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Objectives There are patients who do not undergo colonoscopy even if the fecal immunochemistry test (FIT) results are positive and even with repeated positive test results the following year. We aimed to investigate colorectal cancer (CRC) risk in examinees with positive FIT results in our annual screening program. Methods We analyzed patients who underwent initial colonoscopy from April 2010 to March 2017 because of positive FIT results using an endoscopy database in our hospital. We investigated the difference in the risk of advanced colorectal neoplasia as a surrogate marker of CRC between those who had an initial positive test and those who had repeated positive tests. Results A total of 748 patients were included in this analysis. The advanced neoplasia detection rates were 7.6% (50/656) and 18.5% (17/92) for the initial and repeated positive test groups, respectively. Subgroup analysis of those with repeated positive tests revealed that the detection rates in examinees with positive tests 1-2 and >2 years ago were 16.7% (6/36) and 19.6% (11/56), respectively. The odds ratios for advanced neoplasia detection in patients with positive tests 1-2 and >2 years ago compared with those in the initial positive test group were 2.72 (95% confidence interval [CI], 1.04-7.10) and 3.09 (95% CI, 1.47-6.48), respectively. Conclusions The risk of CRC appears more than doubled in patients with a repeated positive FIT result. Prompt colonoscopy is recommended for FIT-positive cases.

Purpose According to the revised Japanese medical service fees aimed at reducing irrational psychotropic polypharmacy, medical service fees are reduced if the number of simultaneously prescribed psychotropic drugs exceeds the standard. This study primarily aims to examine the effect of the 2018 revision. Methods Using a large Japanese administrative claims database, we retrospectively identified five groups (April 2013–September 2018) prescribed at least one drug from the following drug groups: anxiolytics, hypnotics, sum of anxiolytics and hypnotics, antipsychotics, and antidepressants (study population in each group: 547,511, 406,524, 759,137, 112,929, and 201,046, respectively). We used an interrupted time-series design to evaluate changes in the proportion of patients prescribed more than the standard number of drugs. Results After the 2018 revision, the proportion of patients prescribed more than the standard number of drugs significantly decreased only for the sum of anxiolytics and hypnotics; estimated changes in level and trend were − 0.60% [− 0.69%, − 0.52%] and − 0.04% [− 0.06%, − 0.02%] per month, respectively. The proportion of patients exhibiting a decrease in the number of prescribed drugs from more than the standard to within the standard increased when the revision was enforced (April 2018); this proportion in April 2018 was 36.3%, while all other proportions were in the range of 12.1–22.3%. Conclusion The 2018 revision promoted a reduction in the number of prescribed drugs, which served as an important factor in the decrease in the proportion of patients prescribed more than the standard number of drugs for the sum of anxiolytics and hypnotics.

The purpose of this study was to clarify the process of acquiring a physically active lifestyle in Japan through interviews with amateur runners involved in running projects. Participants were female amateur runners in their early adulthood who run one or more times a week and had continued running for at least a year. Data were collected using a semi-structured interview and analyzed using the Modified Grounded Theory Approach. Following analysis, 3 categories, 7 sub-categories, and 26 concepts were generated. Conclusion 1) In the process of acquiring a physically active lifestyle in Japan, female amateur runners in their early adulthood had 3 steps: “Beginning to run,” “Changing impression of running,” and “Keep running.” 2) For female amateur runners in their early adulthood, the experience of running with “Chatting,” “Wearing make-up,” and “dressing up” was factored to promote “Changing impression of running. ” 3) This suggests that even if an exercise plan is made for improving and maintaining health and improving physical fitness, it may not lead to acquiring a physically active lifestyle even if this plan is performed, as long as one has set the “purpose” as improving health and physical fitness.

Background and Aim As the significance of the quantitative fecal immunochemical test (FIT) in patients who previously underwent a colonoscopy is unknown, this study aimed at investigating the association between fecal hemoglobin concentration and the risk of colorectal cancer (CRC). Methods and Results We retrospectively analyzed FIT‐positive patients who underwent a colonoscopy through our opportunistic annual screening program from April 2010 to March 2017 at the Kyoto Second Red Cross Hospital. We stratified them into no colonoscopy and past colonoscopy (>5 years or ≤5 years) groups based on whether they had a history of undergoing a colonoscopy and analyzed the correlation between fecal hemoglobin concentration and advanced neoplasia or invasive cancer detection in each group. We analyzed 1248 patients with positive FIT results. There were 748 (59.9%), 198 (15.9%), and 302 (24.2%) patients in the no colonoscopy, past colonoscopy (>5 years), and past colonoscopy (≤5 years) groups, respectively. In the no colonoscopy group, the advanced neoplasia detection rate significantly increased with the fecal hemoglobin concentration (P 5 years and ≤5 years) group (P = 0.982). No invasive cancer was detected in the past colonoscopy (≤5 years) group. Conclusion The risk of CRC might be low even if fecal hemoglobin concentration was high, especially in those who underwent colonoscopy within 5 years., We retrospectively analyzed fecal immunochemistrytest positive patients who underwent a colonoscopy. We stratified them into the no colonoscopy and past colonoscopy (>5 years or ≤5 years) groups based on whether they had a history of undergoing a colonoscopy and analyzed the correlation between fecal hemoglobin concentration and advanced neoplasia detection in each group. In the no colonoscopy group, the advanced neoplasia detection rate significantly increased with the fecal hemoglobin concentration. However, no significant trend was observed in the past colonoscopy (both ≥5 years and ≤5 years) group. Especially in those who underwent colonoscopy within 5 years, risk of colorectal cancer might be low even if fecal hemoglobin concentration was high.

