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Background: The efficacy of paclitaxel and bevacizumab (PB) compared with other chemotherapies in patients with human epidermal growth factor receptor 2-negative (HER2 - ) advanced breast cancer is unclear., Patients and Methods: We retrospectively investigated 301 patients with HER2 - ABC who received first-line chemotherapy from January 2011 to December 2016., Results: We included 114 patients who received PB and 187 patients who received other chemotherapies. After propensity score matching, the PB group showed a significantly superior overall response rate (77.8% vs. 38.9%, p<0.0001) and median time to treatment failure (7.3 vs. 5.9 months, p=0.035). In subgroup analyses, PB improved the median overall survival of patients with pleural lesions or pulmonary lymphangiopathy (not reached vs. 18.9 months, p=0.037), and of patients with three or more metastatic sites without liver metastases, (48.0 vs. 27.3 months, p=0.015)., Conclusion: Compared with conventional chemotherapy, PB improved the overall response rate and time to treatment failure in patients with HER2 - advanced breast cancer and improved overall survival in some patient subgroups., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients' survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.

Macrophage plasticity is essential for liver wound healing; however, the mechanisms underlying macrophage phenotype switching are largely unknown. Dendritic cells (DCs) are critical initiators of innate immune responses; as such, they orchestrate inflammation following hepatic injury. Here, we subjected EP3-deficient (Ptger3 -/- ) and wild-type (WT) mice to hepatic ischemia-reperfusion (I/R) and demonstrate that signaling via the prostaglandin E (PGE) receptor EP3 in DCs regulates macrophage plasticity during liver repair. Compared with WT mice, Ptger3 -/- mice showed delayed liver repair accompanied by reduced expression of hepatic growth factors and accumulation of Ly6C low reparative macrophages and monocyte-derived DCs (moDCs). MoDCs were recruited to the boundary between damaged and undamaged liver tissue in an EP3-dependent manner. Adoptive transfer of moDCs from Ptger3 -/- mice resulted in impaired repair, along with increased numbers of Ly6C high inflammatory macrophages. Bone marrow macrophages (BMMs) up-regulated expression of genes related to a reparative macrophage phenotype when co-cultured with moDCs; this phenomenon was dependent on EP3 signaling. In the presence of an EP3 agonist, interleukin (IL)-13 derived from moDCs drove BMMs to increase expression of genes characteristic of a reparative macrophage phenotype. The results suggest that EP3 signaling in moDCs facilitates liver repair by inducing IL-13-mediated switching of macrophage phenotype from pro-inflammatory to pro-reparative., (© 2020 Federation of American Societies for Experimental Biology.)

Aim : Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods : A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results : Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion : A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients., Competing Interests: Competing Interests: Naoya Kato M.D. received a research grant from Otsuka Pharmaceutical. The other authors declare no conflict of interest., (© The author(s).)

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

Ferredoxin NADP + oxidoreductase (Fpr) and oxygen-insensitive NAD(P)H nitroreductase (NfnB) are purified from Escherichia coli JM109 (E. coli JM109) as a predominant free flavin-independent ferric reductase. In the present study, we prepared natural iron storage proteins, E. coli ferritin A (FtnA) and bacterioferritin (Bfr), to show the effective ferrous iron release from these proteins by Fpr and NfnB in the presence of free flavins. Fpr and NfnB showed flavin reductase activity for flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) and riboflavin, and their ferrous iron release activities were positively associated with the catalytic efficiencies (k cat /K m ) for individual flavins. The ferrous iron release activity of E. coli cell-free extracts was affected by flavin reductase activity of the extracts. The Butyl TOYOPEARL column chromatography of the extracts, on the basis of NAD(P)H-dependent flavin reductase activity, resulted in the separation of six active fractions containing Fpr, NfnB, NAD(P)H-quinone oxidoreductase (QOR), flavin reductase (Fre) or alkyl hydroperoxide reductase subunit F (AhpF) as major components. Like Fpr and NfnB, recombinant QOR, Fre, and AhpF showed flavin reductase activity and ferrous iron release activity in the presence of free flavins, indicating an association of flavin reductase activity with ferrous iron releasing activity. Taken together, both free flavin-dependent and free flavin-independent ferric reductases in E. coli require free flavins to mediate an electron transfer from NAD(P)H to ferric iron in the iron storage proteins for the effective ferrous iron release.

