs) are rare but serious and fatal. In patients with hepatic irAEs, immediate steroid treatment is generally recommended; however, the risk factors for ICI-associated DILI remain unknown. In the present study, we identified a risk factor for ICI-associated DILI.

Methods: We retrospectively analyzed 135 patients treated with anti-programmed cell death-1 (PD-1) antibodies, such as nivolumab and pembrolizumab, at Asahikawa Medical University Hospital. We investigated grade ≥ 2 hepatotoxic AEs during anti-PD-1 therapy, and PD-1 inhibitor-associated DILI was then diagnosed according to the Digestive Disease Week Japan (DDW-J) 2004 scale. The risk factors for PD-1 inhibitor-associated DILI were identified by Cox hazard analysis.

Results: Thirty-six patients developed grade ≥ 2 hepatic AEs during anti-PD-1 therapy. Among them, eight patients were diagnosed with PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. Cox hazard analysis revealed that non-alcoholic fatty liver disease (NAFLD) was a risk factor for PD-1 inhibitor-associated DILI. In addition, we revealed that the outcomes of patients with the DDW-J 2004 score = 3 were improved without steroid treatment.

Conclusions: NAFLD is a potential risk factor for PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. The DDW-J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD-1 inhibitor-associated DILI.
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http://dx.doi.org/10.1111/jgh.14889DOI Listing
June 2020

Repeated Perforation of the Gallbladder in a Patient with Hepatocellular Carcinoma Receiving Lenvatinib.

Intern Med 2020 Mar 18;59(5):657-662. Epub 2019 Nov 18.

Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Japan.

A 59-year-old man who was receiving lenvatinib as a third-line tyrosine kinase inhibitor to treat hepatocellular carcinoma and multiple bone metastases complained of general fatigue four months after starting lenvatinib. A blood examination showed unexpectedly elevated serum C-reactive protein (CRP) levels. Computed tomography (CT) revealed rupture of the gallbladder wall, indicating gallbladder perforation. After conservative treatment, the patient received lenvatinib again under informed consent; however, one month later, CT revealed repeated rupture of the gallbladder wall. Gallbladder perforation had again been induced by lenvatinib. For this reason, lenvatinib is strongly considered a causative drug for gallbladder perforation.
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http://dx.doi.org/10.2169/internalmedicine.3806-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086315PMC
March 2020

Long-term growth of intrahepatic papillary neoplasms: A case report.

World J Gastroenterol 2019 Sep;25(36):5569-5577

Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa 0788510, Hokkaido, Japan.

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a type of tumor that presents in the intra- or extrahepatic bile ducts. Cystic-type intrahepatic IPNB often mimics simple liver cysts, making the diagnosis difficult. Because the growth of IPNB is slow, careful follow-up and timely therapeutic intervention is recommended. There are few reports with a follow-up period longer than a decade; thus, we report the case of a patient with an IPNB that grew for over 13 years.

Case Summary: A 65-year-old man was diagnosed, 13 years prior with a cystic hepatic tumor with abnormal imaging findings. The targeted tumor biopsy results showed no malignancy. Biannual follow-up examinations were performed because of the potential for malignancy. The cystic lesions showed gradual enlargement over 11 years and a 4 mm papillary proliferation appeared on the cyst wall, which is compatible with IPNB. The tumor was observed for another 2 years because of the patient's wishes. The imaging findings showed enlargement to 8 mm and a new 9 mm papillary proliferation of the cystic tumor. Contrast-enhanced ultrasonography showed hyperenhancement during the arterial phase in both cyst walls, indicating intraductal tumor progression in both tumors. Thus, liver segment 8 subsegmentectomy was performed. The pathological findings indicated that the tumors contained mucin, and high-grade atypia was observed in the papillary lesions, showing IPNB.

Conclusion: The development of IPNB should be monitored in patients with cystic lesions and ultrasonography are useful tool for the evaluation.
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http://dx.doi.org/10.3748/wjg.v25.i36.5569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767986PMC
September 2019

Skeletal muscle mass is associated with toxicity, treatment tolerability, and additional or subsequent therapies in patients with hepatocellular carcinoma receiving sorafenib treatment.

JGH Open 2019 Aug 12;3(4):329-337. Epub 2019 Mar 12.

Department of Medicine, Division of Gastroenterology and Hematology/Oncology Asahikawa Medical University Asahikawa Japan.