Objectives We report a rare case of B-lymphoblastic lymphoma (B-LBL) and low-grade follicular lymphoma (FL) identified concurrently in biopsies from different sites at the initial diagnosis in a 39-year-old man. The clonal relationship between the 2 histologic subtypes was investigated. Methods A diagnosis of FL grade 1/2 (low grade) was made by bone marrow (BM) biopsy. B-LBL was identified in biopsies from the testis and pancreas. Cytogenetic and molecular analyses were performed to investigate their clonal relationship. Results Interphase fluorescence in situ hybridization analyses and G-banding karyotype analyses identified the BCL2-IGH and MYC-IGH translocation in tumor cells from both the BM and testis. The tumor cells from the BM and testis shared the same IGH VDJ usage and a high degree of somatic mutations. These findings suggest that acquisition of MYC gene rearrangement is a critical event for lymphoblastic transformation of FL. Of note, the presence of intraclonal diversity in the B-LBL sample further suggests an earlier or concurrent event of MYC translocation than the somatic IGH mutation in the germinal center and the dedifferentiation of lymphoma cells to a precursor stage of B-cell development. Conclusions B-lymphoblastic transformation of FL can occur with MYC gene rearrangement.

We present aptamer-based sensing using a coupled acoustic-gravitational (CAG) field, which transduces a change in the density of a microparticle (MP) to a change in the levitation coordinate. A large density of the MP is initially induced by the binding of gold nanoparticles (AuNPs) on the MP through sandwich hybridization with aptamer DNA molecules. Targets added to the system interact with the aptamer DNA molecules to form complexes, and the duplex between the aptamer and the probe DNA molecules is dissociated. This leads to the release of AuNPs from the MP and a decrease in its density. As the target concentration increases, the levitation coordinate of the MP increases. From the levitation coordinate shift, we can determine the target concentration. The detection limits for adenosine triphosphate, dopamine, and ampicillin as test targets are 9.8 nM, 17 nM, and 160 pM, respectively. The dissociation constants for the aptamer-target complexes are quantitatively determined from the dependence of the levitation coordinate on the target concentration. This scheme is a useful analytical tool not only for the trace analyses of targets but also for the evaluation of aptamer-target interactions.

Objective The objectives of the present study were to investigate (1) whether trinary visual interpretation of amyloid positron emission tomography (PET) imaging (negative/equivocal/positive) reflects quantitative amyloid measurements and the time course of 11C-Pittsburgh compound B (PiB) amyloid accumulation, and (2) whether visually equivocal scans represent an early stage of the Alzheimer’s disease (AD) continuum in terms of an intermediate state of quantitative amyloid measurements and the changes in amyloid accumulation over time. Methods From the National Bioscience Database Center Human Database of the Japanese Alzheimer’s Disease Neuroimaging Initiative, we selected 133 individuals for this study including 33 with Alzheimer’s disease dementia (ADD), 52 with late mild cognitive impairment (LMCI), and 48 cognitively normal (CN) subjects who underwent clinical assessment, PiB PET, and structural magnetic resonance imaging (MRI) with 2 or 3-years of follow-up. Sixty-eight of the 133 individuals underwent cerebrospinal fluid amyloid-β1-42 (CSF-Ab42) analysis at baseline. The standard uptake value ratio (SUVR) of PiB PET was calculated with a method using MRI at each visit. The cross-sectional values, longitudinal changes in SUVR, and baseline CSF-Ab42 were compared among groups, which were categorized based on trinary visual reads of amyloid PET (negative/equivocal/positive). Results From the trinary visual interpretation of the PiB PET images, 55 subjects were negative, 8 were equivocal, and 70 were positive. Negative interpretation was most frequent in the CN group (70.8/10.4/18.8%: negative/equivocal/positive), and positive was most frequent in the LMCI group (34.6/1.9/63.5%) and in the ADD group (9.1/6.1/84.8%). The baseline SUVRs were 1.08 ± 0.06 in the negative group, 1.23 ± 0.15 in the equivocal group, and 1.86 ± 0.31 in the positive group (F = 174.9, p 42 level was 463 ± 112 pg/mL in the negative group, 383 ± 125 pg/mL in the equivocal group, and 264 ± 69 pg/mL in the positive group (F = 37, p F = 8.4, p Conclusions Trinary visual interpretation (negative/equivocal/positive) of amyloid PET imaging reflects quantitative amyloid measurements evaluated with PET and the CSF amyloid test as well as the amyloid accumulation over time evaluated with PET over 3 years. Subjects in the early stage of the AD continuum could be identified with an equivocal scan, because they showed intermediate quantitative amyloid PET, CSF measurements, and the amyloid accumulation over time.