Background: Early detection of postoperative increase in C-reactive protein (CRP) correlates with postoperative complications. The present study examined the association between preoperative / intraoperative factors and postoperative CRP levels, with development and validation of a prediction model of early postoperative CRP level, for prophylactic management of postoperative complications in patients undergoing surgery under general anesthesia., Material and Methods: Multivariate regression analysis was retrospectively performed to determine the independent factor of CRP levels on postoperative day (POD) 1 and to develop a prediction model. Validation of the prediction model was prospectively performed. Data from 316 adult patients on perioperative variables were retrospectively obtained in a training cohort in patients undergoing elective non-cardiac surgery. In a validation cohort, 88 patients undergoing mastectomy and 68 patients undergoing laparoscopic colon surgery were prospectively utilized to evaluate the value of the prediction model. Major complications after surgery were defined as the Clavien-Dindo grade IIIa or greater., Results: Duration of surgery, mean nociceptive response (NR) during surgery as intraoperative nociception level, and preoperative CRP level were selected to set up the prediction model of CRP level on POD1 (P < 0.0001). In the validation cohort, the predicted CRP levels on POD1 significantly correlated with the measured CRP after mastectomy (P < 0.0001) and laparoscopic colon surgery (P = 0.0001). Receiver-operating characteristic curve analysis showed that the predicted CRP levels on POD1 was significantly associated with major complications after mastectomy (P = 0.0259) and laparoscopic colon surgery (P = 0.0049). The measured and predicted CRP levels significantly increased in the order of severity of postoperative complications (P < 0.01)., Conclusion: Increases in duration of surgery, intraoperative nociceptive level and preoperative CRP level were selected to predict early increases in CRP level after non-cardiac surgery under general anesthesia. Predicted CRP levels on POD1 were likely associated with severity of postoperative complications., Competing Interests: The authors have declared that no competing interests exist.

We experienced a pregnant woman with superior vena cava syndrome at 15 weeks of pregnancy who was diagnosed with primary mediastinal large B-cell lymphoma and given chemotherapy. In this case, the clinical courses of both the mother and infant were favorable without any serious complications because of close multidisciplinary cooperation. Based on a retrospective review of this case, the administration of CHOP-like regimens during the second and third trimesters appears relatively safe. Because pregnancy and continuation of pregnancy are rare in patients with hematopoietic malignancies, the accumulation of detailed information is important.

Background: WiNTRLINC1 is a long non-coding RNA (lncRNA) that positively regulates the Wnt pathway via achaete-scute complex homolog 2 (ASCL2) in colorectal cancer. ASCL2 was recently reported to play a critical role in chemoresistance, however clinical relevance of the WiNTRLINC1/ASCL2 axis remains obscure in colon cancer., Patients and Methods: WiNTRLINC1/ASCL2 expression was investigated at messenger RNA (mRNA) level in 40 primary colon cancer tissues and the corresponding normal mucosa tissues, together with Wnt-related genes (c-Myc/PRL-3) and other lncRNAs (H19, HOTAIR, and MALAT1). Knock-down experiments of WiNTRLINC1 clarified its role in their expression and chemoresistance., Results: Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed definite overexpression of WiNTRLINC1 mRNA in primary colon cancer compared with the corresponding normal colon mucosa tissues (p = 0.0005), such as ASCL2, c-Myc, and PRL-3 (p < 0.0001). The four gene expression signatures were tightly associated in the center of the ASCL2 gene (r = 0.72, p < 0.0001) in clinical samples. WiNTRLINC1 was not significantly associated with prognostic factors in colon cancer and other lncRNAs, while the WiNTRLINC1/ASCL2/c-Myc signatures were unique to young-onset colon cancer with differentiated histology. On the other hand, undifferentiated histology was significantly associated with H19 expression. Knockdown of the WiNTRLINC1 gene reduced the expression of ASCL2/c-Myc, but rather augmented PRL-3 at mRNA level, and robustly affected cell viability in colon cancer cell lines., Conclusion: The enhanced WiNTRLINC1/ASCL2/c-Myc axis involved in Wnt pathway activation is a common pathway essential for differentiated colon tumorigenesis, especially with young onset, and may be essential for a viable phenotype of colon cancer.

