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BACKGROUND Coronary artery bypass grafting is a surgical treatment for ischemic heart disease. Although development in surgical technique and improvement of perioperative management reduced the postoperative complications, some patients still delayed in progress of postoperative rehabilitation. In this study, we aimed to investigate the effect of daily intake of an herbal medicine-containing drink for rehabilitation after surgery in patients with ischemic heart disease. AIM To investigate the effect of taking an herbal medicine-containing, commercially available drink for postoperative rehabilitation in those patients. METHODS Patients who underwent isolated off-pump coronary artery bypass (OPCAB) surgery were divided into two groups depend on the timing of the admission to the hospital: the Yunker (YKR) group, that consumed one bottle of a caffeine-free nutritional supplement drink on a daily basis and the control group (CTL) that underwent regular rehabilitation. RESULTS A total of 229 patients (CTL = 130, YKR = 99) were enrolled. No significant differences were observed in the baseline characteristics between the two groups. The YKR group had a significantly increased number of daily steps postoperatively (P < 0.05) and had significantly lower postoperative serum tumor necrosis factor-alpha levels (P < 0.01), while no significant differences were observed in the levels of other inflammatory or stress-related cytokines (interleukin-6, adiponectin, superoxide dismutase, and urine 8-hydroxy-2′-deoxyguanosine) between the two groups. Also, the YKR group showed a significant improvement in the Hospital Anxiety and Depression Score (P < 0.05). Moreover, there were no differences in postoperative complications and the duration of postoperative hospital stay between the two groups. CONCLUSION Our results demonstrated that the daily intake of an herbal medicine-containing drink after OPCAB surgery may have beneficial effects on cardiac rehabilitation by reducing inflammation markers and depression.

Patients with aortic stenosis (AS) are likely to have sleep-disordered breathing (SDB) and improvements in AS by transcatheter or surgical aortic valve replacement alter the type and severity of SDB. However, limited data are available whether polysomnographic findings changed following transcatheter aortic valve implantation (TAVI). In this report, we describe the case of a patient with severe AS and SDB whose polysomnographic findings showed that after TAVI, sleep disturbances occurred in association with worsened periodic leg movements despite improvement in the SDB.

Profunda femoris artery aneurysm (PFAA) is rare and has a high incidence of rupture. Herein, we report the case of an 80-year-old man who developed sarcopenia after gastric surgery. The patient presented to our hospital with a reddish thigh and was diagnosed with PFAA rupture. We performed aneurysmectomy and graft interposition in emergency. Postoperative enhanced computed tomography revealed an interposed graft, and the patient was discharged on postoperative Day 7. We considered that the PFAA patients with sarcopenia has a high risk of rupture because the muscles surrounding the profunda femoris artery became weak, and should be followed-up closely.

Limb ischemia caused by tumor embolus is rare. In this study, we report the case of a 77-year-old woman who suffered from acute ischemic limb. Computed tomography showed a tumor in the right bronchus invading the left atrium. The tumor fragments scattered resulting in the occlusion of the right iliac artery. The excluded embolus was revealed as a squamous cell carcinoma. Regarding the popliteal venous thrombus, Trousseau's syndrome was complicated. The patient was discharged without any complications. We believe that advanced lung cancer is a differential diagnosis of acute ischemic limbs and that successful limb rescue contributed to a patient's quality of life.

Steroids are often administered at the time of transcatheter arterial chemoembolization (TACE), a standard treatment of hepatocellular carcinoma (HCC), with the expectation of preventing postembolization syndrome. Here we investigated the precise effects of steroids on TACE. We prospectively enrolled 144 HCC patients from 10 hospitals who underwent TACE. Three hospitals used steroids (steroid group, n=77) and the rest did not routinely use steroids (control group, n=67). The occurrence of adverse events and the algetic degree at 1-5 days post-treatment were compared between the groups. Fever (grades 0-2) after TACE was significantly less in the steroid group (56/21/0) compared to the control group (35/29/3, p=0.005, Cochran-Armitage test for trend). The suppressive effect of steroids against fever was prominent in females (p=0.001). Vomiting (G0/G1/ G2-) was also less frequent in the steroid group (70/5/2) versus the control group (53/10/3), but not significantly (p=0.106). The algetic degree and the grade of hematological adverse events, including hyperglycemia, did not differ between the groups. We conclude that the administration of steroids was useful for the prevention of adverse events after TACE in patients with HCC.