Background And Aim: Several reports have demonstrated that skeletal muscle mass influences mortality in patients with hepatocellular carcinoma (HCC) receiving sorafenib treatment; however, there is still controversy with regard to whether skeletal muscle and adipose tissue are associated with the prognosis in HCC patients. We examined the relationship between body composition and prognosis in HCC patients.

Methods: We retrospectively analyzed 82 patients with unresectable HCC receiving sorafenib treatment. The skeletal muscle area and adipose tissue area were measured by computed tomography. Patients with low skeletal muscle index (male ≤36.2 cm/m, female ≤29.6 cm/m) and high visceral to subcutaneous adipose tissue area ratio (VSR) (male ≥ 1.33, female ≥ 0.93) were diagnosed as low skeletal muscle mass (LSMM) and high VSR, respectively.

Results: A total of 16 and 34 patients were classified as LSMM and high VSR, respectively. LSMM patients frequently experienced serious adverse events (SAEs) and thus had a shorter duration of sorafenib treatment than non-LSMM patients. High VSR was a significant factor for progression-free survival. LSMM patients less frequently received additional/subsequent therapies combined with sorafenib than non-LSMM patients. Multivariate Cox hazard analysis demonstrated that LSMM was a significant factor for the duration of sorafenib treatment. The treatment duration and receiving of additional/subsequent therapies were significantly associated with overall survival (OS) but not with LSMM or high VSR.

Conclusion: LSMM was associated with the frequency of SAEs, treatment tolerability, and treatment duration. LSMM patients were less likely to receive additional/subsequent therapies than non-LSMM patients. Thus, LSMM could identify a subgroup of patients with poor OS.
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http://dx.doi.org/10.1002/jgh3.12167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684515PMC
August 2019

Hepatitis B virus (HBV) reactivation in an acute lymphoblastic leukemia patient despite being vaccinated against HBV in infancy.

Dig Liver Dis 2019 10 30;51(10):1487-1488. Epub 2019 Jul 30.

Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.dld.2019.07.003DOI Listing
October 2019

Development of a C1q-immobilized (Cim) assay to measure total antibodies to infliximab and its clinical relevance in patients with inflammatory bowel disease.

Cytokine 2019 08 16;120:54-61. Epub 2019 Apr 16.

IBD Centre, Toho University Sakura Medical Centre, Chiba, Japan. Electronic address:

Objective: Determination of antibodies to infliximab (ATI) is desirable for the management of patients with inflammatory bowel disease (IBD) who receive infliximab. Conventional ligand-binding ATI-assays detect only free-form of ATI, potentially increasing the proportion of patients with undetectable ATI, but with adequate trough infliximab (TRI) level who experience loss of response (LOR) to infliximab. We investigated this assertion using a novel ATI-Cim assay.

Methods: An ATI-Cim assay was developed by utilizing a C1q-immobilized plate, detecting free-form and ATI-infliximab complexes. Plasma ATI in 137 consecutive IBD patients, 56 with sustained clinical response (SCR), 76 with LOR and 5 with infusion reactions was measured.

Results: ATI levels reached a plateau following addition of up to 25 μg/mL infliximab to different concentrations of free-form ATI. ATI concentration did not significantly change during infliximab infusion (P = 0.4316). ATI concentration > 0.153 μg/mL was associated with LOR (odds ratio 3.0: 95%, confidence interval 1.5 to 6.1, P = 0.0029). The number of patients with undetectable ATI was higher in SCR than in LOR, 53.6% vs 22.4% (P = 0.0004). Patients with SCR and LOR were divided into 4 subgroups by combined cut-off ATI and TRI values. (A) ATI > 0.153 μg/mL and TRI ≤ 2 μg/mL; (B) ATI > 0.153 μg/mL and TRI > 2 μg/mL; (C) ATI ≤ 0.153 μg/mL and TRI ≤ 2 μg/mL; (D) ATI ≤ 0.153 μg/mL and TRI > 2 μg/mL. The frequency of LOR showed a decreasing trend from subgroup A to D, 80.8%, 64.1%, 55.2% and 36.8%, respectively (P = 0.0003).

Conclusions: The measured ATI level appeared to define the patients' response to infliximab. Combining ATI and trough infliximab levels should help to understand the mechanism of LOR and make therapeutic algorithms.
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http://dx.doi.org/10.1016/j.cyto.2019.02.014DOI Listing
August 2019

Successful Treatment of Nivolumab-related Cholangitis with Prednisolone: A Case Report and Review of the Literature.