Background: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA)., Methods: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined., Results: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment., Conclusion: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis including acute liver failure. Hepatitis B infection (HBV) occurs worldwide, with the highest rates in Asian and African countries, and there are several reports that HAV infection may have a more severe clinical course in patients with chronic HBV infection. We previously demonstrated that Japanese miso extracts have inhibitory effects on HAV replication. In the present study, we examined the replication of HAV and HBV in a hepatocyte superinfection model and the inhibitory effects of Japanese miso extracts on both viruses. According to the results, HAV infection inhibited HBV replication in superinfected hepatocytes, and Japanese rice-koji miso extracts had inhibitory effects on HAV replication. Our findings provide useful information for clinicians in managing HAV infection in patients with chronic HBV infection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Fluid responsiveness is an important factor to consider for fluid volume loading during major surgery. The effect of continuous vasopressor infusion on fluid responsiveness during prolonged major surgery is a concern., Objective: We hypothesised that continuous vasopressor infusion during major surgery might not exert significant effects on changes in stroke volume variation (SVV) following fluid bolus infusion, and thereby on fluid responsiveness., Design: Randomised controlled trial., Setting: University hospital from April 2014 to August 2016., Patients: Patients undergoing liver resection who were randomised to receive continuous intravenous infusion of phenylephrine (P group), norepinephrine (N group), or no vasopressor (C group) (n=17/group). Exclusion criteria were cardiac arrhythmia and severe cardiac, pulmonary or renal dysfunction., Intervention: Patients received 4 ml kg fluid boluses of 6% hydroxyethyl starch solution when SVV was at least 12%. Vasopressors were administered continuously to maintain the systemic vascular resistance index at more than 1900 dyn s cm m., Main Outcome Measures: Cardiac index and SVV were measured using the FloTrac/Vigileo system (Version 4.00). The number of fluid boluses with fluid responsiveness (i.e. >15% increase in cardiac index) was compared between groups using multilevel logistic regression analysis., Results: Numbers of fluid responsive boluses in the C, P and N groups were 12 (14%), 22 (34%) and 19 (27%), respectively. Odds ratios on fluid responsiveness for phenylephrine and norepinephrine compared with the control were 3.65 (97.5% confidence interval, 1.15 to 11.6; P = 0.012) and 2.56 (97.5% confidence interval, 0.82 to 8.00; P = 0.064), respectively. Decreases in SVV after fluid bolus infusion for the P and N groups were comparable with the C group (P = 0.23 and 0.53, respectively)., Conclusion: Continuous administration of phenylephrine increased fluid responsiveness during liver resection, suggesting complex effects of continuous vasopressor infusion involving changes in cardiac preload and afterload., Trial Registration: UMIN000011024.

BACKGROUND Regional anesthesia provides excellent analgesic effects after surgery. However, the effects of regional anesthesia on nociceptive levels during surgery under general anesthesia have not been quantitatively evaluated. To reveal the effects of thoracic paravertebral block (PVB) on nociceptive levels after skin incision during general anesthesia, we performed a retrospective cohort study in patients without serious preoperative conditions or comorbidities undergoing elective video-assisted thoracoscopic surgery (VATS). Nociceptive levels during general anesthesia were calculated using our previously determined Nociceptive Response (NR) equation, which utilizes common hemodynamic parameters. MATERIAL AND METHODS Data on 77 adult patients who underwent VATS from May 2018 to August 2018 were retrospectively obtained from our institutional database. We then performed propensity score matching between patients who received thoracic PVB (PVB group: n=29) and those who did not (Control group: n=48). The averaged values of systolic blood pressure (SBP), heart rate (HR), perfusion index (PI), bispectral index (BIS), and NR from 10 to 5 minutes before skin incision (T0), 5 to 10 minutes (T1), 10 to 15 minutes (T2), 15 to 20 minutes (T3), and 20 to 25 minutes after skin incision (T4), were calculated. RESULTS Twenty-four propensity score-matched patients in each group were analyzed. Mean NR values at T1 and T2 in the PVB group were significantly lower than those in the Control group. SBP, HR, PI, and BIS, however, showed no significant differences between the 2 groups, except for SBP at T2. CONCLUSIONS Thoracic PVB prevented an increase in NR values, which quantitatively represent nociceptive levels under general anesthesia, in patients undergoing VATS.