Objective Previous studies have reported that nadir oxygen delivery during cardiopulmonary bypass is associated with the occurrence of postoperative acute kidney injury (AKI). However, these measurements only considered the bottom point of the oxygen delivery (DO2) but did not consider the duration of DO2. We aimed to examine whether the time–dose response of DO2 during cardiopulmonary bypass can be used to estimate the risk for postoperative AKI. Methods We evaluated 112 patients who underwent cardiac surgeries with cardiopulmonary bypass. We analyzed the perfusion parameters recorded every 20 seconds. To obtain time–dose response of DO2 index (DO2i), the area under the curve was calculated as below the 300 mL/min/m2 threshold, which accounts for depth and duration of cumulative oxygen debt. In addition, the cumulative time below DO2i 300 mL/min/m2 was also calculated. Receiver operating characteristic analysis, univariate regression analysis, and multivariate regression analysis were used to evaluate associations between perioperative variables and postoperative AKI. Results Patients who developed AKI had larger area under the curve below the 300 mL/min/m2 threshold (1581 vs 632; P Conclusions The time–dose response of DO2i during cardiopulmonary bypass is a better indicator than nadir DO2i in evaluating AKI risk. Maintaining DO2i levels >300 mL/min/m2 may result in decreased risk for postoperative AKI.

Background Hepatic arterial infusion chemotherapy (HAIC) with cisplatin is beneficial to patients with advanced HCC treated with sorafenib. This study aimed to examine the effect of HAIC with cisplatin before radiofrequency ablation (RFA) in patients with HCC. Methods This was a multicenter, single blinded, randomized controlled study (UMIN000007267). Early-stage HCC patients were randomly assigned (1:1) to receive HAIC with cisplatin before RFA therapy (HAIC group) or RFA monotherapy (non-HAIC group). The primary endpoint was recurrence-free survival. Efficacy analysis and safety analysis followed the intention-to-treat principle. Results Between August 2012 and July 2016, 74 patients were recruited. Seventy eligible patients were randomly assigned to the HAIC group (n = 35) and non-HAIC group (n = 35). Recurrence-free survival rates at 1 (3) year in the HAIC group and non-HAIC group were 82.9% (54.3%) and 74.3% (34.3%), respectively [hazard ratio (HR), 0.597; 95% CI, 0.320-1.091; p = 0.094]. Subgroup analysis revealed that the beneficial effect of HAIC was observed in patients with a single nodule and Child-Pugh 5. Intrahepatic distant recurrence-free survival rate in the HAIC group was significantly better than that in the non-HAIC group (HR, 0.468; 95% CI, 0.235-0.896; p = 0.022). Adverse events were observed only in two patients in the HAIC group (6%), grade 2 cholecystitis, and grade 2 hyperkalemia. Conclusions HAIC with cisplatin before RFA did not significantly decrease recurrence in patients with early-stage HCC. However, it might be effective in preventing intrahepatic distant recurrence. This article is protected by copyright. All rights reserved.

Background and Aim of the Study: Ischemic mitral valve regurgitation (IMR) in patients undergoing coronary artery bypass grafting (CABG) is associated with worse long-term outcomes. The aim of this study was to assess the impact of mitral valve repair with CABG in patients with moderate IMR. Method: This observational study enrolled 3,215 consecutive patients from the Juntendo CABG registry with moderate IMR and multivessel coronary artery disease who underwent CABG between 2002 and 2017. The CABG alone and CABG with mitral valve surgery (MVs) groups were compared. The propensity score was calculated for each patient. Long-term all-cause death, cardiac death, and major adverse cardiac and cerebrovascular events (MACCEs) were compared between the two groups. Results: A total of 101 patients who underwent CABG had moderate IMR in our database. Propensity score matching selected 40 pairs for final analysis. MVs was associated with increased risks of postoperative atrial fibrillation, blood transfusion, and longer hospitalization. There were no differences between the two groups in long-term outcomes, including all-cause mortality, cardiac mortality, and the incidence of MACCEs. Conclusions: Surgical treatment of moderate IMR combined with CABG was as safe as CABG alone, with no differences in long-term outcomes. Further studies are needed to determine the effects of MVs in patients with moderate IMR and severe coronary artery disease.

Transcatheter arterial chemoembolization (TACE) is often performed before radiofrequency ablation (RFA) for the treatment of early-stage hepatocellular carcinoma (HCC). TACE prior to RFA can expand the ablated area and reduce the tumor size, facilitating complete ablation. However, the factors correlated with size reduction remain uncertain. The aim of this study was to identify the factors associated with size reduction by TACE and develop a formula to predict the reduction rate. A total of 100 HCC patients treated with TACE followed by RFA at least 20 days later were enrolled. The tumor size was measured at the time of TACE and RFA, and correlations between the reduction rate and 13 clinical factors were examined. A formula to predict the reduction rate was built using the factors obtained by the analysis. Reduction in the tumor size was observed in 69 nodules, and the median reduction rate was 16.2%. A multivariate regression analysis revealed that a large tumor size (p< 0.01) and a long interval between the therapies (p= 0.01) were factors for a high tumor reduction rate, with tumor size more strongly related to the degree of reduction. A size reduction of more than 10% can be expected by waiting 20 days after TACE when the size of the tumor at TACE is over 25 mm in diameter. The tumor size

Background and Aim Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed. Methods Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice. Results REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6). Conclusions Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