Objective To evaluate the efficacy and safety of tocilizumab (TCZ) monotherapy for large vessel vasculitides (LVV), including Takayasu arteritis (TAK) and GCA. Methods Twelve patients with a newly diagnosed LVV (eight GCA, four TAK) were enrolled. One TAK patient withdrew consent, so 11 (eight GCA, three TAK) were analysed in a prospective, open-label study. TCZ (8 mg/kg) monotherapy, without glucocorticoids or immunosuppressants, was administered every 2 weeks for 2 months and then every 4 weeks for 10 months. Patients were followed for 1 year after the final TCZ dose. Complete and partial responses were defined as disappearance or improvement of all clinical symptoms and normalization of CRP. Relapse was defined as the worsening or recurrence of clinical symptoms, increase in CRP attributable to vasculitis, and/or the need for initiation of glucocorticoids and/or immunosuppressants. Poor clinical response described patients who did not fit the definition of complete response or partial response. Results Complete and partial responses rates were 75/66% and 25/0% in GCA/TAK patients, respectively, at week 24 and week 52. Five GCA patients and one TAK patient remained disease-free for 1 year after therapy. One GCA patient required TCZ discontinuation due to heart failure at week 24. Conclusion TCZ monotherapy showed a high response rate for newly diagnosed LVV patients, and the majority of patients did not relapse for 1 year after TCZ cessation. Result of this study could help us to understand the crucial role of IL-6 in the pathogenesis of LVV.

Background Underwater endoscopic mucosal resection (U-EMR) has emerged as an alternative technique for the resection of colorectal lesions. This study aimed to evaluate our initial experience using U-EMR. Methods This is a single-center, retrospective case series study. We analyzed the clinical outcomes of consecutive patients who underwent U-EMR in our endoscopy center, from December 2015 to February 2017. Results Our analysis included 64 lesions, contributed by 38 patients, with a mean age of 68.6 years (range, 25 to 90 years). The study sample included 33 right-sided and 25 left-sided colon lesions, and seven rectal lesions, with an average size of 16.2 mm (6 - 40 mm). Of these, 46 lesions were polypoid and 18 ones non-polypoid. Histologically, 31 lesions were low-grade adenomas, eight ones were high-grade adenomas, 11 were mucosal cancers, four were submucosal cancers, and 10 were classified as "others". En bloc resection was achieved in 52 (81%) lesions, with an en bloc resection rate of 95% for lesions < 20 mm and 55% for lesions ≥ 20 mm. Complete resection of neoplastic epithelial lesions, defined by a negative pathological margin, was achieved in 32 of 59 neoplastic epithelial lesions (54%). We identified three cases (5%) of post-procedural bleeding and one case of perforation (2%). Conclusions U-EMR can be feasibly used for resection of colonic lesions, including lesions ≥ 20 mm, although the en bloc resection rate for these lesions was lower than for lesions < 20 mm.

Background Efficacy of a physician-controlled wire-guided cannulation of the bile duct has been reported. This study aimed to evaluate a novel sphincterotome with a short tip and a short wire, which can be bowed compactly compared to conventional sphincterotomes. Methods This was a single-arm, single-center, prospective study. We enrolled patients with choledocholithiasis and/or obstructive jaundice and/or cholangitis for whom endoscopic sphincterotomy was planned. The main outcome measurement was the proportion of successful selective bile duct cannulation by physician-controlled wire-guided cannulation within 10 min. Results The study cohort consisted of 40 patients. The proportion of successful selective bile duct cannulation within 10 min was 72.5% (n = 29). The proportion of post-endoscopic retrograde cholangiopancreatography pancreatitis was 2.5% (mild, n = 1) and the proportion of hemorrhage was 2.5% (moderate, n = 1). Conclusions Although physician-controlled wire-guided cannulation using a novel sphincterotome with a short tip and a short wire was not superior to wire-guided cannulation using conventional sphincterotomes reported in a previous study, it remains a safe and efficacious alternative in terms of successful biliary cannulation.

We report the first case demonstrating an association between Kawasaki disease (KD) and erythema nodosum (EN). A 3-year-old girl presented with EN as an initial manifestation of KD. At the initial visit, she showed high fever of 40°C, injection of the oropharynx, cervical lymphadenopathy, and red-purple cutaneous nodules, particularly on the lower limbs. She complained of severe pain in the neck and cutaneous lesions. Initially, the development of EN was attributed to Salmonella spp infection, which was detected in stool culture. However, the patient did not respond to high-dose ampicillin/sulbactam to which the Salmonella spp is sensitive. Echocardiography performed as screening for fever of unknown origin revealed medium-sized aneurysms of the left anterior descending artery. EN masked the diagnosis of KD, and the patient developed a coronary artery lesion. KD should be considered in the differential diagnosis of refractory EN in pediatric patients.

