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Many studies have revealed numerous potential biomarkers for atherosclerosis, but tissue-specific biomarkers are still needed. Recent lineage-tracing studies revealed that smooth muscle cells (SMCs) contribute substantially to plaque formation, and the loss of SMCs causes plaque vulnerability. We investigated the association of SMC-specific myosin heavy chain 11 (myosin-11) with atherosclerosis. Forty-five patients with atherosclerosis and 34 control subjects were recruited into our study. In the atherosclerosis patients, 35 patients had either coronary artery disease (CAD) or peripheral artery disease (PAD), and 10 had both CAD and PAD. Coronary arteries isolated from five patients were subjected to histological study. Circulating myosin-11 levels were higher in the CAD or PAD group than in controls. The area under the receiver operating characteristic curve of myosin-11 was 0.954. Circulating myosin-11 levels in the CAD and PAD group were higher than in the CAD or PAD group, while high-sensitivity C-reactive protein concentrations did not differ between these groups. Multinomial logistic regression analyses showed a significant association of myosin-11 levels with the presence of multiple atherosclerotic regions. Myosin-11 was expressed in the medial layer of human atherosclerotic lesions where apoptosis elevated. Circulating myosin-11 levels may be useful for detecting spatial expansion of atherosclerotic regions.

Background Phase-contrast (PC) cine magnetic resonance imaging (MRI) of the coronary sinus is a noninvasive method to quantify coronary flow reserve (CFR). Objectives This study sought to compare the prognostic value of CFR by cardiac magnetic resonance (CMR) and stress perfusion CMR to predict major adverse cardiac events (MACE). Methods Participants included 276 patients with known coronary artery disease (CAD) and 400 with suspected CAD. CFR was calculated as myocardial blood flow during adenosine triphosphate infusion divided by myocardial blood flow at rest using PC cine MRI of the coronary sinus. Results During a median follow-up of 2.3 years, 47 patients (7%) experienced MACE. Impaired CFR ( 10% ischemia on stress perfusion CMR were significantly associated with MACE in patients with known CAD (hazard ratio [HR]: 5.17 and HR: 5.10, respectively) and suspected CAD (HR: 14.16 and HR: 6.50, respectively). The area under the curve for predicting MACE was 0.773 for CFR and 0.731 for stress perfusion CMR (p = 0.58) for patients with known CAD, and 0.885 for CFR and 0.776 for stress perfusion CMR (p = 0.059) in the group with suspected CAD. In patients with known CAD, sensitivity, specificity, and positive and negative predictive values to predict MACE were 64%, 91%, 38%, and 97%, respectively, for CFR, and 82%, 59%, 15%, and 97%, respectively, for stress perfusion CMR. In the suspected CAD group, these values were 65%, 99%, 80%, and 97%, respectively, for CFR, and 72%, 83%, 22%, and 98%, respectively, for stress perfusion CMR. Conclusions The predictive values of CFR and stress perfusion CMR for MACE were comparable in patients with known CAD. In patients with suspected CAD, CFR showed higher HRs and areas under the curve than stress perfusion CMR, suggesting that CFR assessment by PC cine MRI might provide better risk stratification for patients with suspected CAD.

Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. UMIN000011118 (date of registration: July 4, 2013).

The present study evaluated the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies. Patients ≥70 years of age who underwent surgery for gastrointestinal or lung malignancy were eligible for participation in the study. The 186 eligible patients were randomly assigned at a 1:1 ratio to receive TJ-54 or control during their peri-operative care (between 7 days prior to surgery and 4 days following surgery, except for the operation day). The signs and symptoms of delirium were assessed using the Diagnostic and Statistical Manual of Mental Disorders-IV by the investigator during the peri-operative period. A total of 186 eligible gastrointestinal or lung malignancy patients were analyzed (93, TJ-54; 93, control). There were no marked differences between the two randomized groups. The incidence of delirium was 6.5% (6 patients) in the TJ-54 group and 9.7% (9 patients) in the control group, with no significant difference (P=0.419). However, of the patients categorized with a mini-mental state examination (MMSE) score of ≤26, the incidence of postoperative delirium was 9.1% in the TJ-54 group and 26.9% in the control group [risk ratio, 0.338; 95% confidence interval (0.078-1.462), P=0.115]. Treatment with TJ-54 reduced the incidence of postoperative delirium compared with the control group. Although TJ-54 did not demonstrate any contribution to preventing or treating postoperative delirium in patients following surgery for gastrointestinal or lung malignancy, TJ-54 reduced the risk of postoperative delirium in the patients who were classified as MMSE ≤26. Further phase III studies with a larger sample size are required in order to clarify the effects of TJ-54 against postoperative delirium.

Aims/Introduction We compared the satisfaction levels of patients with type 2 diabetes undergoing combination therapy with lixisenatide (LIX) and basal insulin with that of patients undergoing multiple daily insulin injection (MDI) therapy. Materials and Methods The study was a 12-week open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes receiving MDI for more than 3 months. Patients were randomly assigned to each treatment cohort: (1) a group that continued MDI (MDI group); and (2) a group that switched from MDI to combination therapy with LIX and basal insulin (LIX group). The primary outcome was change in Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores from baseline to 12 weeks between these two groups. Key secondary outcomes were HbA1c and body weight changes. Results Thirty-one patients were initially enrolled in the study, and 26 of them completed the study. The change in DTSQ scores in the LIX group was significantly greater compared with that in the MDI group. Mean changes in HbA1c levels were −0.05 ± 0.37% in the MDI group and 0.04 ± 0.38% in the LIX group (P = 0.36). Mean changes in body weight were +0.6 ± 1.8 kg in the MDI group and −2.5 ± 1.8 kg in the LIX group (P < 0.01). Conclusion Switching from MDI to combination therapy with LIX and basal insulin improved satisfaction levels while maintaining glycemic control in Japanese patients with type 2 diabetes. This article is protected by copyright. All rights reserved.