Background We aimed to determine expression patterns of cardiac stem cells in the left atrium (LA) tissue from patients with atrial fibrillation. Methods LA appendages were obtained during open-heart surgery and processed for explant cell culture and tissue analysis ( n = 319). The total number of grown cells and c-kit positive cells were analyzed by flow cytometry after 4 weeks of culture. The remaining tissue was used for Masson's trichrome staining to determine the area of the fibrosis. Results The diameter of the LA, as measured by echocardiography, was significantly larger in the AF group than in the sinus rhythm group. Reverse transcription polymerase chain reaction analysis revealed higher expression of collagen in the AF group and an increase in the expression of basic fibrosis growth factor and transforming growth factor-2 and -3. Masson's trichrome staining showed progression of fibrosis in the AF tissue. In addition, the expression of apoptosis-related genes were significantly higher in AF group. There was no difference in the expression of connexin-40 between groups, while the expression of connexin-43 was decreased and that of connexin-45 was increased in the AF group. The total numbers of grown cells as well as c-kit positive cells after 4 weeks of cardiac tissue culture were significantly lower in the AF group. Conclusion Progression of remodeling in LA tissue was observed in AF patients. The number of c-kit positive cells cultured from LA appendages was reduced in AF patients, suggesting impairments in self-renewal.

Background and Aim Few reports describe the endoscopic double-stenting procedure for malignant biliary and duodenal obstructions. We evaluated the clinical outcomes from double stenting, and analyzed the risk factors for biliary stent dysfunction following double stenting. Methods Eighty-one patients who underwent endoscopic double stenting for malignant biliary and duodenal obstructions were retrospectively analyzed. We determined the stent dysfunction rate and the biliary stent dysfunction risk factors, and analyzed the endoscopic reintervention results. Results Overall survival time and survival time following double stenting were 365 (38–1673) days and 73 (20–954) days, respectively. After double stenting, the 3-month and 6-month duodenal stent dysfunction rates were 14% and 41%, respectively. Reintervention technical success rate was 100% (10/10), and mean gastric outlet obstruction scoring system scores improved from 0.7 to 2.4 points (P < 0.001). The 3-month and 6-month biliary stent dysfunction rates were 26% and 41%, respectively. The reintervention technical and clinical success rates were 95% (20/21) and 81% (17/21), respectively. Risk factors for biliary stent dysfunction following double stenting were events associated with duodenal stent dysfunction (odds ratio [OR], 11.1; 95% confidence interval [CI], 2.09–87.4; P = 0.0044) and the biliary stent end's location (OR, 6.93; 95% CI, 1.37–40.2; P = 0.0019). Conclusions Some patients had stent dysfunction irrespective of the survival period after double stenting. Endoscopic reintervention was technically feasible and clinically effective even after double stenting. Duodenal stent dysfunction and biliary stent end's location were risk factors for biliary stent dysfunction.

Background and Aim Transcatheter arterial chemoembolization (TACE) is a standard therapy for the treatment of intermediate-stage hepatocellular carcinoma (HCC). In this study, we tried to elucidate the possibility of using radiofrequency ablation (RFA) as an alternative treatment of intermediate-stage HCC. Methods Among 246 patients who were initially diagnosed with intermediate-stage HCC, 76 who were treated with TACE (TACE group) and 91 who were treated with RFA (RFA group) were enrolled in this study. The risk for survival was analyzed with the Cox Proportional Hazard Model, and the survival rates were compared using propensity score matching. Results About half (50.6%) of the intermediate-stage HCC patients in the RFA group were diagnosed with Barcelona Clinic Liver Cancer substage-B1 (BCLC-B1) compared with only 19.7% of the patients in the TACE group. Survival of the RFA group was longer than that of TACE group in patients with BCLC-B1 and BCLC-B2. In contrast, no difference between groups was observed in patients with BCLC-B3/4. Multivariate analysis revealed that large tumor size (>30 mm, hazard ratio = 1.685, P = 0.043), high des-γ-carboxyprothrombin (>100 mAU/mL, hazard ratio = 1.920, P = 0.012), and TACE group (hazard ratio = 1.896, P = 0.016) were significant risk factors for survival. Overall 3-year survival of the patients in the RFA group (69.5%) was significantly longer than that of patients in the TACE group (51.5%) after propensity score matching (P = 0.032). No significant adverse events were observed in either group. Conclusions RFA was useful for the treatment of less advanced intermediate-stage HCC and could be an alternative to TACE in selected cases.

Purpose: To describe a technique suitable for treating severely angulated (>75°) necks during endovascular aneurysm repair using the Endurant stent-graft. Technique: In the push-up technique, the suprarenal stent is released early to fix the proximal stent-graft in place so that each stent in the neck can be deployed individually without displacing the device upward. It is important to push the delivery system up after each stent deployment to allow the fabric between the stents to fold up circumferentially. By doing so, there is minimal upward force applied to the suprarenal stent. Because the stents expand along the angulated neck while catching blood flow, this anatomical deployment is feasible, with hardly any change to the proximal neck shape after stent-graft implantation. Conclusion: The push-up technique and anatomical deployment with the Endurant stent-graft system are effective and safe methods for treating aneurysms with severely angulated necks.

Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

Following the publication of this article, we realize that there were some errors in the manuscript. Details of the experiments describing the gene silencing of RUNX3 with small interfering RNA (siRNA) were erroneously included in this paper, and all references to siRNA should have been deleted from the manuscript prior to publication. In the subsection entitled 'Cell lines and cell culture' on page 2577, the left‑hand column, the text should have indicated that the human HCC cell lines Hep3B and Huh7 were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA), whereas HLF cells were obtained from the Japanese Cancer Resources Bank (Tokyo, Japan). Lastly, an error was made in describing the calculation of the IC50 values, which did not correlate with the data shown in Fig. 2. Therefore, the subsection entitled 'Ectopic RUNX3 protein expression suppresses cell growth...' should have been entitled 'Ectopic RUNX3 protein expression increases 5‑FU and CDDP sensitivity', and the text herein should have read as follows: We analyzed the effects of RUNX3 on chemosensitivity in the RUNX3‑ or CAT (mock)‑transfected Hep3B and Huh7 cells. RUNX3 expression enhanced 5‑FU sensitivity in both cell lines; the cell viability with 5‑FU (100 nM) decreased from 66.3±4.6 to 34.3±5.0%, and from 71.0±4.7% to 27.0±5.5% in the Hep3B and Huh7 cells, respectively (Fig. 2A). RUNX3 expression also enhanced CDDP sensitivity in both cell lines; the cell viability with CDDP (100 nM) decreased from 58.7±2.6% to 25.7±4.9%, and from 67.7±4.1% to 25.7±7.5% in the Hep3B and Huh7 cells, respectively (Fig. 2B). We sincerely apologize for these errors and oversights, which have not affected any of the overall conclusions reported in the study, and regret any inconvenience they may have caused. [the original article was published in the Oncology Reports 35: 2576-2582, 2016; DOI: 10.3892/or.2016.4681].

Aim Recurrence of hepatocellular carcinoma (HCC) is observed frequently, even after curative treatments. The aim of this study is to elucidate the risk factors for recurrence of HCC after radiofrequency ablation (RFA), focusing on the carcinogenic potential of the liver assessed by α-fetoprotein (AFP). Methods We enrolled 357 consecutive patients who underwent complete ablation by RFA for primary HCC (≤3 cm, ≤3 tumors) and analyzed the correlation between 17 critical parameters, including AFP and HCC recurrence. Results Recurrence was observed in 236 patients during a mean observation period of 54.3 months. Multivariate analysis revealed that multiple tumors (risk ratio [RR] = 1.70, 95% confidence interval [CI] = 1.27–2.26, P 10 ng/mL, RR = 1.45, 95% CI = 1.09–1.94, P 40 mAU/mL, RR = 1.52, 95% CI = 1.13–2.02, P

According to recent advances in operative techniques, an increasing number of patients with liver dysfunction have been subjected to cardiac surgery. Model of End-Stage Liver Disease (MELD and MELD-XI) scores allow risk stratification of patients undergoing cardiac and non-cardiac surgeries.We retrospectively analyzed 1856 consecutive patients (69.3% male, mean 66.8 ± 12.2 years) undergoing cardiac surgery between 2008 and 2013 at our institution.The mean values of MELD/MELD-XI scores obtained from the total cohort were 9.7 ± 4.6/11.9 ± 4.8. Patients with high MELD/MELD-XI scores (12) were older, more anemic, and had lower left ventricular ejection fraction than those with low scores (all p0.0001). High scores were associated with longer hospitalization (36.8 ± 33.0 vs. 23.6 ± 21.5 days for MELD, 36.7 ± 34.0 vs. 23.5 ± 21.0 days for MELD-XI, both p0.0001) and higher in-hospital all-cause mortality (6.6% vs. 1.0% for MELD, 7.7% vs. 0.7% for MELD-XI). Atrial fibrillation occurred more frequently in the high MELD group, but this difference was not found for MELD-XI. MELD/MELD-XI could predict mortality with a sensitivity of 64.3%/60.0% and specificity of 79.1%/85.3%. Comparison of AUC values among MELD scores, individual MELD components, and Child-Turcotte-Pugh (CTP) classification showed that the predictive strength of MELD scores for mortality was stronger than individual parameters or CTP classification (AUC: 0.7702 for MELD, 0.7655 for MELD-XI, 0.5799 for CTP classification with pairwise p0.0001 and p=0.0002 vs. MELD and MELD-XI, respectively).Assessment of liver dysfunction using the MELD scores can be useful for predicting postoperative morbidity and mortality, which may allow additional risk stratification in patients undergoing cardiac surgery.