Background: Adenoid cystic carcinoma (ACC) is a relatively rare malignant neoplasm that occurs in salivary glands and various other organs. Recent studies have revealed that a significant proportion of ACCs harbor gene alterations involving MYB or MYBL1 (mostly fusions with NFIB ) in a mutually-exclusive manner. However, its clinical significance remains to be well-established., Methods: We investigated clinicopathological and molecular features of 36 ACCs with special emphasis on the significance of MYBL1 alterations. Reverse-transcription polymerase-chain reaction (RT-PCR) and fluorescence in-situ hybridization (FISH) were performed to detect MYB/MYBL1-NFIB fusions and MYBL1 alterations, respectively. Immunohistochemistry was performed to evaluate MYB expression in the tumors. The results were correlated with clinicopathological profiles of the patients., Results: RT-PCR revealed MYB-NFIB and MYBL1-NFIB fusions in 10 (27.8%) and 7 (19.4%) ACCs, respectively, in a mutually-exclusive manner. FISH for MYBL1 rearrangements was successfully performed in 11 cases, and the results were concordant with those of RT-PCR. Immunohistochemically, strong MYB expression was observed in 23 (63.9%) tumors, none of which showed MYBL1 alterations. Clinicopathologically, a trend of a better disease-specific survival was noted in patients with MYBL1 alterations than in those with MYB-NFIB fusions and/or strong MYB expression; however, the difference was not significant. Interestingly, we found tumors with MYBL1 alterations significantly frequently occurred in the mandibular regions ( P = 0.012). Moreover, literature review revealed a similar tendency in a previous study., Conclusion: Our results suggest that there are some biological or etiological differences between ACCs with MYB and MYBL1 alterations. Moreover, the frequent occurrence of MYBL1 -associated ACC in the mandibular regions suggests that MYB immunohistochemistry is less useful in diagnosing ACCs arising in these regions. Further studies are warranted to verify our findings.

Purpose: We performed antegrade thoracic endovascular aneurysm repair via the ascending aorta in selected high-risk patients scheduled for open surgery, in whom an iliofemoral or abdominal aortic approach was not feasible. We present our initial experience with this approach., Methods: Of 16 consecutive patients who underwent antegrade endovascular aneurysm repair via the ascending aorta at our institution, 3 had an emergency intervention for rupture and 3 had an urgent intervention for impending rupture or complicated aortic dissection. The procedure was scheduled in 10 patients. The median patient age was 77 years. In 13 patients, one or more concomitant procedures were performed. In 6 patients, vascular access for endovascular aneurysm repair was obtained via a branch of the replacement graft. In 10 patients, direct cannulation of the ascending aorta was carried out using 2 pursestring sutures., Results: The initial success rate was 100%. Early mortality occurred in 2 (12.5%) patients because of multiple organ failure in one and heart failure in the other. No patient required a second intervention during follow-up. The mean duration of follow-up was 19 months., Conclusion: The antegrade approach is a useful alternative in patients with no access suitable for endovascular aneurysm repair and who are not appropriate candidates for open conventional thoracic aortic surgery. This approach is applicable to selected patients.

