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Kōbe-shi, Japan

Shiokawa M.,Kyoto University | Kodama Y.,Kyoto University | Yoshimura K.,Kyoto University | Kawanami C.,Red Cross | And 22 more authors.
American Journal of Gastroenterology | Year: 2013

OBJECTIVES:Although simultaneous occurrences of autoimmune pancreatitis (AIP) and cancer are occasionally observed, it remains largely unknown whether cancer and AIP occur independently or these disorders are interrelated. The aim of this study was to examine the relationship between AIP and cancer.METHODS:We conducted a multicenter, retrospective cohort study. One hundred and eight patients who met the Asian diagnostic criteria for AIP were included in the study. We calculated the proportion, standardized incidence ratio (SIR), relative risk, and time course of cancer development in patients with AIP. We also analyzed the clinicopathological characteristics of AIP patients with cancer in comparison with those without cancer.RESULTS:Of the 108 AIP patients, 18 cancers were found in 15 patients (13.9%) during the median follow-up period of 3.3 years. The SIR of cancer was 2.7 (95% confidence interval (CI) 1.4-3.9), which was stratified into the first year (6.1 (95% CI 2.3-9.9)) and subsequent years (1.5 (95% CI 0.3-2.8)) after AIP diagnosis. Relative risk of cancer among AIP patients at the time of AIP diagnosis was 4.9 (95% CI 1.7-14.9). In six of eight patients whose cancer lesions could be assessed before corticosteroid therapy for AIP, abundant IgG4-positive plasma cell infiltration was observed in the cancer stroma. These six patients experienced no AIP relapse after successful cancer treatment.CONCLUSIONS:Patients with AIP are at high risk of having various cancers. The highest risk for cancer in the first year after AIP diagnosis and absence of AIP relapse after successful treatment of the coexisting cancers suggest that AIP may develop as a paraneoplastic syndrome in some patients. © 2013 by the American College of Gastroenterology.


Bito T.,Kobe University | Nishikawa R.,Kobe University | Hatakeyama M.,Kobe University | Kikusawa A.,Kobe University | And 10 more authors.
British Journal of Dermatology | Year: 2014

Background Current treatment with biologics has produced dramatic therapeutic effects in patients with psoriasis, although these agents occasionally decrease in efficacy. One of the main factors responsible for this attenuation is attributed to the development of antidrug antibodies (ADAs). Objectives To analyse the relationship between serum drug concentrations, the presence of ADAs and treatment efficacy of adalimumab and infliximab, and to determine the optimal use of these biologics. Methods This was a 1-year prospective study in the dermatology departments of Kobe University Hospital and collaborating hospitals. All patients starting a regimen of adalimumab and infliximab for psoriasis were included. We measured the serum concentration of the drugs and titres of antibodies to adalimumab and infliximab, as well as the Psoriasis Area and Severity Index scores at weeks 0, 4, 12, 24 and 48 during the first year of treatment. Results We observed a 50% positive rate of ADAs to adalimumab, and a 41% positive rate of ADAs to infliximab. The titres of ADAs showed a wide range from low to high titres. In the high-titre groups, the patients exhibited a decreased clinical response, and demonstrated a negative correlation between titre and clinical response. However, an equivalent therapeutic effect was observed between the low-titre group and the group with no antibodies detected for adalimumab. For infliximab, the patients with ADAs showed decreased clinical response. An apparent negative correlation between antibody production and reduced clinical response was observed. Conclusions Two biologics, adalimumab and infliximab, showed different therapeutic behaviour. The measurement of ADAs and drug concentrations has important implications for treatment with biologics. What's already known about this topic? High frequent production of antidrug antibodies (ADAs) has been observed in patients treated with biologics, and the production has caused impairment of treatment efficacy. What does this study add? The optimal use of the biologics should be determined by the measurement of ADAs and each drug concentration in each patient because the standard protocol may not uniformly fit all patients. © 2013 British Association of Dermatologists.


Takahashi Y.,Okayama University of Science | Takata K.,Okayama University of Science | Kato S.,Nagoya University | Sato Y.,Okayama University of Science | And 10 more authors.
Cancer Science | Year: 2014

Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated γδ T-cells of a cytotoxic phenotype. Because primary cutaneous γδ T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) γδ cells are typically immunostained in frozen sections or determined by TCRβ negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the γδ phenotype (CTCL-γδ) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-γδ without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-γδ with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-γδ patients with SPTCL features and SPTCL-γδ patients described in the previous literature. A univariate analysis of 17 CTCL-γδ patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-γδ patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-γδ with SPTCL features and CTCL-γδ without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-γδ. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the γδ phenotype (CTCL-γδ) in a clinicopathological and molecular study using paraffin-embedded sections. The univariate analysis of 17 CTCL-γδ patients showed that more than 60 years old age, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. There was a strikingly significant difference in overall survival among SPTCL, CTCL-γδ with SPTCL features and CTCL-γδ without SPTCL features (P = 0.0005). © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.


Suzukawa M.,National Hospital Organization | Koketsu R.,Nishikobe Medical Center | Baba S.,University of Tokyo | Igarashi S.,National Hospital Organization | And 7 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2015

There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation. © 2015 the American Physiological Society.


Kawai T.,Kyoto University | Yasuchika K.,Kyoto University | Ishii T.,Nishikobe Medical Center | Katayama H.,Kyoto University | And 8 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Keratin 19 (K19) is a known marker of poor prognosis and invasion in human hepatocellular carcinoma (HCC). However, the relationship between K19 and cancer stem cells (CSCs) is unclear. Here, we determined whether K19 can be used as a new CSC marker and therapeutic target in HCC. Experimental Design: HCC cell lines were transfected with a K19 promoter-driven enhanced green fluorescence protein gene. CSC characteristics, epithelial-mesenchymal transition (EMT), and TGFb/Smad signaling were examined in FACS-isolated K19+/K19- cells. K19 and TGFb receptor 1 (TGFbR1) expression in 166 consecutive humanHCCsurgical specimens was examined immunohistochemically. Results: FACS-isolated single K19+ cells showed self-renewal and differentiation into K19- cells, whereas single K19- cells did not produce K19+ cells. K19+ cells displayed high proliferation capacity and 5-fluorouracil resistance in vitro. Xenotransplantation into immunodeficient mice revealed that K19+ cells reproduced, differentiated into K19- cells, and generated large tumors at a high frequency in vivo. K19+ cells were found to be involved in EMT and the activation of TGFb/Smad signaling, and these properties were suppressed by K19 knockdown or treatment with a TGFbR1 inhibitor. The TGFbR1 inhibitor also showed high therapeutic effect against K19+ tumor in the mouse xenograft model. Immunohistochemistry of HCC specimens showed that compared with K19- patients, K19+ patients had significantly poorer recurrencefree survival and higher tumor TGFbR1 expression. Conclusions: K19 is a new CSC marker associated with EMT and TGFb/Smad signaling, and it would thus be a good therapeutic target for TGFbR1 inhibition. © 2015 American Association for Cancer Research.

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