Background Graft-versus-host disease (GVHD) is a common complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Endoscopic biopsy can provide a definitive diagnosis, but the optimal endoscopic approach for diagnosis remains uncertain. This study evaluated whether ileocolonoscopic imaging can predict acute GVHD severity after allo-HSCT. Methods Consecutive patients who underwent allo-HSCT were referred to our institution, and those diagnosed with acute GVHD by pathology were included in this retrospective study. Results Fifty-one of 261 patients who underwent ileocolonoscopy were suspected to have acute intestinal GVHD. We performed univariate and multivariate conditional logistic regression with stepwise variable selection; villous atrophy in the terminal ileum remained a statistically significant predictor of GVHD severity (odds ratio, 4.69; 95% confidence interval, 1.07–20.60, P = 0.04). Patients were classified into three groups based on ileal endoscopic findings in the terminal ileum: group S, GVHD with severe villous atrophy; group M, mild atrophy; and group N, no atrophy. Compared with patients in groups M and N, those in group S had significant clinical GVHD at diagnosis (P = 0.03). In group S, three of four, compared with five of 13 patients in groups M and N, required the addition of second-line agents (P = 0.02). Conclusions This study showed that severe atrophy of the terminal ileum predicts severe clinical GVHD that is likely to be refractory to steroid treatment. Thus, the severity of terminal ileum atrophy may serve as a tool in predicting clinically severe GVHD. Trial registration Trial Registration Number UMIN 000022805, Registration date July 1, 2016.

BACKGROUND Low flow (LF; i.e., reduced left ventricular stroke volume index

Background Bleeding after endoscopic submucosal dissection (ESD) in antithrombotic drug users is still one of the important issues to be solved. We performed scheduled second-look endoscopy (SLE) 5 days after ESD, when the resumption of antithrombotic agents is assumed to have achieved a steady state, rather than on the day after ESD. We investigated bleeding incidence and the status of ulcers. Methods A total of 299 lesions in 299 patients subjected to ESD for gastric neoplasms were enrolled. A double dose of proton pump inhibitors was administered after ESD. SLE was planned 5 days after ESD. Post-ESD bleeding occurring before SLE was defined as early phase post-ESD bleeding, whereas bleeding after SLE was defined as later phase post-ESD bleeding. Forrest IIa and IIb ulcers are defined as high-risk ulcers requiring prophylactic hemostasis. We investigated risk factors for post-ESD bleeding, particularly focusing on the use of antithrombotic agents and the presence of high-risk ulcers requiring prophylactic hemostasis during SLE. Results Under a double dose of proton pump inhibitors, early phase post-ESD bleeding occurred in 2.3% of non-users (5/218) and 6.2% of users of antithrombotic agents (5/81). High-risk ulcers were found in 19.0% of the cases during scheduled SLE (55/289). Later phase bleeding occurred in 5.5% of cases [2.8% of non-users (6/213) and 13.2% of users of antithrombotic agents (10/76)]. Cox regression analysis revealed that the risk factor for post-ESD bleeding was antithrombotic treatment (HR: 3.56; 95% CI: 1.63–8.02, p = 0.002) alone. Among patients with high-risk ulcers, a statistically significant increase in bleeding was observed in the later phase in patients under antithrombotic therapy, compared to those not receiving any antithrombotic agents (p = 0.001). Conclusions Antithrombotic treatment is a risk factor for post-ESD bleeding despite SLE being scheduled 5 days after ESD. Later phase post-ESD bleeding was observed in 13.2% of the patients under antithrombotic treatment even after prophylactic hemostasis for high-risk ulcers. Trial registration This study was registered in the UMIN Clinical Trials Registry System (000023306). Retrospectively registered on 23rd July 2016.

Aortic root operations are established procedures for patients with aortic root aneurysms, however there is a little insight for comparative long-term outcomes among different types of anatomical abnormalities and procedures. In this study, we sought to compare the results of patients with aortic abnormalities undergoing different procedures. From January 2008 to March 2017, a total of 105 patients without aortic dissection were performed the elective aortic root surgery. Patients with bicuspid aortic valve had enlarged annulus, and those with Marfan syndrome had enlarged Valsalva without enlarged annulus. Bentall operation with mechanical valve or bioprothetic valve was performed for patients with enlarged annulus and/or abnormal aortic cusp, and David operations for patients with normal cusps. This comparative study showed that these different procedures according to our policy were associated with reduced cardiac mortality and valve-related complications. The results suggest David procedure is the treatment of choice for young patients with aortic root aneurysm and normal aortic cusps, however, careful patient selection is paramount.

Renal dysfunction is a major adverse event after cardiovascular surgery. Therefore, the preoperative prediction of which patients will require renal replacement therapy (RRT) after cardiac surgery is an important issue. In the present study, 1,822 consecutive patients who underwent cardiovascular surgery from 2008 and 2013 at a single institution were reviewed. Patients who were already receiving long-term hemodialysis before surgery (n = 134) were excluded. The remaining 1,688 patients were separated into 2 groups: those requiring postoperative RRT and those without RRT requirement. A total of 128 patients (7.6%) required RRT. Patients requiring RRT had greater perioperative blood loss, longer intubation time, and longer hospital stays (p0.0001 for all). Multivariate analysis revealed that cardiopulmonary bypass use, preoperative body surface area, the left ventricular ejection fraction, serum albumin, and creatinine were independent risk factors for postoperative RRT (odds ratios 2.435, 0.204, 0.976, 0.556, and 5.394, 95% confidence intervals 1.471 to 4.140, 0.054 to 0.841, 0.962 to 1.025, 0.363 to 0.860, and 3.671 to 8.223, respectively, p0.05 for all). A subgroup of patients with relatively preserved renal function before surgery (creatinine1.12 mg/dl, a cut-off value for RRT requirement obtained from receiver-operating characteristic curve analysis [area under the curve 0.74748, sensitivity 60.2%, specificity 85.0%]) showed that preoperative serum albumin concentration was most significantly associated with postoperative RRT requirement (odds ratio 0.048, 95% confidence interval 0.023 to 0.095, p0.0001). In conclusion, cardiopulmonary bypass use, preoperative renal impairment as reflected by elevated creatinine level, small body size, a low left ventricular ejection fraction, and hypoalbuminemia were associated with a requirement for postoperative RRT. In patients with preserved renal function, hypoalbuminemia was most significantly related to requirement for RRT.