Background: Patients with type 2 diabetes mellitus often take multiple anti-diabetic drugs for a long period. Fixed dose combination (FDC) therapy is expected to improve drug adherence for patients with diabetes. The effect of switching from a loose dose combination (LDC) regimen to an FDC regimen at equivalent dosage on glycemic control has not been evaluated fully. Therefore, we investigated the effect of switching from LDC to FDC at equivalent dosage for 6 months on glycemic control in Japanese patients with type 2 diabetes. Methods: Thirty-eight Japanese patients with type 2 diabetes who were taking anti-diabetic drugs including pioglitazone + metformin, pioglitazone + alogliptin, or pioglitazone + glimepiride were enrolled. These drugs were switched to an FDC of Metact ® , Liobel ® or Sonias ® , respectively, at equivalent dosage. Other anti-diabetic drugs and units of insulin were not changed during the study if possible. HbA1c and body weight were measured 0, 2, 4 and 6 months after switching from an LDC to FDC. We also conducted a questionnaire survey 2 months after the start of the FDC regimen. Results: HbA1c levels at 2, 4, and 6 months were not significantly changed compared with prior to switching from an LDC to FDC regimen. Moreover, 74.2% of patients considered decreasing the number of drugs to be “very good” or “good”. Conclusion: HbA1c levels did not differ between patients receiving LDC and FDC therapy at equivalent dosage in this study. J Clin Med Res. 2017;9(8):719-724 doi: https://doi.org/10.14740/jocmr3067w

Purpose Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. Methods 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. Results The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15–2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97–2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). Conclusion The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.

Although magnifying endoscopy with narrow-band imaging (ME-NBI) can help identify the horizontal margin (HM) of early gastric cancer (EGC), little is known about the factors that can clarify the HM by using ME-NBI. We aimed to characterize the pathological features of lesions in which the HM was identified using ME-NBI. The HMs of 639 differentiated-type EGCs treated with endoscopic submucosal dissection or surgery were analyzed using conventional endoscopy and ME-NBI. The number and width of the intervening parts (IP) and the number, width, and depth of the subepithelial capillaries (SEC) in cancerous and noncancerous areas were measured. In 13 lesions (2.0%), more than 90% of the HM was not recognized with conventional endoscopy, but 11 of these lesions were detectable with ME-NBI (NBI group). The HMs of the other 626 lesions were mostly recognized using conventional endoscopy (WLI/CE group). In the NBI group, the IP width, standard deviation (SD), and number of IPs did not significantly differ between the cancerous and noncancerous areas. However, the SEC number was significantly larger and the depth was shallower in cancerous areas. In the WLI/CE group, the IP width and SD were significantly larger, but the IP number was significantly smaller in cancerous areas. The SEC depth was significantly shallower in cancerous areas. Differences of IP width, SD, and IP number may be factors for identifying HMs with conventional endoscopy. Because NBI can better visualize vessel structures, the increased SEC number and shallow SECs may clarify the HM.

Laparoscopic surgery has been widely accepted for the treatment of colorectal cancer; however, long-term outcomes in elderly patients remain controversial. The midterm results of a randomized trial comparing open surgery with laparoscopic surgery in elderly patients with colorectal cancer are presented. This was a randomized trial comparing open surgery with laparoscopic surgery in elderly patients with colorectal cancer. The primary outcome was complication rate, and secondary outcomes included 3-year recurrence-free survival and overall survival. A total of 200 patients were randomly assigned to open surgery or laparoscopic surgery between 2008 and 2012. The main study objective was to compare the midterm outcomes of open surgery with those of laparoscopic surgery in elderly patients with colorectal cancer. This trial is registered with Clinical Trials.gov (NCT01862562). There were no differences between the laparoscopic surgery group and open surgery group in the 3-year overall survival rate (91.5% for laparoscopic surgery vs. 90.6% for open surgery, p = 0.638) or the 3-year recurrence-free survival rate (84.8% for laparoscopic surgery vs. 88.2% for open surgery, p = 0.324). The local recurrence rate was significantly higher in the laparoscopic surgery group than in the open surgery group in rectal cancer (13.8% for laparoscopic surgery vs. 0% for open surgery, p = 0.038). In subgroup analysis according to tumor location, there were no significant differences in the 3-year overall survival rate or 3-year recurrence-free survival rate between the two treatment groups. The midterm outcomes of laparoscopic surgery are similar to those of open surgery in elderly patients with colorectal cancer.

Background The incidence of biliary tract infection (BTI), especially healthcare-associated cholangitis, is increasing. However, there are few reports concerning biomarkers of acute cholangitis. We therefore performed an exhaustive investigation of several biomarkers. Methods We retrospectively measured eleven cytokines, six chemokines and procalcitonin (PCT), and endotoxin activity assay (EAA) values (IRB: 110512019) of sixty-one samples with acute cholangitis. Result The 28-day mortality rate was 9.8%. The levels of most cytokines and chemokines were significantly correlated with each other. A low IL-7 level was found to predict of blood culture positivity. Low IL-7 level was also found to predict DIC. Low IL-7 levels and a high PCT level were found to be predictors of severe cholangitis. The 28-day mortality in the group of patients with an IL-7 level of ≤6.0 and a PCT level of >0.5 was 18.2%. It was significantly higher than in the other group. Conclusion The combined use of IL-7 and PCT may be useful for evaluating severe acute cholangitis; these results may suggest that severe acute cholangitis is affected by immunosuppressive changes. This article is protected by copyright. All rights reserved.