Background: Promoter DNA methylation of Cysteine dioxygenase type1 (CDO1) gene has been clarified as a molecular diagnostic and prognostic indicator in various human cancers. The aim of this study is to investigate the clinical relevance of CDO1 methylation in primary biliary tract cancer (BTC)., Methods: CDO1 DNA methylation was assessed by quantitative methylation-specific PCR in 108 BTC tumor tissues and 101 corresponding normal tissues. BTC was composed of extrahepatic cholangiocarcinoma (EHCC) (n = 81) and ampullary carcinoma (AC) (n = 27)., Results: The CDO1 methylation value in the tumor tissues was significantly higher than that in the corresponding normal tissues (p<0.0001). The overall survival (OS) in EHCC patients with hypermethylation was poorer than those with hypomethylation (p = 0.0018), whereas there was no significant difference in AC patients. Multivariate analysis identified that CDO1 hypermethylation, preoperative serum CA19-9 and perineural invasion were independent prognostic factors in EHCC. The EHCC patients with CDO1 hypermethylation exhibited more dismal prognosis than those with hypomethylation even in low group of CA19-9 level (p = 0.0006)., Conclusions: Our study provided evidence that promoter DNA methylation of CDO1 gene could be an excellent molecular diagnostic and prognostic biomarker in primary EHCC. The combination of CDO1 methylation and preoperative serum CA19-9 effectively enriched EHCC patients who showed the most dismal prognosis. These markers would be beneficial for clinical clarification of the optimal strategies in EHCC., Competing Interests: The authors have declared that no competing interests exist.

Hepatitis A virus (HAV) infection is one of the major causes of acute hepatitis and acute liver failure in developing and developed countries. Although effective vaccines for HAV infection are available, outbreaks of HAV infection still cause deaths, even in developed countries. One approach to control HAV infection is prevention through diet, which can inhibit HAV propagation and replication. Glucose-regulated protein 78 (GRP78) is a member of the heat shock protein 70 family of molecular chaperone required for endoplasmic reticulum stress and stress-induced autophagy. We previously showed that the elevation of GRP78 expression inhibits HAV replication. It has been reported that Japanese miso extracts, which was made from rice-koji, enhance GRP78 expression. In the present study, we used human hepatoma Huh7 cells and human hepatocyte PXB cells to examine the efficacy of Japanese miso extracts as antiviral agents against HAV. Japanese miso extracts enhanced GRP78 expression and inhibited HAV replication in human hepatocytes. Together, these results demonstrate that Japanese miso extracts may partly modulate GRP78 expression and additively or synergistically work as antivirals against HAV infection. Japanese miso extracts can be used as effective dietary supplements for severe hepatitis A., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

BACKGROUND Routine hemodynamic monitoring parameters under general anesthesia, such as heart rate (HR), systolic blood pressure (SBP), and perfusion index (PI), do not solely reflect intraoperative nociceptive levels. We developed a hemodynamic model combining these 3 parameters for nociceptive responses during general anesthesia, and evaluated nociceptive responses to surgical skin incision. MATERIAL AND METHODS We first retrospectively performed discriminant analysis using 3 values - HR, SBP, and PI - to assess response to skin incision during tympanoplasty, laparoscopic cholecystectomy, and open gastrectomy to determine if combined use of these parameters differentiates nociceptive levels among these 3 surgeries. Secondly, ordinal logistic regression analysis was applied using the 3 parameters to develop an equation representing nociceptive response during general anesthesia, and then evaluated its utility to discern nociceptive responses to skin incision. RESULTS We developed the following hemodynamic model as calculated nociceptive response= -1+2/(1+ exp(-0.01 HR -0.02 SBP +0.17 PI)), and prospectively determined that calculated nociceptive responses to small skin incision for laparoscopic surgery were significantly lower than responses to large skin incision for laparotomy. CONCLUSIONS Our hemodynamic model using HR, SBP, and PI likely reflects nociceptive levels at skin incision during general anesthesia, and quantitatively discerned the difference in nociceptive responses to skin incision between laparoscopy and laparotomy. This model could be applicable to assess either real-time nociceptive responses or averaged nociceptive responses throughout surgery without using special equipment.

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.