Background/objectives Diagnosing the invasiveness of intraductal papillary mucinous neoplasms (IPMNs) is difficult, especially by blood test. Alterations in serum glycan profiles have been reported for several cancers, but changes in serum glycan profiles have not been investigated in patients with IPMNs. The objectives of this study were to determine the serum N -glycan profile and to investigate its clinical utility in patients with IPMNs. Methods We measured serum N -glycan profiles in 79 patients with IPMNs, including 13 invasive IPMNs, by performing comprehensive glycome analysis and assessed the relationship between N -glycan changes and clinical parameters. Results Seventy glycans were identified and their expression profiles were significantly different depending on the cyst size, the presence of an enhancing solid component, and the histological grade of the IPMN. Nine glycans were highly expressed in patients with invasive IPMNs. The glycan m/z 3195, which is a fucosylated tri-antennary glycan, had the highest diagnostic value for distinguishing invasive IPMNs from non-invasive IPMNs (area under the receiver operating characteristic curve = 0.803). Multivariate analyses revealed high levels of m/z 3195 [odds ratio (OR), 20.5; 95% confidence interval (CI) 2.60–486.4] and the presence of enhancing solid components (OR, 35.8; 95% CI, 5.39–409.6) were significant risk factors for invasive IPMNs. Conclusions We performed a comprehensive evaluation of the changes in serum N -glycan profiles in patients with IPMNs for the first time. We determined that increased expression of fucosylated complex-type glycans, especially m/z 3195, is a potential marker for invasive IPMNs.

Background and Aims Serum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). Methods We collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined. Results Among the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis. Conclusion We clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

Aim Most of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application. Methods We analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters. Results The total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (>3), large tumor size (>3 cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver–operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC. Conclusion We demonstrate the full spectrum of the alterations of serum N-glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression.

We determined the factors associated with the expression of c-kit in the heart and the proliferation of c-kit-positive (c-kitpos) cardiac stem cells among the outgrowth cells cultured from human cardiac explants.Samples of the right atrium (RA), left atrium (LA), and left ventricle obtained from patients during open-heart surgery were processed for cell culture of outgrowth cells and tissue analysis. The total number of growing cells and the population of c-kitpos cells were measured and compared with c-kit expression in native tissues and characteristics of the patients according to the region of the heart.We analyzed 452 samples from 334 patients. Atrial fibrillation (AF) in the patients reduced the number of outgrowth cells from the RA and LA, and aging was a co-factor for the LA. The c-kitpos population from the RA was associated with serum brain natriuretic peptide (BNP). C-kit expression in native tissue was also associated with BNP expression. However, we observed no relationship in expression between outgrowth cells and native tissue. In addition, the RA tissue provided the highest number of c-kitpos cells, and the left ventricle provided the lowest.C-kit was weakly expressed in response to damage. In addition, no correlation between outgrowth cells and native tissue was found for c-kit expression.

Background and study aims Few studies have directly compared endo-knives for endoscopic submucosal dissection (ESD) in humans. We compared the performances of the Mucosectom2 and SB knife Jr. Patients and methods Two trainee endoscopists performed ESD of 36 lesions in this prospective, randomized controlled trial. Mucosal incision with a 1.5-mm Dual knife and submucosal dissection using the Mucosectom2 were performed in 1 group. Mucosal incision with a 1.5-mm Dual knife and submucosal dissection with a SB knife Jr. were performed in the other group. The primary outcome was the ESD procedure time. Secondary outcomes were total procedure time, self-completion rates, and adverse events. Results ESD time in Mucosectom2 patients was not significantly shorter than in SB knife Jr. patients (57 ± 32 min vs. 61 ± 44 min, respectively; P = 0.94). Total procedure time in Mucosectom2 patients was not significantly shorter than in SB knife Jr. patients (81 ± 42 min vs. 82 ± 51 min, respectively; P = 0.85). The trainee self-completion rate was slightly higher in SB knife Jr. patients than in Mucosectom2 patients, although the difference was not significant (94 % vs. 100 %, respectively; P = 0.959). Fewer hemostatic procedures using the Coagrasper were performed in Mucosectom2 patients than in SB knife Jr. patients, although the difference was not significant (0.62 vs. 0.7, respectively; P = 0.432). Conclusions Mucosectom2 and SB knife Jr. did not significantly differ in performance for colorectal ESD to safely and reliably enhance ESD. Knife selection is not as important for learning colorectal ESD as patient- and lesion-related factors.