The concept of the quality loss derived by Taguchi has been accepted as the evaluation measure of quality instead of the traditional attribute property such as the proportion of non-conforming items. Since the variable single sampling plan having the desired operating characteristics indexed by the quality loss was proposed in 1997, various kinds of sampling plans indexed by the quality loss have been considered. Among them, there are two kinds of rectifying variable single sampling (RVSS) plans indexed by the quality loss. In the RVSS plans, two inspection schemes called the acceptance quality loss limit (AQLL) scheme and the permissible average outgoing surplus quality loss limit (PAOSQLL) scheme have been formulated. Note that the concepts of the AQLL and PAOSQLL schemes in the RVSS plans indexed by the quality loss are equivalent to those of the lot tolerance percent defective (LTPD) and the average outgoing quality limit (AOQL) schemes in the traditional rectifying attribute single sampling plans, respectively. On the other hand, in the sampling plan having the desired operating characteristics, an attribute repetitive group sampling plan was proposed for the purpose of reducing the average sampling number in the inspection. Recently, by applying the repetitive group sampling to the rectifying variable sampling plan for the AQLL scheme, the rectifying variable repetitive group sampling (RVRGS) plan for the AQLL scheme has been considered for the purpose of reducing the average total inspection (ATI). However, the RVRGS plan for the PAOSQLL scheme has not been investigated yet. Accordingly, the RVRGS plan for the PAOSQLL scheme must be investigated to complete the RVRGS plans indexed by the quality loss. In this article, the RVRGS plan for the PAOSQLL scheme is addressed. Then, the design procedure in the RVRGS plan for the PAOSQLL scheme is proposed for the purpose of reducing ATI. Through some numerical investigations, the effectiveness to reduce ATI by the RVRGS plan for the PAOSQLL scheme is confirmed.

The acceptance of foreign comparator products is the most limiting factor for the development and regulatory assessment of generic medicines marketed globally. Bioequivalence studies have to be repeated with the local comparator products of each jurisdiction because it is unknown if the comparators of the different countries are the same product, with the consequent duplication of efforts by regulators and industry alike. The regulatory requirements on the acceptability of foreign comparator products of oral dosage forms differ between countries participating in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme. Brazil, Colombia, the European Union member States, Japan, Mexico, South Korea and the United States only accept bioequivalence studies with their local comparator. In contrast, Australia, Canada, New Zealand, Singapore, South Africa, Switzerland and Taiwan accept studies with foreign comparators under certain conditions. Canada limits its use to highly soluble drugs with a wide therapeutic range in immediate release products. Australia requires a comparison of the quantitative composition. In contrast, there are fewer restrictions on the acceptance of foreign comparators in New Zealand, Singapore, South Africa, Switzerland and Taiwan. For the WHO Prequalification of Medicines and for developing generics of the essential medicines the WHO lists comparators from different countries. In conclusion, there is currently no consensus amongst regulators on the acceptability of foreign comparator products.

Background:It is important to use vascular imaging modalities such as CT, MRI and PET-CT to evaluate disease activity of Takayasu arteritis (TAK). In particular, under treatment with tocilizumab (TCZ), redsidual vasculitic disease activity may remain even if serum CRP becomes negative. Contrast-enhanced CT,MRI and PET-CT can evaluate the morphology of blood vessel walls and the distribution of lesions and vasculitic activity, but it is invasive (radiation or contract media exposure), and costly. Ultrasound is superior in terms of morphological evaluation, cost, convenience, and low invasiveness. In particular, Superb Micro-vascular Imaging(SMI) is one of the micro blood flow display methods that can be installed in the ultrasound diagnostic device Aplio series.There are some case reports in which micro blood flow signals of the carotid artery walls were detected using SMI in Takayasu arteritis [1] [2]. Both reports indicate that SMI blood flow is a comparable indicator of disease activity as serum CRP.Objectives:To report the usefulness of SMI in 2 TAK patients who had negative serum CRP but had residual disease activity, leading to appropriate adjustment of treatment.Methods:Two TAK patients who had been newly diagnosed in our department from May 2015 to October 2018 and had received SMI to detect carotid artery wall blood flow signal were retrospectively analyzed.Results:Case 1A 32-year-old woman developed neck pain, headaches, fever and she had high serum levels of CRP (8.1 mg/dl) and elevated ESR (98 mm/h). Contrast-enhanced CT showed thickening of the carotid artery, left subclavian artery and thoracic aorta and SMI detected blood flow signal in carotid artery wall. Diagnosis of TAK was made. After 2-week treatment with 1 mg/kg/day of PSL, CRP became negative but the micro blood flow in carotid arterity walls was detedted by SMI. Therefore,subcutaneous TCZ (162 mg/week)was added in combination with PSL.One year later, micro blood flow disappeared and we could judge there was no vasculitis activity (Figure A).Before treatment starts2 weeks after starting treatmentOne year after starting treatmenttreatment-PSL 1mg/kg/day ongoingPSL 7mg/day ongoingTCZ 162 mg/week ongoingCRP(mg/dl)+ (8.1)−(0.0)−(0.0)SMI signal++−Figure 1.A. Clinical course of Case 1Case 2A 17-year-old woman developed proximal upper limb pain and fever with high serum CRP levels (7.1 mg/dl) and elevated ESR (>110 mm/h), and contrast-enhanced CT showed thickening of the carotid arteries and aortic arch. Two weeks after the start of PSL (1 mg/kg/day), CRP became negative at 0.3 mg/dl, but intramural blood flow detected by SMI remained. Then subcutaneous TCZ was added. Two weeks later, CRP became negative, and the SMI blood flow also disappeared (Figure B).Before treatment starts2 weeks after starting treatment4 weeks after starting treatmenttreatment-PSL 1mg/kg/day ongoingPSL 50 mg/day ongoingTCZ 162 mg/week addedCRP(mg/dl)+ (7.1)−(0.3)−(0.0)SMI signal++−Figure 2.B. Clinical course of Case 2Conclusion:Although SMI has the limitation that it cannot evaluate deep vascular lesions such as aorta, it is neither invasive nor costly and may be a good tool for evaluation of residual vasculitis activity of TAK.References:[1]Sato W, Sato T, Iino T, Seki K, Watanabe H. Visualization of arterial wall vascularization using superb microvascular imaging in active-stage Takayasu arteritis.European Heart Journal - Cardiovascular Imaging. 2019;20(6):719[2]Ito S, Tahara N, Hirakata S, et al. Signal intensity of superb micro-vascular imaging associates with the activity of vascular inflammation in Takayasu arteritis.Journal of Nuclear Cardiology:Official Publication of the American Society of Nuclear Cardiology. 2019 Mar DOI: 10.1007/s12350-019-01665-4.Acknowledgments:We thank Minako.Yamashita and Masahiro.setoyama for her technical assistance to conduct SMI.Disclosure of Interests:None declared