Intern Med 2019 Jun 25;58(12):1747-1752. Epub 2019 Feb 25.

Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.

The patient was a 76-year-old man who was treated with nivolumab due to recurrent gastric cancer. A blood examination revealed grade 3 alkaline phosphatase (ALP) elevation. A histopathological examination revealed marked portal infiltration, including eosinophils and CD4+ and CD8+ T lymphocytes, suggesting nivolumab-related cholangitis accompanied by the features of both an immune-related adverse event (irAE) and drug-induced liver injury (DILI) with allergic reaction. The patient's ALP level immediately decreased after the administration of prednisolone. Although nivolumab-related cholangitis, a rare irAE, has been reported to be refractory to steroid therapy, patients with features of irAE and allergic DILI might immediately respond to prednisolone.
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http://dx.doi.org/10.2169/internalmedicine.2330-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630117PMC
June 2019

A Data Mining-based Prognostic Algorithm for NAFLD-related Hepatoma Patients: A Nationwide Study by the Japan Study Group of NAFLD.

Sci Rep 2018 Jul 11;8(1):10434. Epub 2018 Jul 11.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

The prognosis of patients with nonalcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) is intricately associated with various factors. We aimed to investigate the prognostic algorithm of NAFLD-HCC patients using a data-mining analysis. A total of 247 NAFLD-HCC patients diagnosed from 2000 to 2014 were registered from 17 medical institutions in Japan. Of these, 136 patients remained alive (Alive group) and 111 patients had died at the censor time point (Deceased group). The random forest analysis demonstrated that treatment for HCC and the serum albumin level were the first and second distinguishing factors between the Alive and Deceased groups. A decision-tree algorithm revealed that the best profile comprised treatment with hepatectomy or radiofrequency ablation and a serum albumin level ≥3.7 g/dL (Group 1). The second-best profile comprised treatment with hepatectomy or radiofrequency ablation and serum albumin levels <3.7 g/dL (Group 2). The 5-year overall survival rate was significantly higher in the Group 1 than in the Group 2. Thus, we demonstrated that curative treatment for HCC and serum albumin level >3.7 g/dL was the best prognostic profile for NAFLD-HCC patients. This novel prognostic algorithm for patients with NAFLD-HCC could be used for clinical management.
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http://dx.doi.org/10.1038/s41598-018-28650-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041283PMC
July 2018

Cytapheresis (CAP) with leukocyte removal filter/bead column as one therapeutic option for inflammatory bowel disease.

Authors:
Koji Sawada

Transfus Apher Sci 2017 Oct 30;56(5):689-697. Epub 2017 Aug 30.

Chionkai, Dojima General and Gastroenterology Clinic (Inflammatory Bowel Disease & Liver Disease), B1F Shin-Fujita Bild. Dojima 2-4-27, Kita-ku, Osaka 530-0003, Japan. Electronic address:

Inflammatory bowel disease (IBD) like Crohn's disease and ulcerative colitis are chronic inflammatory disorders that affect the bowel. The disease is characterized by periods of clinical remission and relapse due to severe intestinal inflammation. Drug therapy of IBD is associated with unpleasant side effects. Further, efficacies of conventional drugs decrease with chronic use and this can represent a major difficulty in the long term management of IBD. However, in active IBD, leukocytes are elevated in the lesion they may be able to be a factor of IBD aggravation. Membrane filters column and leukocyte adsorbing beads have been developed which are direct blood perfusion systems for removing any desired level of leukocytes. Clinical studies with these two new models have shown good effects for active IBD. Clinical data suggest that leukocytapheresis might be an effective adjunct to therapy of IBD, to promote remission, taper conventional drug dosage and potentially should reduce the number of patients who require colectomy. The results may further understandings of the pathophysiology of IBD and this in turn should contribute to a more effective treatment of this disorder.
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http://dx.doi.org/10.1016/j.transci.2017.08.016DOI Listing
October 2017

Tegafur-uracil-induced rapid development of advanced hepatic fibrosis.

World J Gastroenterol 2017 Aug;23(31):5823-5828

Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan.