The case is reported of a 79-year-old female who received a patch augmentation of the tricuspid anterior and septal leaflets with a resected left atrial wall to address recurrent tricuspid regurgitation, including tricuspid valve tethering. The patient was admitted to the authors' hospital for chronic heart failure with paravalvular leakage after aortic valve replacement and recurrent severe tricuspid regurgitation. She had undergone two previous cardiac surgeries. Re-tricuspid repair required an augmentation of the tricuspid valve leaflets in addition to tricuspid annuloplasty. As the autologous pericardium was unsuitable for a patch due to thickened and stiffened changes, the decision was taken to use a left atrial wall resected to reduce the size of giant left atrium, which was thin and easy to handle. This is the first report of tricuspid leaflet augmentation using a patch derived from the left atrial wall, which is a useful method in patients where pericardium is not available.

Aim Recently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC). Methods We examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case–control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC. Results In the case–control study, multivariate analysis revealed that high platelet counts (odds ratio [OR] = 4.84; 95% confidence interval [CI] = 1.29–29.54; P = 0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time = 23.3 months). On multivariate analysis, high tumor number, high des-γ-carboxyprothrombin (DCP) and Child–Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR = 1.73; 95% CI = 0.99–3.14; P = 0.055). Conclusion HCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child–Pugh class A, are at risk for EHM.

Introduction: We hypothesized to demonstrate whether there are significant differences in blood endotoxin (Et) levels after abdominal aortic surgery between endovascular aortic repair (EVAR) and open abdominal surgery. Methods: The patients who underwent the surgical treatment for abdominal aortic aneurysm were divided into two groups according to the procedures: open abdomen surgery (OP) and EVAR (SG). The value of Endotoxin Activity Assay (EAA) was compared between groups. Results: After surgery, Et level was significantly higher in the OP group than in the SG group on postoperative day 3. Neutrophil count was significantly higher in the OP group immediately after treatment, but no significant difference was seen thereafter. There were no differences between the groups in other inflammatory markers. Conclusions: This study indicated that EVAR was less invasive compared to an open abdominal surgery from the standpoint of assessing postoperative endotoxin activity (EA) levels measured by EAA.

Background: In most guidelines, no other interventional therapy but liver transplantation is recommended for the treatment of hepatocellular carcinoma (HCC) with Child-Pugh C cirrhosis (CP-C). However, in Japan, patients were sometimes treated with expectation of benefit. Summary: A workshop was conducted to explore the state of treatments for CP-C HCC in Japan. After the workshop, a questionnaire on therapies was given to the panelists. Clinical data of 769 patients with CP-C HCC from 8 hospitals as well as analyses of data collected by the Liver Cancer Study Group of Japan (LCSGJ) consisting of 1,344 CP-C HCC cases were presented. Patients who underwent liver transplantation were excluded. In total, 424 out of the 769 patients (55.1%) from the 8 hospitals and 537 out of 828 CP-C HCC cases (64.8%) from the LCSGJ data received interventional therapies, such as local ablation and transcatheter arterial chemoembolization. All panelists agreed that there was a subgroup of CP-C patients who benefitted from the locoregional therapies. The major goals for the therapies were to prevent HCC rupture and avoid obstruction of major vessels by tumor growth, which can lead to a sudden deterioration of the patients' condition. Patient liver function and tumor stage are both important factors for the decision to undergo treatment; however, the inclusion criteria for the treatments varied among the centers. Key Message: There exists a subgroup of CP-C patients who benefit from interventions for HCC.

Introduction: Anticoagulation is essential during CPB in cardiac surgery. It is generally performed using heparin; however the widely used formula for its dosing is based solely on body weight. Although the formula assumes activated clotting time (ACT) to be within normal range, baseline ACT varies in each patient. Thus, we developed an original formula, which takes into account baseline ACT in addition to body weight to calculate a more proper dose for initial administration of heparin. In this study, we monitored the ACT to examine if the dose of heparin calculated using our formula can prolong the ACT to the target range, and we determined the factors which interfere with the prolongation of ACT. Methods: Between October 2010 and April 2011, 141 consecutive patients underwent cardiac surgery requiring cardiopulmonary bypass at our hospital. We measured ACT 3 minutes after the initial administration of heparin and considered ACT values >400 seconds as appropriate for safe initiation of CPB. Results: Using the proposed formula, administered heparin dose was 241 ± 27 IU/kg and target ACT was achieved in 86.4% of patients. Multivariate analysis was performed to determine the effect of patient background factors on target ACT achievement. Body weight, age, and preoperative heparin therapy, which showed significant differences, were further analyzed. Conclusions: This study demonstrated that our newly developed formula could be used to properly calculate the optimal initial dose of heparin.