Background Japan is the ultra-ageing society ahead of any other country in the world, which ageing rate (the ratio of the population aged 65 and older to the total population) was reported to be 27.3% on October 1, 2016. The rate of aged patients, who followed up at the division of rheumatology in Saitama medical centre, had exceeded 40%. Objectives The aim of our study is to reveal recent clinical features and problems of elderly onset rheumatoid arthritis (EORA) patients for better management. Methods Patients had a diagnosis by 1987 classification criteria or 2010 ACR/EULAR criteria. We firstly listed up RA patients who were followed up our hospital from April 1 to September 30, and above aged 65 years old as of September 30. Then we retrospectively collected clinical information of EORA patients who onset above 60 years old, diagnosed and made starts of treatment in our hospital, and observed more than 6 months, from medical records. Results One hundred eighty eight EORA patients were enrolled in this study. Female were 116 (62.0%). Mean observation period from first visit until September 30, was 68 months. Rheumatoid factor positive rate was 67.0%. Anti-CCP antibody-positive was 68.2% (107/157), and most of them (65.5%, 70/107) had high antibody titer over 100 U/mL. At the time of diagnosis, average CRP was 3.1 mg/dL. Respiratory complications were seen in 26.1% (49 cases), including 28 interstitial lung disease, 10 COPD/emphysema, 7 non-tuberculous mycobacteriosis/obsolete tuberculosis, and 6 bronchiectasis. Other complications were diabetes 16.5% (past 25 cases, new 6), hypertension 38.3% (past 66, new 6), and hyperlipidemia 23.9% (past 33, new 12). Histories of cerebrovascular or cardiovascular events were seen in 10.6% (20 cases), and history of malignancy was seen in 6.9% (13 cases). During observation period, newly developed malignancy was seen in 14 cases (14.1/1000 person-years) including 4 MTX related lympho-proliferative disorders (MTX-LPD), 3 gastrointestinal cancer, 3 gynaecological cancer, 2 lung cancer, and so on. Infectious adverse event were occurred in 35 patients (35.3/1000 person-years). From the point of treatment, corticosteroids were prescribed in 32%, csDMARDs 88%, and biological DMARDs (BIO) 47%. Of 89 EORA patient treated with BIO, average DAS28-ESR was 5.77, and HAQ-DI 1.48 at the baseline. Twenty-nine cases were started to treat with BIO as monotherapy, 13 cases as switching to BIO from csDMARDs, and 47 as addition BIO to csDMARDs. During observation period, reasons of cessation of the first BIO were remission in 21, adverse events in 19 (7 infections, 6 injection-site/infusion reaction, 3 malignancies, and so on), insufficient response in 16, and patient’s hope in 2. Conclusions RF/anti-CCP antibody positive rate was lower than general RA population, but slightly higher than previous reports on EORA.1) BIO could be discontinued in 24% of 89 patients who received BIO because of remission. On the other hand, the frequency of infection and malignancy was still higher in EORA patients. So it is necessary to adjust anti-rheumatic therapy for poor prognostic cases, and we should be careful to follow up EORA patients. References [1] Boeters DM, et al. Arthritis Res Ther. 2017May 31;19(1):115. [2] Sugimoto N, et al. Rheumatol Int. 2017Nov;37(11):1871–1878. Disclosure of Interest T. Kurasawa: None declared, Y. Okada: None declared, A. Shibata: None declared, S. Saito: None declared, K. Chino: None declared, A. Okuyama: None declared, H. Takei: None declared, T. Kondo: None declared, K. Amano Grant/research support from: Chugai Pharmaceutical Co. Ltd., Speakers bureau: Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo Co., Ltd., Pfizer Japan Inc., Mitsubishi Tanabe Pharma Corporation