Tegafur-uracil has been reported to have only minor adverse effects and is associated with liver injury in 1.79% of Japanese patients. The development of tegafur-uracil-induced hepatic fibrosis with portal hypertension is rare. Here, we report a case of a 74-year-old woman with rapidly developing tegafur-uracil-induced hepatic fibrosis. The patient had no history of liver disease and had been treated with tegafur-uracil for 8 mo after breast cancer surgery. The patient was admitted to our hospital for abdominal distension and leg edema associated with liver dysfunction. Computed tomography imaging revealed massive ascites and splenomegaly, and a non-invasive assessment of liver fibrosis indicated advanced fibrosis. The histopathological findings revealed periportal fibrosis and bridging fibrosis with septation. The massive ascites resolved after discontinuing tegafur-uracil. These findings suggest that advanced hepatic fibrosis can develop from a relatively short-term administration of tegafur-uracil and that non-invasive assessment is useful for predicting hepatic fibrosis.
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http://dx.doi.org/10.3748/wjg.v23.i31.5823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569298PMC
August 2017

Treatment options for children and adolescents with inflammatory bowel disease: is granulomonocytapheresis an effective alternative to drug therapy?

Expert Rev Gastroenterol Hepatol 2017 Aug 28;11(8):749-758. Epub 2017 Jun 28.

d Department of Gastroenterology , Cisanello Pisa University Hospital, Gastroenterology and Metabolic Diseases Unit , Pisa , Italy.

Introduction: Patients with inflammatory bowel diseases (IBD) require life-long medications, which even if effective have the potential to cause adverse effects as additional morbidity factors. In pediatric patients, drug therapy has more serious limitations, including impaired physical and mental development. A non-drug therapeutic option is believed to be depletion of elevated and activated granulocytes and monocytes known to release inflammatory cytokines, like the CD14+CD16+ monocyte phenotype known to release tumor necrosis factor-α. Areas covered: Granulomonocyteapheresis (GMA) with an Adacolumn as a treatment option for IBD patients has been applied for the past 15 years. This article reviews the argument that GMA is a relevant and effective non-pharmacologic intervention in pediatric IBD setting. Expert commentary: GMA with an Adacolumn has shown promise in adult, pediatric, and adolescent patients with active IBD. There is evidence of post-GMA immunomodulation in terms of increased regulatory T-cell and B-cell activities. Additionally, patients who respond to GMA may attain a favorable long-term clinical course by avoiding pharmacologicals during an early phase of their active IBD. GMA has a good safety profile, especially in difficult-to-treat and pediatric settings. An additional trial is warranted to assess the efficacy of GMA in the early phase of pediatric IBD to optimize patient selection.
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http://dx.doi.org/10.1080/17474124.2017.1341309DOI Listing
August 2017

Polymorphism of receptor-type tyrosine-protein phosphatase delta gene in the development of non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2018 Jan;33(1):283-290

Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.

Background And Aim: Some single-nucleotide polymorphisms (SNPs) are associated with the development of non-alcoholic fatty liver disease (NAFLD). As one of the genetic factors, PNPLA3 rs738409 (I148M) is important to associate with pathogenesis of NAFLD. Because other SNPs remain unclear in Japan, we performed a high-throughput sequencing that targeted more than 1000 genes to identify a novel genetic variant in Japanese patients with NAFLD.

Methods: The present study in 36 NAFLD patients and 27 healthy volunteers was performed. A high-throughput sequencer was used to detect the gene variations. Candidate genes were validated by TaqMan SNP genotyping assay in 53 NAFLD patients and 41 healthy volunteers. To investigate the function of candidate gene, we performed biochemical analyses in cultured hepatocytes and liver tissues.

Results: EXO1 rs1047840, PTPRD rs35929428, IFNAR2 rs2229207, CPOX rs1131857, IL23R rs1884444, IL10RA rs2228055, and FAM3B rs111988437 were identified as candidate genetic variants, and PTPRD rs35929428 was only extracted as a SNP predicting to cause protein dysfunction. In validation analysis, PTPRD rs35929428 associated with the development of NAFLD (P = 0.015, odds ratio = 5.00, 95% confidence interval: 1.33-18.70). In addition, PTPRD rs35929428 was associated with Fib-4 index and with hepatic fat droplets. Biochemical analyses indicated that PTPRD rs35929428 promoted dephosphorylation of tyrosine 705 signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes.

Conclusion: PTPRD rs35929428 was a novel SNP in patients with NAFLD. Through exacerbation of the dephosphorylation of signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes, PTPRD rs35929428 might play a role in hepatic lipid accumulation and fibrosis, followed by the development of NAFLD.
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http://dx.doi.org/10.1111/jgh.13820DOI Listing
January 2018

A case of liver hemangioma with markedly reduced tumor size after metformin treatment: a case report.

Clin J Gastroenterol 2017 Feb 19;10(1):63-67. Epub 2016 Dec 19.

Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 1-1-1 Midorigaoka Higashi 2 Jo, Asahikawa, Hokkaido, 078-8510, Japan.

A 52-year-old man with a 9-year history of hepatic hemangioma was treated with the anti-diabetic drug metformin, resulting in complete remission of the tumor. In 2006, a hemangioma with diameter of 20 × 25 mm was detected incidentally in the liver. The results of imaging studies including ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) were all compatible with that of hepatic hemangioma. The patient consequently underwent imaging annually from 2006 to 2015. The tumor size increased slightly, to 30 × 35 mm in 2012; however, the general tumor characteristics in imaging were not changed. Beginning May 2012, metformin (750 mg/day) was administered because of an increase in blood sugar and hemoglobin A1c levels. After the start of metformin treatment, the tumor size on US gradually decreased. Finally, in October 2015, the tumor was no longer detected. Dynamic CT study also demonstrated markedly reduced tumor size, with a decrease of 2-3 mm in diameter. These results indicate that metformin treatment strongly suppressed cell proliferation in liver hemangioma. The anti-angiogenic effect of metformin was indicated as a possible cause of the reduction in tumor size.
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http://dx.doi.org/10.1007/s12328-016-0705-0DOI Listing
February 2017

Bone morphogenetic protein-binding endothelial regulator of liver sinusoidal endothelial cells induces iron overload in a fatty liver mouse model.

J Gastroenterol 2017 Mar 30;52(3):341-351. Epub 2016 Jun 30.

Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Japan.

Background: Non-alcoholic fatty liver disease (NAFLD) is frequently accompanied by iron overload. However, because of the complex hepcidin-regulating molecules, the molecular mechanism underlying iron overload remains unknown. To identify the key molecule involved in NAFLD-associated iron dysregulation, we performed whole-RNA sequencing on the livers of obese mice.

Methods: Male C57BL/6 mice were fed a regular or high-fat diet for 16 or 48 weeks. Internal iron was evaluated by plasma iron, ferritin or hepatic iron content. Whole-RNA sequencing was performed by transcriptome analysis using semiconductor high-throughput sequencer. Mouse liver tissues or isolated hepatocytes and sinusoidal endothelial cells were used to assess the expression of iron-regulating molecules.

Results: Mice fed a high-fat diet for 16 weeks showed excess iron accumulation. Longer exposure to a high-fat diet increased hepatic fibrosis and intrahepatic iron accumulation. A pathway analysis of the sequencing data showed that several inflammatory pathways, including bone morphogenetic protein (BMP)-SMAD signaling, were significantly affected. Sequencing analysis showed 2314 altered genes, including decreased mRNA expression of the hepcidin-coding gene Hamp. Hepcidin protein expression and SMAD phosphorylation, which induces Hamp, were found to be reduced. The expression of BMP-binding endothelial regulator (BMPER), which inhibits BMP-SMAD signaling by binding BMP extracellularly, was up-regulated in fatty livers. In addition, immunohistochemical and cell isolation analyses showed that BMPER was primarily expressed in the liver sinusoidal endothelial cells (LSECs) rather than hepatocytes.

Conclusions: BMPER secretion by LSECs inhibits BMP-SMAD signaling in hepatocytes and further reduces hepcidin protein expression. These intrahepatic molecular interactions suggest a novel molecular basis of iron overload in NAFLD.
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http://dx.doi.org/10.1007/s00535-016-1237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323480PMC
March 2017

A selective splicing variant of hepcidin mRNA in hepatocellular carcinoma cell lines.

Biochem Biophys Res Commun 2016 08 2;476(4):501-507. Epub 2016 Jun 2.

Department of Gastroenterology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan.

Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. By RT-PCR/agarose gel electrophoresis of hepcidin mRNA in a hepatocellular carcinoma cell line HLF, a smaller mRNA band was shown in addition to the wild-type hepcidin mRNA. From sequencing analysis, this additional band was a selective splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene, producing the transcript that encodes truncated peptide lacking 20 amino acids at the middle of preprohepcidin. In the present study, we used the digital PCR, because such a small amount of variant mRNA was difficult to quantitate by the conventional RT-PCR amplification. Among seven hepatoma-derived cell lines, six cell lines have significant copy numbers of this variant mRNA, but not in one cell line. In the transient transfection analysis of variant-type hepcidin cDNA, truncated preprohepcidin has a different character comparing with native preprohepcidin: its product is insensitive to digestion, and secreted into the medium as a whole preprohepcidin form without maturation. Loss or reduction of function of HAMP gene by aberrantly splicing may be a suitable phenomenon to obtain the proliferating advantage of hepatoma cells.
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http://dx.doi.org/10.1016/j.bbrc.2016.05.153DOI Listing
August 2016

Safety and Tolerability of Nafamostat Mesilate and Heparin as Anticoagulants in Leukocytapheresis for Ulcerative Colitis: Post Hoc Analysis of a Large-Scale, Prospective, Observational Study.