Background Recently, new non-invasive vascular indexes named arterial velocity pulse index (AVI) and arterial pressure volume index (API), which is evaluated by a multifunctional blood pressure monitoring device, were developed using cuff oscillometric technologies and suprasystolic cuff oscillometric wave measurement. However, although a few studies including a computational model have been performed, data on subjects with cardiovascular diseases in actual outpatient clinics remain scant. Methods We examined a total 252 consecutive outpatients and analyzed two vascular indexes with various clinical parameters to explore potential utilities of these two indexes in actual clinical settings. Results Although we found that two indexes were correlated with each other, the clinical implications of these indexes seemed to differ. Our analyses showed that AVI significantly correlated with augmentation index, but not with flow-mediated dilatation, and multivariate analyses suggested that enhanced AVI represents increased workload on the heart with elevated central blood pressure. In contrast, although the results of analyses performed to identify clinical parameters independently related to API were obscure and non-specific, after adjustment for multiple clinical variables, API was found to be significantly and independently associated with both Framingham Cardiovascular Risk Score and the Suita Score, suggesting that API is a useful predictor of future cardiovascular events. Conclusions These two new vascular indexes might be useful in actual clinical settings to evaluate cardiovascular risks with various clinical backgrounds.

Background The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. Methods Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. Results For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0–18.8) in the HAIC group and 15.2 months (95% CI, 8.2–19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7–5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3–6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. Conclusions Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. Trial registration UMIN ID 000006147, registration data: August 11, 2011.

Purpose To investigate the differences between a 7.5-Fr sheathless guides and a 7-Fr Glidesheath slender sheath (GSS) /7-Fr guiding catheter combination regarding access-site complications and process time metrics in percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). Methods We enrolled 609 patients undergoing PCI for AMI at our hospital using either a 7.5-Fr sheathless guides or a 7-Fr GSS/7-Fr guiding catheter combination; 1:1 propensity score matching was performed. A propensity score was estimated using a multivariate logistic regression model. Variables included were age, gender, weight, hypertension, diabetes, smoking, statin, estimated glomerular filtration rate, end-procedural activated clotting time, oral anticoagulants, SYNTAX score I, previous PCI, history of MI, Killip class, prior ipsilateral transradial intervention, and radial artery diameter. Results A total of 336 subjects were included in the propensity-matched sample. Compared with the GSS group, the sheathless group had significantly less frequent severe radial spasm (Sheathless: 0.6% vs. GSS: 4.8%, p=0.037) and Bleeding Academic Research Consortium type 2, 3, or 5 bleeding events (Sheathless: 12.5% vs. GSS: 21.4%, p=0.041). Procedure outcomes Variables Total population Propensity-matched population Sheathless (n=368) Glidesheath (n=241) OR (95% CI) p Sheathless (n=168) Glidesheath (n=168) OR (95% CI) p Primary outcomes RAO at 30 days 10 (2.7) 3 (1.2) 0.45 (0.08–1.77) 0.26 4 (2.4) 1 (0.6) 0.25 (0.03–2.22) 0.37 Severe radial spasm (grade 3 or 4) 5 (1.4) 12 (5.0) 3.78 (1.22–13.87) 0.011 1 (0.6) 8 (4.8) 8.35 (1.03–67.52) 0.037 BARC type 2, 3, or 5 bleeding within 30 days 40 (10.9) 45 (18.7) 1.87 (1.15–3.05) 0.008 21 (12.5) 36 (21.4) 1.91 (1.06–3.43) 0.041 Procedural success 361 (98.6) 238 (98.8) 1.10 (0.21–7.14) 0.54 167 (99.4) 166 (98.8) 0.50 (0.05–5.53) 1.0 Secondary outcomes Coronary ostial dissection 7 (1.9) 3 (1.2) 0.65 (0.11–2.87) 0.75 4 (2.4) 3 (1.8) 0.75 (0.16–3.38) 1.0 MACCEs within 30 days 4 (1.1) 7 (2.9) 2.70 (0.68–12.73) 0.12 4 (2.4) 0 (0) n/a 0.12 Puncture to balloon time, min 26.0 (21.0–35.0) 27.0 (20.0–38.0) n/a 0.52 26.5 (21.0–37.0) 27.0 (20.0–38.0) n/a 0.77 Data are presented as median (interquartile range) or n (%), unless otherwise indicated. Bleeding Academic Research Consortium; CI, confidence interval; MACCEs, major adverse cardiac and cerebrovascular events; OR, odds ratio; RAO, radial artery occlusion. MACCEs include all-cause death, myocardial infarction, target-vessel revascularization, and cerebrovascular accident. Conclusions These data demonstrate a clear advantage of sheathless guides over GSS/guiding catheter combination for decreased risk of severe radial spasm and bleeding.