Background Polymyalgia rheumatic (PMR) is a chronic inflammatory rheumatic disease in the elderly people. Glucocorticoid (GC) is still definitely a mainstay for the treatment of PMR, but long-term GC therapy is a major risk factor of osteoporotic fractures, diabetes, hyperlipidemia, cardio-cerebral vascular events, glaucoma, etc. So GC-free treatment strategies for PMR are awaited for some PMR patients with these comorbidities. IL-6 is involved in the pathogenesis of PMR and several case reports have already shown the efficacy of tocilizumab (TCZ), anti-IL-6 receptor antibody, in PMR patients1,2) and there is a report of TCZ mono-therapy as the first-line therapy in PMR3). Objectives To assess the efficacy and safety of TCZ mono-therapy for PMR Methods Thirteen PMR patients (male 3, female 10) who had been diagnosed by 2012 ACR/EULAR classification criteria from Jan 2013 to Feb 2015 were enrolled in our single-centre, prospective study (IRB application No. 638, UMIN No. 000008812) after obtaining the written informed consent. TCZ (8 mg/kg) was administered biweekly for the first 8 weeks (5 infusions) and every 4 weeks thereafter for 40 weeks (total 15 infusions). ESR, CRP, patient’s global health assessed by visual analogue scale (VAS), PMR activity score4) were evaluated every 4 week prospectively. Primary endpoint was remission rate at week 52. Remission was defined as PMR activity score less than 1.54). Patients were followed up for another one year without any treatment and flare rate was assessed at week 104. Results Baseline patients’ characteristics revealed various kinds of comorbidities in 11 patients; hypertension in 7, hyperlipidemia in 5, diabetes mellitus in 3, osteoporotic vertebral fractures in 2, history of angina pectoris in 1, history of brain infarction in 1, history of hematemesis due to NSAID ulcer in 1 and glaucoma in one patient. Nine patients could complete this 104 week trial and all 9 patients could achieve remission at week 52 and 8 of 9 patients fulfilled remission criteria at week 104. Two patients discontinued TCZ because of no response at week 6 (No.1) and week 16 (No. 8) respectively. One patient (No.2), who were in clinical remission of PMR, dropped out from this study due to pemphigoid at week 50 and received GC therapy. Patient No. 12 abandoned TCZ at week 12 because of lung infiltrates although she was treated successfully with TCZ mono-therapy, and she had been in remission without any treatment until week 104. The other 3 patients could obtain remission with GC therapy at week 52. There were no serious adverse events during 104 week treatment period. Conclusions TCZ mono-therapy was effective in most (9 out of 13) PMR patients although response was not so rapid as compared to GC. TCZ mono-therapy may be a good alternative therapy instead of GC for elderly patients with various comorbidities. References [1] Unizony S, et al.: Arthritis Care Res2012;64(11):1720–1729. [2] Macchioni P, et al.: Semin Arthritis Rheum2013;43(1):113–118. [3] Devauchelle-Pensec V, et al.: Ann Rheum Dis2016;75(8):1506–1510. [4] Leeb BF, et al.: Arthritis Rheum2007;57(5):810–815. Disclosure of Interest K. Amano Grant/research support from: Chugai Pharmaceutical Co. Ltd., Speakers bureau: Chugai, Daiichi-Sankyo, Pfizer Japan, Tanabe-Mitsubishi, K. Chino: None declared, Y. Okada: None declared, A. Shibata: None declared, S. Saito: None declared, T. Kurasawa: None declared, A. Okuyama: None declared, H. Takei: None declared, R. Sakai: None declared, T. Kondo: None declared

Dimerization in signal transduction is a dynamically regulated process and a key regulatory mechanism. Signal transducer and activator of transcription 3 (STAT3) dimerizes after tyrosine phosphorylation upon cytokine stimulation. Because only the STAT3 dimer possesses the trans-activation activity, dimerization is an indispensable process for cytokine signaling. Here we report the detection of dynamic STAT3 dimerization in living cells using the homoFluoppi system. This method allowed us to validate the presence of an intact Src homology 2 domain and STAT3 Tyr705 phosphorylation, which facilitate puncta formation and homodimerization. Puncta formation was reversible, as determined by a decreased punctate signal after washout of oncostatin M. We analyzed STAT3 mutants, which have been reported in patients with hyper IgE syndrome and inflammatory hepatocellular adenoma (IHCA). Analysis of the IHCA mutants using homoFluoppi revealed constitutive activity independent of cytokine stimulation and novel insight into kinetics of dimer dissociation process. Next, we used homoFluoppi to screen for inhibitors of STAT3 dimerization, and identified 3,4-methylenedioxy-β-nitrostyrene as a novel inhibitor. The results of this study show that homoFluoppi is a useful research tool for the analysis of proteins like STAT3 that dynamically dimerize, and is applicable for the screening of dimerization modulators.

