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.
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.
Hayashi S.,Nishikobe Medical Center |
Takeda N.,Nishikobe Medical Center |
Komura E.,Kobe University
Neurologia Medico-Chirurgica | Year: 2010
A 30-year-old woman suffered cerebellar hemorrhage during the delivery of her first child. She had undergone surgical removal of a symptomatic cerebellar hemangioblastoma 6 years previously. Neuroradiological examinations indicated recurrent hemangioblastoma, confirmed by histological examination of the surgical specimen. She was discharged with no neurological deficit. Hemangioblastomas are benign tumors that are curable with surgical removal, but can grow during pregnancy. Women of reproductive age who have been treated for hemangioblastoma need careful long-term follow up, even if they show no signs of lesion recurrence.
Taniguchi T.,Kyoto University |
Morimoto T.,Hyogo College of Medicine |
Shiomi H.,Kyoto University |
Ando K.,Kokura Memorial Hospital |
And 32 more authors.
Journal of the American College of Cardiology | Year: 2015
Background Current guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS). Objectives The study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS. Methods We used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm2) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score-matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report. Results Baseline characteristics of the propensity score-matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively). Conclusions The long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140) © 2015 American College of Cardiology Foundation.
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.
PubMed | Red Cross, Nishikobe Medical Center, Nara University, Koto Memorial Hospital and 20 more.
Type: | Journal: JACC. Cardiovascular interventions | Year: 2017
The purpose of this study was to evaluate long-term clinical impact of routine follow-up coronary angiography (FUCAG) after percutaneous coronary intervention (PCI) in daily clinical practice in Japan.The long-term clinical impact of routine FUCAG after PCI in real-world clinical practice has not been evaluated adequately.In this prospective, multicenter, open-label, randomized trial, patients who underwent successful PCI were randomly assigned to routine angiographic follow-up (AF) group, in which patients were to receive FUCAG at 8 to 12 months after PCI, or clinical follow-up alone (CF) group. The primary endpoint was defined as a composite of death, myocardial infarction, stroke, emergency hospitalization for acute coronary syndrome, or hospitalization for heart failure over a minimum of 1.5 years follow-up.Between May 2010 and July 2014, 700 patients were enrolled in the trial among 22 participating centers andwere randomly assigned to the AF group (n= 349) or the CF group (n= 351). During a median of 4.6 years of follow-up (interquartile range: 3.1 to 5.2), the cumulative 5-year incidence of the primary endpoint was 22.4% in the AF group and 24.7% in the CF group (hazard ratio: 0.94; 95% confidence interval: 0.67 to 1.31; p= 0.70). Any coronary revascularization within the first year was more frequently performed in AF group than in CF group (12.8% vs. 3.8%; log-rank p<0.001), although the difference between the 2 groups attenuated over time with a similar cumulative 5-year incidence (19.6% vs. 18.1%; log-rank p= 0.92).No clinical benefits were observed for routine FUCAG after PCI and early coronary revascularization rates were increased within routine FUCAG strategy in the current trial. (Randomized Evaluation of Routine Follow-up Coronary Angiography After Percutaneous Coronary Intervention Trial [ReACT]; NCT01123291).
PubMed | Teikyo University, National Hospital Organization Tokyo National Hospital, Nishikobe Medical Center and University of Tokyo
Type: Journal Article | Journal: 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-B 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- and IFN-, 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-B 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.
Final results from a multicenter prospective study ( JROSG 05-5) on postoperative radiotherapy for patients with ductal carcinoma in situ with an involved surgical margin or close margin widths of 1 mm or less
PubMed | Japan National Institute of Radiological Sciences, Nishikobe Medical Center, Kanagawa Cancer Center, Showa University and 8 more.
Type: Journal Article | Journal: Journal of radiation research | Year: 2015
This multicenter prospective study (Japanese Radiation Oncology Study Group: JROSG 05-5) aimed to evaluate the effectiveness of postoperative radiotherapy (PORT) in patients with ductal carcinoma in situ (DCIS) with an involved surgical margin or close margin widths of 1 mm or less. PORT consisted of whole-breast irradiation (50 Gy in 25 fractions) followed by boost irradiation (10 Gy in 5 fractions). Eligibility criteria were as follows: (i) DCIS without an invasive carcinoma component, (ii) age between 20 and 80 years old, (iii) involved margin or close margin widths of 1 mm, (iv) refusal of re-resection, (v) performance status of 0-2, and (vi) written informed consent. The primary endpoint was ipsilateral breast tumor recurrence (IBTR), and secondary endpoints were overall survival (OS), relapse-free survival (RFS), recurrence patterns, and adverse events. A total of 37 patients from 12 institutions were enrolled from January 2007 to May 2009. The median follow-up time was 62 months (range, 28-85 months). The median pathological tumor size was 2.5 cm (range, 0.3-8.5 cm). Of the 37 patients, 21 had involved margins, and 16 had close margins. The 5-year IBTR, OS and RFS rates were 6% (95% confidence interval [CI]: 2-21), 97% (95% CI: 83-99) and 91% (95% CI: 77-97), respectively. Two patients developed local recurrence at the original site after 39 and 58 months. No severe adverse events were found. Our study suggests that this PORT regimen could be a treatment option for patients with DCIS with involved margin or close margin who dont desire re-resection.
PubMed | Matsubara Mayflower Hospital, Kobe University, Nishikobe Medical Center, West Dermatology and Hyogo Prefectural Kakogawa Medical Center
Type: Journal Article | Journal: The Journal of dermatology | Year: 2016
Anti-tumor necrosis factor (TNF)- therapy is used for the treatment of psoriasis, with varying outcomes. However, the specific cause of inadequate response or treatment failure remains unknown. The aim of the present study was to identify useful clinical biomarkers for predicting therapeutic responses or to serve as new drug targets for refractory psoriasis cases. We performed a genome-wide association study (GWAS) of 65 psoriasis patients who were prospectively followed after beginning anti-TNF- therapy using Human Omni Express-8 v1.2 Beadchips. Patients were enrolled at the dermatology departments of Kobe University Hospital and six collaborative hospitals. Associations between single nucleotide polymorphisms (SNP) and changes in the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment were evaluated. After genome data collection and quality control, a total of 731 442 SNPs were identified in 65 Asian psoriasis patients who were treated with adalimumab or infliximab. Here, we present 10 SNPs, such as those in JAG2 and ADRA2A, that were associated with treatment responses to anti-TNF- agents (strongest effect, P < 7.11E-06). This is the first GWAS to examine SNP associated with treatment responses in psoriasis patients. In addition, we identified other SNP that exhibited potential associations with anti-TNF- treatment response, which merit further study. Of these, rs11096957 on TLR10, which is associated with increased TNF- production, was previously reported to be associated with treatment responses to TNF- inhibitors.
PubMed | Kyoto University and Nishikobe Medical Center
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2015
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.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 human HCC surgical specimens was examined immunohistochemically.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 recurrence-free survival and higher tumor TGFbR1 expression.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.