Although colorectal endoscopic submucosal dissection (ESD) has become a standardized procedure worldwide, the difficulty of the procedure is well known. However, there have been no studies assessing the causes of treatment interruption. The present study aimed to evaluate the factors involved in the interruption of colorectal ESD. We retrospectively analyzed 1116 consecutive superficial colorectal neoplasms of 1012 patients who were treated with ESD between August 2008 and September 2018. The clinicopathological characteristics and treatment outcomes were analyzed. Interrupted ESD was reported in 14 lesions (1.3%) of the total study population. Univariate analysis of clinical characteristics indicated that age, 0–I macroscopic-type tumor, and tumor location on the left side colon were risk factors for interruption. Multivariate analysis revealed that 0–I macroscopic-type tumor was the sole preoperative independent risk factor for interruption. Univariate analysis revealed that the presence of muscle-retracting sign (MRS), deep submucosal tumor invasion, and intermediate invasive growth pattern represented the etiology of interruption. Multivariate analysis indicated that MRS can be a sole key sign for the interruption. Additionally, the resectability and curability of 0–I type tumors were significantly inferior to those of predominantly lateral spreading tumors. Observations of 0–I macroscopic-type tumors, MRS, and submucosal deep invasion were significantly more frequent in interrupted cases. Conventional endoscopic images without magnification endoscopy were more associated with interruption than irregular surfaces or Vi pit patterns in cases with 0–I type tumors. ESD of 0–I type tumors is highly disruptive, and undiagnosable submucosal infiltration can reduce the curability.

Background: Patients taking opioids are known to develop opioid-induced constipation (OIC), which reduces their quality of life (QOL). The aim of this study is to compare magnesium oxide and naldemedine to determine which is more effective in preventing OIC. Methods: This is a proof of concept, prospective, randomized controlled trial, conducted in Japan in March 2018. Initially, a questionnaire survey will be carried out targeting adult cancer patients who had concomitantly commenced opioid and OIC prevention treatment. Patients will then be randomly allocated into a magnesium oxide (500 mg, tid) group or a naldemedine (0.2 mg, sid) group. Each drug will be orally administrated for 12 weeks. The primary endpoint is defined as any improvement in the Japanese version of Patient Assessment of Constipation Quality of Life (JPAC-QOL) scores from the baseline to 2 weeks of treatment. Discussion: The primary endpoint is changes in the JPAC-QOL scores from the baseline to 2 weeks of intervention. The key secondary endpoint will be changes in spontaneous bowel movements (SBMs) at 2 and 12 weeks of intervention. This study will determine whether magnesium oxide or naldemedine is more effective for the prevention of OIC.Trial registration: This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000031891). Registered 25 March 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000036408.

The advantages of sheathless guiding catheters over the conventional approach using sheaths in percutaneous coronary intervention (PCI) regarding access-site complications, particularly ultrasound-diagnosed radial artery occlusion (RAO), remain unknown. The present study investigated the incidence of access-site complications of transradial primary PCI using sheathless guiding catheters in acute coronary syndrome (ACS). This prospective study evaluated access-site complications in 500 patients with ACS undergoing sheathless transradial primary PCI. Doppler ultrasound evaluation of the radial arteries was performed 2 and 30 days after the procedure. Sheathless guiding catheters (7.5-Fr) were used in 91.0% of the patients. The procedural success rate was 98.4%. Ultrasound-diagnosed RAO rates were 2.0% and 3.8% at 2- and 30-day follow-ups, respectively. Logistic regression analysis identified that the sheath-to-artery ratio (per 0.1) (odds ratio [OR] 5.71; 95% confidence interval [CI] 1.18–27.71; p = 0.001) was associated with more frequent RAO and that hypertension (OR 0.22; 95% CI 0.06–0.81; p = 0.023) was associated with less frequent RAO. Receiver operating characteristic curve analysis revealed that a sheath-to-artery ratio of 1.47 was the cutoff for 30-day post-procedural RAO (sensitivity 72%, specificity 81%). Sheathless transradial primary PCI for ACS was associated with a low incidence of access-site complications and a higher sheath-to-artery ratio cutoff for RAO than that expected from conventional PCI using sheaths based on historical data, demonstrating the access-site safety of sheathless guiding catheters and their benefit in PCI for ACS (University Hospital Medical Information Network-Clinical Trial Registry Number UMIN000019931).

Background Haploinsufficiency of A20 (HA20) is caused by loss-of-function TNFAIP3 variants. Phenotypic and genetic features of HA20 remain uncertain; therefore, the clinical distinction between HA20 and Behçet’s disease (BD) requires clarification. Methods We have collected 12 Japanese BD-like families. Probands of these families were analyzed by whole exome sequencing (WES) and subsequent Sanger sequencing. Clinical features were compared between 54 HA20 patients (including previously reported and new cases) and 520 Japanese BD patients. Results We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family. Four HA20 patients in the two families presented with childhood-onset recurrent oral and genital ulcers and were initially diagnosed and treated as BD. Consistent with the clinical features of HA20, recurrent, refractory fever attacks (three of four patients), and digestive ulcers (two of the four patients) were observed. A comparison of clinical features between HA20 patients and cohorts of BD patients revealed several critical features specific to HA20. These were early-onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement. Conclusions We identified a novel nonsense variant and deletion of the entire TNFAIP3 gene in two unrelated Japanese HA20 families. Genetic screening of TNFAIP3 should be considered for familial BD-like patients with early-onset recurrent fevers. Electronic supplementary material The online version of this article (10.1186/s13075-019-1928-5) contains supplementary material, which is available to authorized users.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4–10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders. A newly developed PET tracer allows visualization of AMPA receptors in the living human brain, providing a new tool to study their potential involvement in neurological or psychiatric disorders.