A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma. Therefore, sorafenib was administered;however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

Background: The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear. Methods: The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy. Results: A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41–0.56; P

The aim of this study was to evaluate the histologic diagnosis of hypovascular hepatic lesions showing hypointensity on hepatobiliary phase images of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI (EOB-MRI). In 38 patients with hepatocellular carcinoma (HCC) after curative treatments and 18 patients with liver cirrhosis, 105 hypovascular nodules that were hypointense at the hepatobiliary phase of EOB-MRI were biopsied and the clinical usefulness of these EOB-MRI findings for the diagnosis of HCC was examined. Of the 105 nodules (median diameter = 12mm), 78 (74.3%), 11 (10.5%), and 16 (15.2%) were diagnosed as HCC, dysplastic, and non-neoplastic, respectively. The positive predictive value (PPV) of hypointensity at the hepatobiliary phase of EOB-MRI for the diagnosis of HCC increased to 77-90% when combined with the following factors: washout appearance on the delayed phase of triple-phase CT, hyperintensity in diffusion-weighted image of MRI, or the appearance of a hypoechoic part in ultrasonography. PPV increased to 100% when all 3 factors were positive. A relatively large proportion of hypovascular lesions that showed hypo-intensity in the hepatobiliary phase were confirmed to be HCC, and the accuracy of HCC increased when combined with other imaging findings.

Background and aim Follistatin (FST) is a glycoprotein expressed in most organs, which interacts with activins or other members of the transforming growth factor beta family. Recently, several reports have shown that FST regulates a variety of processes during tumor progression. Here, serum FST in patients with liver diseases was measured, and its clinical utility as a biomarker was assessed. Methods Serum was collected from 162 patients (91 hepatocellular carcinoma [HCC], 43 liver cirrhosis, and 28 chronic hepatitis) as well as from 16 healthy volunteers. FST was quantified by enzyme-linked immunosorbent assays, and levels were compared with clinical parameters including survival of the HCC patients. Results Median serum FST levels in HCC, liver cirrhosis, chronic hepatitis, and healthy volunteers were 1168, 1606, 1324, and 1661 pg/mL, respectively, not significantly different. In HCC patients, higher serum FST was associated with greater age, hepatitis C virus antibody-negativity, large tumor size, g-glutamyl transpeptidase, des-gamma carboxyprothrombin and presence of portal vein tumor thrombus. Survival of HCC patients with high FST levels was significantly shorter than for those with low levels (P = 0.004). Multivariate analysis revealed that in addition to large tumor size and presence of portal vein thrombus, high FST levels were independently correlated with poor prognosis (hazard ratio = 2.41, 95% confidence interval = 1.16-5.00, P = 0.02). Conclusions Serum FST levels are significantly associated with HCC prognosis and could represent a predictive biomarker in this disease.

Aim We investigated whether continuous sorafenib administration keeps suppressing the growth of hepatocellular carcinoma (HCC) after first progressive disease (PD), and whether it prolongs patients' survival. Methods The size of metastatic lesions was measured in 36 patients with advanced HCC treated with sorafenib. The tumor growth rates before and after radiological PD as well as survival were compared between the patients who continued (n = 23) and stopped (n = 13) sorafenib at first radiological PD. Results The growth rate did not differ between before and after PD in patients who continued sorafenib, while it increased after PD in patients who stopped sorafenib at PD (P = 0.002). Survival beyond first progression was longer in patients who continued sorafenib than in those who stopped it at PD (P = 0.012), and this tendency was observed even when the analysis was limited to Child-Pugh class A patients (P = 0.085). Conclusion Sorafenib administration beyond first radiological PD could continuously suppress HCC growth and may have survival benefit.

Most of the glycan changes reported in cancers were based on the examinations of a small number of patients or particular proteins. The aim of this study was to determine the changes of the serum N-glycan profile comprehensively in a large number of pancreatic cancer patients and investigate its clinical utility.Glycan levels in the serum of 92 pancreatic cancer patients and 243 healthy volunteers (HLT) were examined by comprehensive quantitative high-throughput glycome analysis and were compared with clinical parameters.Out of 66 glycans detected, 15 were differentially expressed in pancreatic cancer, and 10 out of the 15 glycans were significantly up-regulated in cases with distant metastasis. There was a clear increase in overall expression of serum glycans, especially highly-branched glycans with fucose moieties, in pancreatic cancer. Among these 15 glycans, a tri-antennary complex type glycan (m/z 3195) showed the highest area under the receiver operating characteristic curve (AUROC = 0.799) for the diagnosis of pancreatic cancer. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) was found to be significantly higher in pancreatic cancer than in HLT (median = 1.11 and 0.41, respectively; p 0.0001, AUROC = 0.831). For this pair ratio, the hazard ratio for survival (2.60, 95 % CI = 1.44-4.79) was higher than that of any single glycan and 1-year survival of patients with a high and low ratio was 36.9 and 69.2 %, respectively, (p = 0.001).Comprehensive glycome analysis can be used to know the presence of pancreatic cancer, distant metastasis, and patient prognosis, simultaneously.

Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.