Two antigenically distinct B strain lineages of influenza virus have co-circulated since the mid-1980s; however, inactivated trivalent influenza vaccines contain only one B lineage. The mismatch between the circulating and vaccine lineages has been a worldwide issue. In this study, an inactivated quadrivalent influenza vaccine (QIV) candidate containing two B lineages was manufactured and its immunogenicity and safety evaluated in an open-label, uncontrolled trial. In this phase II trial, 50 subjects aged 20-64 years received two doses of QIV s.c. 1 to 4 weeks apart. Sera were collected pre- and post-vaccination and safety assessed from the first vaccination to 21 ± 7 days after the second vaccination. After the first vaccination, hemagglutination inhibition titers against each strain increased markedly; the seroconversion rate, geometric mean titer ratio and seroprotection rate being 94.0%, 24.93, and 100.0%, respectively, for the A/H1N1pdm09 strain; 94.0%, 12.47, and 98.0%, respectively, for the A/H3N2 strain; 54.0%, 4.99, and 66.0%, respectively, for B/Yamagata strain, and 72.0%, 6.23 and 80.0%, respectively, for the B/Victoria strain, thus fulfilling the criteria of the European Medical Agency's Committee for Medicinal Products for Human Use. Also, the QIV induced sufficient single radial hemolysis and neutralizing antibodies against all four vaccine strains. No noteworthy adverse events were noted. The results of this trial demonstrate that QIV is well tolerated and immunogenic for each strain, suggesting that QIV potentially improves protection against influenza B by resolving the issue of B lineage mismatch.

Background Polymyalgia rheumatic (PMR) is a chronic inflammatory rheumatic disease in the elderly people. Glucocorticoid (GC) is still definitely a mainstay for the treatment of PMR, but long-term GC therapy is a major risk factor of osteoporotic fractures, diabetes, hyperlipidemia, cardio-cerebral vascular events, glaucoma, etc. So GC-free treatment strategies for PMR are necessary for some patients with PMR. IL-6 is involved in the pathogenesis of PMR and quite a few case reports have already shown the efficacy of tocilizumab (TCZ) in PMR patients and some of them received TCZ monotherapy without GC. Objectives To assess the efficacy and safety of TCZ monotherapy for PMR Methods Thirteen PMR patients (male 3, female 10) who had been diagnosed by 2012 ACR/EULAR classification criteria from Jan 2013 to Feb 2015 were enrolled in our study (IRB application No. 638, UMIN registration No. 000008812) after obtaining the written informed consent. TCZ (8 mg/kg) was administered biweekly for the first 2 months (5 infusions) and every 4 weeks thereafter for 40 weeks (total 48 weeks). ESR, CRP, patient9s global health assessed by visual analog scale (VAS), PMR activity score were evaluated every 4 week prospectively and were evaluated at week 52. Remission was defined as PMR activity score less than 1.5. Results Baseline patients9 characteristics revealed various kinds of comorbidities in 11 patients; hypertension in 7, hyperlipidemia in 5, diabetes mellitus in 3, osteoporotic vertebral fractures in 2, history of angina pectoris in 1, history of brain infarction in 1, history of hematemesis due to NSAID ulcer in 1 and glaucoma in one patient. Nine patients could complete this 52-week trial and could achieve remission at week 52. Two patients discontinued TCZ because of no response at week 6 (No.1) and week 16 (No. 8) respectively. One patient (No.2), who were in clinical remission of PMR, dropped out from this study due to pemphigoid at week 50 and received GC therapy. Patient No. 12 abandoned TCZ at week 12 because of lung infiltrates although she was treated successfully with TCZ monotherapy, and she had been in remission without any treatment until week 52. The other 3 drop-out patients could obtain remission with GC therapy at week 52. There were no serious adverse events during 52-week treatment period. Conclusions TCZ mono-therapy was effective in most (9 out of 13) PMR patients although response was not so rapid as compared to GC. TCZ mono-therapy may be a good alternative therapy instead of GC for elderly patients with various comorbidities. References Unizony S, et al.: Arthritis Care Res 2012; 64(11):1720–1729. Macchioni P, et al.: Aemin Arthritis Rheum 2013; 43(1): 113–118. Toussirot E, et al.: J Rheumatol 2016 43(1): 249–251. Leeb BF, et al.: Arthritis Rheum 2007; 57(5): 810–815. Acknowledgements We will thank Izumi Oshima, Takashi Kukita for data collection and management of this study. Disclosure of Interest K. Amano Grant/research support from: Chugai Pharnmaceutical Co.Ltd., K. Chino: None declared, Y. Okada: None declared, A. Shibata: None declared, A. Okuyama: None declared, T. Kurasawa: None declared, H. Takei: None declared, T. Kondo: None declared