BACKGROUND Patients with severe aortic stenosis (AS) and an extra-large annulus (ELA) area (>683 mm2) can rarely be treated by transcatheter aortic valve replacement (TAVR) because of the size limitation of the transcatheter heart valves. This study aimed to evaluate the feasibility of TAVR using a 29-mm SAPIEN3 (S3) valve in patients with ELA and S3-dimensions by post-procedural computed tomography (post-CT). Methods and Results: We included 261 patients undergoing TAVR using a 29-mm S3: 30 patients with ELA and 231 with non-ELA were identified. S3-dimensions were evaluated at the S3 inflow and annulus level by post-CT in 129 patients. The ELA group had a greater aortic annulus area measured by pre-procedural CT (737.3±54.7 vs. 578.4±41.9 mm2, P

Introduction: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. Methods: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. Results: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). Conclusions: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

The favorable oncological impact of D3 lymph node dissection after colon cancer surgery has been described previously. However, D3 lymph node dissection is potentially more invasive than conventional D2 lymph node dissection. The oncological merit of D3 lymph node dissection in elderly patients with colon cancer remains unclear. This study aimed to clarify the oncological outcome after D3 lymph node dissection in patients with colon cancer aged > 75 years. This is a retrospective cohort analysis using propensity matching method. The study was conducted at a university hospital and two community teaching hospitals in a large urban city. A total of 378 consecutive patients with pathological stage II and stage III colon cancer who underwent primary resection with either D2 or D3 lymph node dissection were retrospectively identified on a prospective database between 2000 and 2015. The primary and secondary outcomes of interests were recurrence-free survival and postoperative complication rate, respectively. After propensity matching, 232 patients were analyzed. The long-term findings showed that the elderly who underwent D3 lymph node dissection had significantly better recurrence-free survival than those who underwent D2 lymph node dissection (p = 0.01). The incidence of postoperative complication was almost similar between the two groups. D3 lymph node dissection provides better recurrence-free survival than D2 lymph node dissection after primary resection for elderly patients with pathological stage II and stage III colon cancer.

ObjectivesPatients’ backgrounds and clinical outcomes in urgent/emergent/salvage transcatheter aortic valve replacement (Em-TAVR) remain unclear. We investigated patient characteristics and the mortality in Em-TAVR and the predictors for the need for Em-TAVR.MethodsWe consecutively enrolled 1613 patients undergoing TAVR for severe aortic stenosis between October 2013 and July 2016 from the Optimised transCathEter vAlvular interventioN (OCEAN)-transcatheter aortic valve implantation (TAVI) registry. The urgency was based on the European System for Cardiac Operative Risk Evaluation II. Urgent, emergent or salvage were included with the Em-TAVR group and elective with the El-TAVR group.ResultsEm-TAVR was observed in 87 (5.4%) patients. A higher Clinical Frailty Scale (CFS), peripheral artery disease (PAD), hypoalbuminaemia, reduced left ventricular ejection fraction (LVEF) and preoperative at least moderate mitral regurgitation (MR) predicted the need for the Em-TAVR by the multivariate logistic regression analysis. The Em-TAVR group had the higher Society of Thoracic Surgeons Score (13.7 (IQR 8.2–21.0) vs 6.5 (IQR 4.6–9.2); pConclusionsEm-TAVR was performed in 5.4% of patients. Higher CFS, PAD, hypoalbuminaemia, reduced LVEF and preprocedural MR predicted the need for Em-TAVR. Em-TAVR was not a predictor for mortality in the multivariate analysis, suggesting that it is a reasonable treatment option.

Aims To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. Methods We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). Results Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. Conclusions More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients. This article is protected by copyright. All rights reserved.

Aspirin use is reportedly not to be associated with fecal immunochemical occult blood test (FIT) false-positive results for the detection of colorectal cancer. The need for additional small bowel exploration in FIT-positive, low-dose aspirin users with a negative colonoscopy is controversial. The aim of this study was to assess the ability of FIT to judge whether capsule endoscopy (CE) should be performed in low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy findings by comparing FIT results with CE findings. A total of 264 consecutive low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy who were scheduled to undergo CE at five hospitals in Japan were enrolled. Patients had been offered FIT prior to the CE. The association between the FIT results and the CE findings was then assessed. One hundred and fifty-seven patients were included in the final analysis. Eighty-four patients (53.5 %) had positive FIT results. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of positive FIT results for small bowel ulcers were 0.56, 0.47, 0.30, and 0.73, respectively. Furthermore, the NPV of positive FIT results for severe small bowel injury (Lewis score ≥790) was markedly high (0.90). When the analysis was performed only in low-dose aspirin users with anemia, the sensitivity of the positive FIT results was notably improved (0.72). Small bowel evaluation using CE is not recommended for FIT-negative, low-dose aspirin users. However, small bowel evaluation using CE should be considered in both FIT-positive and anemic low-dose aspirin users.

Summary Background The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. Methods This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. Findings Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38·0%; 95% CI 26·7–49·3] of 71 patients, placebo group 35 [56·5%; 95% CI 44·1–68·8] of 62; p=0·034, risk ratio [RR] 0·67 [95% CI 0·47–0·97]; adenomas: metformin group 22 [30·6%; 95% CI 19·9–41·2] of 71 patients, placebo group 32 [51·6%; 95% CI 39·2–64·1] of 62; p=0·016, RR 0·60 [95% CI 0·39–0·92]). The median number of polyps was zero (IQR 0–1) in the metformin group and one (0–1) in the placebo group (p=0·041). The median number of adenomas was zero (0–1) in the metformin group and zero (0–1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. Interpretation The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. Funding Ministry of Health, Labour and Welfare, Japan.