Background: Of all parotid gland tumors, only oncocytoma has been reported to appear isointense to the parotid gland, namely vanishing, on fat-saturated T2 and T1 postcontrast gadolinium-enhanced magnetic resonance imaging (MRI). The purpose of this study was to evaluate vanishing of parotid tumors on conventional MRI with and/or without postcontrast gadolinium-enhancement and on diffusion weighted imaging (DWI)., Methods: In 8 of 51 patients, ten parotid gland tumors had homogeneously enhanced lesions and were retrospectively analysed. Comparisons of signal intensity between those parotid tumors and parotid glands and evaluations of vanishing were performed on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), fat-suppressed T2WI (FS-T2WI), postcontrast gadolinium-enhanced T1WI (CE-T1WI) and fat-suppressed CE-T1WI (FS-CE-T1WI), DWI as well as apparent diffusion coefficient (ADC)., Results: Ten parotid gland tumors consisted of five Warthin tumors, two pleomorphic adenomas, two parotid carcinomas (small cell carcinoma and adenoid cystic carcinoma) and one oncocytoma. All tumors showed hypointensity on T1WI and hyperintensity on DWI. Nine of ten tumors showed vanishing on the other MR sequences. All Warthin tumors showed vanishing on FS-T2WI, FS-CE-T1WI and the ADC map. One oncocytoma showed vanishing on FS-T2WI and the ADC map and hyperintensity on FS-CE-T1WI. All pleomorphic adenomas showed vanishing on T2WI and CE-T1WI. One adenoid cystic carcinoma showed vanishing only on CE-T1WI., Conclusion: Vanishing of parotid tumors can be observed not only on FS-T2WI and FS-CE-T1WI but also on T2WI, CE-T1WI and ADC mapping.

Background: Sustained virologic response (SVR) by interferon and interferon-free treatment can results in the reduction of advanced liver fibrosis and the occurrence of hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). Recent interferon-free treatment for HCV shortens the duration of treatment and leads to higher SVR rates, without any serious adverse events. However, it is important to retreat patients who have had treatment-failure with HCV non-structural protein 5A (NS5A) inhibitor-including regimens. Combination of sofosbuvir and ledipasvir only leads to approximately 100% SVR rates in HCV genotype (GT1b), NS5A inhibitor-naïve patients in Japan. This combination is not an indication for severe renal disease or heart disease, and these patients should be treated or retreated with a different regimen., Case Summary: Retreatment with HCV non-structural protein 3/4A inhibitor, grazoprevir, and HCV NS5A inhibitor, elbasvir, successfully eradicated HCV RNA in three patients with HCV genotype 1b infection who discontinued prior interferon-free treatments including HCV NS5A inhibitors due to adverse events within 2 weeks., Conclusion: Retreatment with the 12-week combination regimen of grazoprevir and elbasvir is effective for HCV GT1b patients who discontinue the HCV NS5A inhibitor-including regimens within 2 weeks. The treatment response may be related to the short duration of initial treatment, which did not produce treatment-emergent RASs., Competing Interests: CONFLICTS OF INTEREST Tatsuo Kanda received research grants from Merck Sharp and Dohme (MSD), Chugai Pharm and AbbVie. Naoya Kato received research grants and lecture fees from Gilead, BMS, Merck Sharp and Dohme (MSD), Chugai Pharm and AbbVie. The founding sponsors played no role in the study design, data collection, analyses, interpretation, writing of the manuscript, or in the decision to publish the results. The other authors have declared that there are no conflicts of interest.