Background Adult-onset Still9s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Corticosteroids still provide mainstay AOSD therapy despite various adverse effects. Recently, AOSD patients have been successfully treated with anti-cytokine therapies such as with TNF-α blocking agents, an IL-1 receptor antagonist, and an anti-IL-6 receptor monoclonal antibody. Among these case reports, TCZ seems to be highly effective for treating patients refractory to TNF antagonists and IL-1 antagonist. Objectives To assess the efficacy and safety of tocilizumab (TCZ) monotherapy for the induction therapy of adult onset Still9s disease (AOSD) in a prospective single-arm, single-center, cohort, pilot study. Methods Seven AOSD patients (male 2, female 5) who had agreed with our prospective trial since April 2010 till May 2015 were enrolled. Our study protocol is that patients received 8 mg/kg of intravenous TCZ fortnightly for the first two months (five courses), then monthly for the next 5 months and after that they stop TCZ therapy and we monitor symptoms about AOSD relapses. In this report, we evaluated the efficacy and safety in 52 week. Efficacy was evaluated by serum markers (WBC, CRP and serum ferritin), clinical symptoms and ratio of patients who required additional therapy, and safety was evaluated by adverse events for 52 week. Results The mean age was 41.4. The ratio of fever, arthralgia, rash and sore throat are 100% (n=7/7), 100% (n=7/7), 85.7% (n=6/7) and 71.4% (n=5/7) respectively. LOCF analysis revealed that WBC, CRP and serum ferritin level decreased significantly from 14757±4667/μl to 6985±2903/μl, from 13.4±7.1mg/dl to 0.3±0.6mg/dl and from 6927±5376ng/ml to 2416±5589ng/ml at month 7 (TCZ final infusion) respectively (each, P Conclusions TCZ monotherapy can be an alternative treatment strategy for AOSD in some patients. References Sakai R, et al.:Clin Rheumatol. 2012 Mar;31(3):569–74. Ortiz-Sanjuan F et al.: Arthritis Rheumatol. 2014 Jun;66(6):1659–65. Disclosure of Interest T. Kondo: None declared, Y. Okada: None declared, A. Shibata: None declared, K. Chino: None declared, T. Kurasawa: None declared, A. Okuyama: None declared, H. Takei: None declared, K. Amano Grant/research support from: Chugai Pharmaceutical Co.Ltd.

Background and study aims: An iincreasing number of reports describe endoscopic ultrasound-guided hepaticogastrostomy for malignant biliary obstruction in patients with endoscopic retrograde cholangiopancreatography failure. However, this procedure has not yet been standardized; as a result, the rate of adverse events, including bile leakage and stent migration, is relatively high. Here, we report our experience with four cases of endoscopic ultrasound-guided hepaticogastrostomy performed according to our institutional procedure.

Polyvinyl alcohol (PVA) has been used to prevent flaking of paint pigments on traditional Japanese Shohekiga painted screens and panels. However, over time these PVA coatings whiten. To date, the mechanism of this whitening has not been studied from the point of view of polymer degradation. In this study, a piece of whitened PVA was obtained from a painted wooden panel. The PVA whitening mechanism was studied in this piece using scanning electron microscopy (SEM) and functional group analysis by Fourier transform-infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). SEM showed that the surface of the whitened PVA thin film was irregular and rugged, and many micrometer-sized cracks were observed. This suggests that efficient scattering of all visible light from the cracks causes whitening. FT-IR and XPS measurements revealed that inter- and intra-chain dehydration and chemical crosslinking (C–O ether linkage) occur on the surface of the whitened PVA. Polyvinyl alcohol (PVA), which has been used to prevent flaking of paint pigments on traditional Japanese Shohekiga, became white and we investigated its phenomenon. The surface of whitened PVA was irregular and rugged, and many micrometer size cracks were observed. This suggests that efficient scattering of all visible region light from the cracks causes whitening. Fourier transform-infrared spectroscopy and X-ray photoelectron spectroscopy measurements revealed that interchain dehydration and chemical crosslinking (C–O ether linkage) occurred on the surface of whitened PVA.

This study aims to discuss role-play activity in oral proficiency interviews (OPIs) in terms of its construct validity; that is, whether it correlates with what it is supposed to measure. The data for the analysis were obtained from 71 role-play activities conducted during an OPI. The analysis is based on conversation analytic (CA) methodology and invokes the analytic frameworks of interactive footing and interactional competencies. Conversational analyses performed on the data revealed that candidates executed not only the role-play instructions but also the interviewers’ explicit and implicit requirements of the next desirable action. In doing so, candidates employed and displayed their interactional competencies in role-play interactions. The role-play activity in the OPI being managed by the interviewer created an asymmetrical relationship between the interviewers and the candidates in terms of speaking rights (i.e., turn-taking and topical organization). Nevertheless, competencies that candidates displayed in performing a role-play activity did not seem different from those employed in ordinary conversations. Thus, role-play activity in OPIs, if recognized as an interactional phenomenon co-constructed by participants’ display of their turn-by-turn practical evaluation of each other's actions, seems to be a valid instrument for assessing the candidates’ performance of the given tasks.