We compared the efficacy and safety of taking miglitol dissolved in water during a meal and taking a miglitol tablet just before a meal. Primary efficacy parameter is the area under the curve (AUC) for postprandial plasma glucose.Miglitol was administered according to three different intake schedules in each subject: intake schedule A, no miglitol; intake schedule B, administration of miglitol (50 mg) just before breakfast; intake schedule C, dissolving miglitol (50 mg) in water and taking it just before (1/3), during (1/3), and just after breakfast (1/3). Blood samples were collected at 0, 30, 60, 120, and 180 min after breakfast.The AUCs for plasma glucose, insulin, and total glucose-dependent insulinotropic polypeptide (GIP) were significantly lower for intake schedules B and C, compared with those for intake schedule A. The AUC for total glucagon like peptide-1(GLP-1) was higher for intake schedule C than for intake schedule A. The coefficient of variation (CV) of plasma glucose was significantly lower for intake schedule C than for intake schedules A and B.Taking miglitol dissolved in water was equivalent to taking a miglitol tablet. The CV of plasma glucose was significantly lower for the dissolved-dose regimen.

Atypical protein kinase C λ/ι (aPKCλ/ι) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKCλ/ι may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKCλ/ι expression and CIN. aPKCλ/ι expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKCλ/ι overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKCλ/ι nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P

We evaluated the influence of short-term treatment with exenatide twice daily or liraglutide once daily on daily blood glucose fluctuations in 40 patients with type 2 diabetes inadequately controlled by sulfonylureas. The patients in a multicenter, open-label trial were randomly assigned to receive add-on exenatide (10 μg/day, n = 21) or add-on liraglutide (0.3-0.9 mg/day, n = 19), and underwent 24-hour continuous subcutaneous glucose monitoring. There was no significant between-group difference in glucose fluctuations during the day, as assessed by calculating mean amplitude of glycemic excursion (MAGE) and standard deviation (SD). However, the mean blood glucose levels at 3 hours after breakfast and dinner were significantly lower in the exenatide group than the liraglutide group (breakfast: 127.3 ± 24.1 vs. 153.4 ± 28.7 mg/dL; p = 0.006, dinner: 108.7 ± 17.3 vs. 141.9 ± 24.2 mg/dL; p < 0.001). In contrast, mean blood glucose levels and their SD were significantly lower between 0000 h and 0600 h in the liraglutide group than the exenatide group (average glucose: 126.9 ± 27.1 vs. 107.1 ± 24.0 mg/dL; p = 0.029, SD: 15.2 ± 10.5 vs. 8.7 ± 3.8; p = 0.020). Both groups had similar glucose fluctuations despite differences in 24-hour blood glucose profiles. Therefore, each of these agents may have advantages or disadvantages and should be selected according to the blood glucose profile of the patient.

Background: Patients with schizophrenia have abnormal autonomic nervous system (ANS) activity compared with the general population. One reason for this difference is the muscarinic affinity for antipsychotic drugs; therefore, single nucleotide polymorphisms (SNPs) of the muscarinic receptor gene influence this ANS dysfunction. This study sought to determine the effect of SNPs of the cholinergic muscarinic receptor (CHRM) gene on ANS activity in patients with schizophrenia receiving antipsychotic drugs. Methods: A total of 173 Japanese patients with schizophrenia were included in this study. Heart rate variability (HRV) was measured as an index of ANS activity. SNPs in CHRM1 (rs542269 and rs2075748), CHRM2 (rs324640, rs8191992, rs1824024, and rs7810473), and CHRM3 (rs3738435, rs4620530, and rs6429157) were genotyped using the TaqMan® method. Patients were grouped according to standard equivalent conversions of chlorpromazine (CP) into a high-CP group (HG; ≥1,000 mg) and a low-CP group (LG; p value was Results: The A allele of the CHRM2 rs8191992 polymorphism in HG was associated with decreased ANS activity. Conclusion: Our results show reduced ANS activity in association with the CHRM2 rs8191992 polymorphism in patients with schizophrenia on high-dose antipsychotics. CHRM2 polymorphisms may play an important role in ANS activity in patients with schizophrenia.

Background The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. Patients and Methods This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m2/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

BACKGROUND There is no consensus on blood adrenal androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, dehydroepiandrosterone (DHEA) concentrations in blood were examined by ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed the correlation between DHEA concentrations in blood and clinicopathological findings of prostate cancer. METHODS We analyzed 196 men (mean age 70 years) with prostate cancer. The patients underwent systematic needle biopsy, and peripheral blood sampling was conducted for measurement of DHEA. DHEA concentrations in blood were determined using LC-MS/MS method. Patient age, serum prostate-specific antigen, prostate volume measured by ultrasound, and DHEA levels in blood were compared with Gleason score and clinical stage by multivariate analyses. RESULTS Median value of PSA and prostate volume were 11.5 ng/ml and 27.7 ml, respectively. Median concentration of DHEA in blood was 1,506.4 pg/ml. There was no correlation between serum DHEA and clinical variables such as age, serum PSA, and prostate volume. In multivariate analysis, low serum DHEA levels in prostate cancer patients were significantly related to high Gleason score and advanced clinical stage. Serum PSA levels in prostate cancer patients were also significantly associated with high Gleason score and advanced clinical stage. High serum PSA and low serum DHEA levels were significantly associated with poor prognosis factors in men with hormone-naive prostate cancer. CONCLUSIONS DHEA concentrations in blood were examined by newly developed ultrasensitive LC-MS/MS. We confirmed that low serum DHEA levels in prostate cancer patients were related to high Gleason score and advanced clinical stage. These results suggest that serum DHEA level may be a useful prognostic factor in prostate cancer patients. Prostate © 2015 Wiley Periodicals, Inc.