Ther Apher Dial 2016 Apr 14;20(2):197-204. Epub 2016 Jan 14.

Center for Advanced IBD Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.

Nafamostat mesilate is the first anticoagulant of choice for leukocytapheresis (LCAP) with a Cellsorba E column for treating ulcerative colitis (UC). However, because of complications, mainly due to allergy to nafamostat mesilate, heparin may be used as a substitute. To evaluate the safety and tolerability of nafamostat mesilate and heparin as anticoagulants in LCAP for UC, we conducted post hoc analysis of data from a large-scale, prospective, observational study of LCAP, which was conducted at 116 medical facilities in Japan between May 2010 and December 2012. Of 832 patients included in this analysis, nafamostat mesilate and heparin were used in 676 (81.3%) and 113 (13.6%), respectively. There were no significant differences in the incidence of adverse reactions (8.6% vs. 7.1%) and intrafilter pressure increases (12.7% vs. 16.8%) between the nafamostat mesilate and heparin groups. Adverse reactions of hemorrhage or blood pressure decreases associated with heparin use were not observed. There were no significant differences in rates of clinical remission (69.1% vs. 68.1%) and mucosal healing (62.9% vs. 63.6%) between the nafamostat mesilate and heparin groups. Thus, the safety and tolerability were comparable in the nafamostat mesilate and heparin groups, indicating that both nafamostat mesilate and heparin can be well tolerated as anticoagulants in LCAP for UC.
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http://dx.doi.org/10.1111/1744-9987.12357DOI Listing
April 2016

Factors associated with treatment outcome, and long-term prognosis of patients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: a prospective multicenter study.

Cytotherapy 2015 May 21;17(5):680-8. Epub 2015 Mar 21.

Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan.

Background: Patients with ulcerative colitis (UC) have elevated/activated myeloid lineage leucocytes and may respond favorably to adsorptive granulocyte/monocyte apheresis (GMA). However, there are patients who respond well to GMA, and patients who do not benefit. Therefore, predictive factors of GMA efficacy need to be defined.

Methods: In a prospective multicenter setting, 200 UC patients at 32 institutes received one GMA session per week over 10 weeks. Patients who achieved remission were followed for 12 months. The Clinical Activity Index (CAI) ≤3 meant remission, and response meant CAI decreased by ≥3. Quality of life was evaluated by the Inflammatory Bowel Disease Questionnaire (IBDQ).

Results: After final GMA, remission, response and no response rates were 67.0%, 15.0% and 18%, respectively. The remission group had a significant decrease in myeloid leucocytes and platelets. Corticosteroid dose decreased (P < 0.001); 49 of 97 patients on corticosteroids became steroid-free. Baseline CAI was lower in the remission group versus non-remission (P < 0.01), whereas IBDQ was higher in the remission group versus non-remission (P < 0.05). After 12 months, 52 of 134 patients had maintained remission. Disease duration was longer in the relapsed group versus maintained remission group (P = 0.041). Male gender, first UC episode and corticosteroid responder were significant factors for maintaining remission, whereas corticosteroid dependent UC was associating with relapse.

Discussion: Selective myeloid leucocyte depletion was effective for remission induction and improving patients' quality of life. Baseline demographics such as disease activity level, duration and corticosteroid dependency appear to predict response to GMA. Additionally, patients with a first UC episode who were drug naive responded well to GMA and achieved a favorable long-term disease course by avoiding pharmacologics from an early stage of their inflammatory bowel disease. These findings should help to end unnecessary use of medical resources by targeting GMA to patients who may respond well.
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http://dx.doi.org/10.1016/j.jcyt.2015.02.007DOI Listing
May 2015

Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs.

World J Gastroenterol 2014 Aug;20(29):9699-715

Abbi R Saniabadi, Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Ulcerative colitis and Crohn's disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients' own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients' disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.
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http://dx.doi.org/10.3748/wjg.v20.i29.9699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123360PMC
August 2014
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