In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

After major liver resections, infections and liver insufficiency are the most common complications; these may coincide. We performed a randomized clinical trial to clarify ability of early enteral nutrition to prevent infectious complications and liver failure following major hepatectomy. We prospectively allocated consecutive patients who underwent major liver resection into either an early enteral nutrition group in which such nutrition was initiated on the first postoperative day or a nonenteral nutrition group. The primary study endpoint was rate of infectious complications. Thirty-two patients were randomly allocated to the enteral nutrition group, while 31 were assigned to the nonenteral nutrition group. No significant difference in rate of infection complications was evident between enteral (9.4%) and nonenteral group (22.6%, P = 0.184). However, complications of grade III severity or worse were significantly less frequent in the enteral (9.4%) than in the nonenteral group (32.3%, P = 0.031). Further, postoperative serum concentrations of pre-albumin and reduced-state albumin were greater in the enteral than in the nonenteral group. Early enteral nutrition did not significantly improve prevention of infectious complications, but some effectiveness in preventing severe complications and improving nutritional status was demonstrated.

Useful prognostic markers for patients with diffuse large B cell lymphoma (DLBCL) have been reported. To identify which biomarker best predicts the prognosis of patients with DLBCL, we performed a retrospective study that included 319 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy between 2003 and 2012. We assessed the prognostic significance of six biomarkers [lactate dehydrogenase, soluble interleukin-2 receptor, thymidine kinase activity, beta-2 microglobulin (B2M), C-reactive protein, and ferritin] and representative clinical characteristics using progression-free survival (PFS) as the endpoint. The study group included 181 men and 138 women with a median age of 63 years (range, 22-89 years). In a multivariate analysis, the serum B2M level most strongly correlated with PFS (hazard ratio, 2.11; P=0.04). In a univariate analysis, patients with serum B2M levels >1.75μg/mL (n=210) had a worse 3-year PFS rate (71.2%) than those with B2M levels

Stroke during transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS) remains a concerning complication, and its mechanism is still unclear [(1)][1]. Histopathological analyses of debris captured by a cerebral protection during TAVR showed that the debris consisted of diverse material

Background: The incidence of nonalcoholic fatty liver disease (NAFLD) has increased recently and is related to obesity and the associated surge in type 2 diabetes mellitus (DM) and metabolic syndrome diagnoses. We aim to compare the effectiveness of tofogliflozin and pioglitazone treatment on hepatic steatosis in patients with NAFLD with type 2 DM. Methods: This is an open label, prospective, randomized exploratory study. Patients who meet the inclusion criteria and do not meet any exclusion criteria will undergo magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF). Patients with ≥10% liver fat content on MRI-PDFF will be randomly assigned to receive tofogliflozin 20 mg per day (n = 20) or pioglitazone 15–30 mg per day (n = 20). MRI will be performed after 24 weeks following initiation of medication therapy. Then, patients will take tofogliflozin and pioglitazone in combination in both groups for 24 weeks. MRI will be performed again at 48 weeks (24 weeks after initiation medication in combination). Results: Our study's primary endpoint will be change in hepatic steatosis measured by MRI-PDFF at 24 weeks after medication therapy. The secondary endpoint will be change in alanine aminotransferase at 24 weeks of medication therapy and the main exploratory endpoint will be changes in liver fat content and liver sclerosis at 48 weeks of medication. Conclusions: We will compare the effectiveness of tofogliflozin and pioglitazone treatment using MRI for improving hepatic steatosis in patients with NAFLD complicated by DM and investigate if the combination of these two medications is effective for treating NAFLD. Trial registration: This trial is registered in the Japan Registry of Clinical Trials (jRCTs031180159). Protocol version: 1.2, 14 December 2018. Keywords: Non-alcoholic fatty liver disease, Tofogliflozin, Pioglitazone, Diabetes mellitus, Hepatic steatosis, MRI-Based proton density fat fraction

285 Background: A complete resection of the omentum has been believed as a standard procedure for advanced gastric cancer. However, there was no evidence for survival significance of omentectomy. Therefore, we conduct the Phase II trial (TOP-G trial) comparing gastrectomy with omentectomy and omentum preserving gastrectomy. Here, we present the short-term outcomes which was a secondary endpoint of TOP-G trial. Methods: Enrollment criteria included histologically confirmed cT2-4a and N0-2 gastric adenocarcinoma. The extent of nodal dissection was performed based on the Gastric Cancer Treatment Guidelines in Japan. All procedure was performed through laparotomy. Laparoscopic approach was not accepted. Surgical outcomes morbidity, and mortality were compared between gastrectomy with omentectomy group (group A) and omentum preserving gastrectomy group (group B). Postoperative complication was evaluated with Clavien-Dindo classification. Results: A total of 251 patients were randomly assigned to group A (n = 125) or group B (n = 126) between April 2011 and October 2018. After excluding patients who received bypass or no surgery, 246 patients were analyzed as actual treatment group. There was no difference between two groups in patient characteristics and pathological findings. There was no difference in operation time (median 244 vs 204 min, p = 0.156) and in blood loss (median 260 vs. 210 ml, p = 0.371). Median number of totally retrieved lymph nodes was similar (median 36 vs. 37, p = 0.758). There was no difference in the incidence of any postoperative complication (28.9% vs. 25.8%, p = 0.584). There was no mortality in both groups. Conclusions: Omentum preserving gastrectomy for advanced gastric cancer was similar short-term outcomes with gastrectomy with omentectomy. Clinical trial information: UMIN000005421.

BACKGROUND/AIM Atypical protein kinase C λ/ι (aPKCλ/ι) is a cell polarity-regulator localized in the tight junction and apical membrane in epithelial cells. Previous studies suggested that aPKCλ/ι overexpression and abnormal localization were involved in tumor progression in several cancers. We investigated the relationship between aPKCλ/ι and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS The correlation between the aPKCλ/ι expression and the clinicopathological parameters in 76 OSCC cases was examined using immunohistochemical analyses. RESULTS aPKCλ/ι overexpression was observed in 36.8% of cases. aPKCλ/ι expression was more intense in poorly differentiated OSCC and younger patients (

Purpose: To investigate if balloon angioplasty with a prolonged inflation time (>3 minutes) can prevent postdilation dissection in femoropopliteal lesions. Methods: A retrospective single-center analysis examined 294 consecutive patients (mean age 74.1±8.7 years; 215 men) with de novo femoropopliteal lesions treated with balloon angioplasty between 2013 and 2018. The patients were classified into 2 groups to compare angiographic dissection patterns: 175 patients treated with balloon angioplasty for 3 minutes (3-minute group) and 119 treated for >3 minutes (>3-minute group). Results: Mean balloon inflation time was 7.8±2.7 minutes in the >3-minute group. Severe dissections (type C or higher) were observed less frequently after balloon dilation in the >3-minute group (22.7% vs 50.9%, p3-minute group had successful endovascular treatment after initial balloon angioplasty (57.1% vs 38.3%, p=0.001). Additional balloon dilation was attempted more frequently in the 3-minute group (30.9% vs 14.3%, p=0.001); as a result, there were more patients in whom additional balloon dilation repaired severe dissection that occurred after the initial dilation (25.1% vs 10.9%, p=0.001). Multivariate analysis revealed that chronic total occlusion (p3 minutes) may be effective as an initial strategy to prevent severe dissection in femoropopliteal lesions compared to inflation for 3 minutes.

To compare the outcomes of radical prostatectomy (RP), intensity-modulated radiation therapy (IMRT), and low-dose-rate brachytherapy (BT) using propensity score matching analysis in patients with clinically localized prostate cancer. A group of 2273 patients with clinically localized prostate cancer between January 2004 and December 2015 at the Yokohama City University hospital were identified. The records of 1817 of these patients, who were followed up for a minimum of 2 years, were reviewed; 462 were treated with RP, 319 with IMRT, and 1036 with BT. The patients were categorized according to the National Comprehensive Cancer Network risk classification criteria, and biochemical outcomes and overall survival rates were examined. Biochemical failure for RP was defined as prostate-specific antigen (PSA) levels > 0.2 ng/ml, and for IMRT and BT as nadir PSA level + 2 ng/ml. Propensity scores were calculated using multivariable logistic regression based on covariates, including the patient's age, preoperative PSA, Gleason score, number of positive cores, and clinical T stage. Median follow-up was 77 months for the RP, 54 months for IMRT, and 66 months for BT patients. After the propensity scores were adjusted, a total of 372 (186 each) and 598 (299 each) patients were categorized into RP vs IMRT and RP vs BT groups, respectively. Kaplan–Meier analysis did not show any statistically significant differences in terms of overall survival rate between these groups (RP vs IMRT: p = 0.220; RP vs BT: p = 0.429). IMRT was associated with improved biochemical failure-free survival compared to RP in all risk groups (high-risk: p

Background It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. Methods The PubMed database was examined (1989‐2017) for studies published in English language regarding the prospective follow‐up results for the development of HCC in various liver diseases. A meta‐analysis was performed for each liver disease. Results The annual incidence (%) of HCC in the non‐cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non‐cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73‐fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07‐fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88‐fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79‐fold), and (e) NASH (0.03%→1.35%, 45.00‐fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow‐up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. Conclusions When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.

The optimal primary transradial intervention (TRI) technique has not been established in non-ST segment elevation acute coronary syndrome (NSTEACS) patients, because they often, but not always, undergo immediate revascularization after coronary angiography (CAG). Moreover, TRI failure has been reported in 5%-10% of cases. We investigated whether a newly designed strategy of immediate TRI using one sheathless hydrophilic-coated guiding catheter (SH-GC) after diagnostic CAG with one 4.0 Fr sheath via a single access site (the 1-1-1 strategy) could be beneficial for NSTEACS patients.We performed immediate TRI prospectively using SH-GC in consecutive NSTEACS patients in our hospital and compared the procedural success rate with that of conventional TRI performed before this study.Between 2015 and 2017, immediate TRI using SH-GC was performed in 330 consecutive NSTEACS patients after CAG using a 4.0 Fr sheath. Compared with the conventional TRI group (n = 330), the procedural success rate was significantly higher in the SH-GC group (P.01), as SH-GC prevented TRI failure due to radial spasm (P.01). SH-GC use was also significantly associated with completion of both diagnostic CAG and immediate TRI using only one sheath (P.001) and one guiding catheter (P=.02). Multivariate analysis revealed that SH-GC use was an independent predictor of successful TRI (P.01). The rates of major adverse cardiac events were comparable; however, rates of major access-site bleeding (P.01) and blood transfusion (P=.02) were significantly lower in the SH-GC group.The 1-1-1 strategy using SH-GC may offer better TRI treatment than conventional systems for NSTEACS patients and simultaneously prevent access-site bleeding.