Aims/introduction: The aim of the present study was to evaluate the efficacy and safety of ipragliflozin in treating Japanese type 2 diabetes patients with inadequate glycemic control by investigating diurnal variations of blood glucose and body composition., Materials and Methods: This was an investigator-initiated, multicenter, prospective study with a 6-month treatment period. The primary outcome investigated was change in hemoglobin A1c levels from baseline. Secondary outcomes included changes in fasting plasma glucose, insulin resistance, variations in 24-h glucose levels detected by continuous glucose monitoring, bodyweight, body composition, waist circumference and serum lipids. Adverse events were evaluated throughout the study., Results: A total of 98 patients completed the study. Over the 6-month period, ipragliflozin-treated patients showed reduction in hemoglobin A1c levels by 0.3%, fasting plasma glucose levels by 13.0 mg/dL, bodyweight by 2.1 kg, body fat mass by 1.5 kg and extracellular water by 0.3 kg, as well as a decrease in systolic/diastolic blood pressures. Significant reductions from baseline in mean amplitude of glucose excursions and standard deviation, and the reduced frequency of hyperglycemia were confirmed. High-density lipoprotein cholesterol was also significantly improved. Notably, the subgroup analysis of hemoglobin A1c levels, bodyweight, waist circumference, and body composition based on age, sex and body mass index showed similar reductions within each subgroup. The incidences of adverse events and adverse drug reactions were 20.0% and 1.0%, respectively, over the 6-month period., Conclusions: Ipragliflozin is a useful oral antidiabetic medication for patients with a wide range of background characteristics., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases., Results: All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment., Conclusions: Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments., Methods: Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed., Competing Interests: CONFLICTS OF INTEREST Tatsuo Kanda received research grants from AbbVie, MSD, Sysmex and Chugai Pharmaceutical. Naoya Kato received grants from AbbVie, MSD, Sysmex, Chugai Pharmaceutical, Gilead Sciences and BMS. The founding sponsors played no role in the study design, data collection, analyses, or interpretation, writing of the manuscript, or in the decision to publish the results. The other authors have declared no conflicts of interest.

Background: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ∼70% SVR rates., Case Summary: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment., Conclusion: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment., Competing Interests: CONFLICTS OF INTEREST Tatsuo Kanda received research grants from Merck Sharp and Dohme (MSD), Chugai Pharm and AbbVie. Naoya Kato received research grants and lecture fees from Gilead and BMS. The founding sponsors played no role in the study design, data collection, analyses, or interpretation, writing of the manuscript, or in the decision to publish the results. The other authors have declared no conflicts of interest.

Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis B virus (HBV) infections is 6.5% and accounts for 60% of hepatocellular carcinoma. HBV has nine genotypes that have been identified by molecular genetic analysis. HBV genotypes are associated with several clinical features. We reviewed the prevalence of HBV genotypes in Myanmar and neighboring countries. We also reviewed HBV genotypes in refugees from Myanmar. HBV subgenotype C1 is predominant in Myanmar. As HBV genotype C is associated with hepatocellular carcinoma (HCC), it is important to screen for cirrhosis and HCC and to prevent their development in HBV-infected individuals of Myanmar., Competing Interests: The authors declare no conflict of interest.

Background: There have been no reports about quantitative evaluations of enhancing components of parotid tumors on conventional MR imaging., Purpose: To evaluate the signal intensity of the enhancing components of tumors, including pleomorphic adenomas (PAs), Warthin tumors (WTs) and malignant tumors (MTs), on various MR sequences and to assess the usefulness of quantitative evaluations for differentiation among the three groups of tumors., Material and Methods: A total of 39 histologically proven tumors, including 15 PAs, 17 WTs and 7 MTs, were enrolled in this study. The tumor-to-spinal cord contrast ratio (TSc-CR) was calculated by dividing the signal intensity of the lesion by that of the spinal cord on MR sequences, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and postcontrast gadolinium-enhanced T1WI (CE-T1WI). The mean apparent diffusion coefficient (ADC) value was selected in each tumor. Furthermore, the differences in the TSc-CRs and the ADC values among the three groups of tumors were statistically evaluated. Cutoff values were determined for the prediction of tumor histology., Results: The TSc-CRs of PAs were significantly higher than those of WTs and MTs on T2WI and CE-T1WI. The sensitivities and specificities were 100% and 87.5%, respectively, at a cutoff value of 1.31 for the TSc-CR of T2WI; and 83.3% and 100%, respectively, at a cutoff value of 2.00 for the TSc-CR of CE-T1WI. For the ADC values, sensitivity and specificity for discriminating PAs from WTs or MTs were both 100% when the cutoff value of the ADC was set at 1.40×10 -3 mm 2 /s., Conclusion: ADC maps and the quantitative evaluations using the TSc-CRs on T2WI and CE-T1WI were useful for discriminating WTs or MTs from PAs. However, discrimination between WTs and MTs was difficult using any MR sequence., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Genetic variation near the interferon lambda 3 ( IFNL3 ) is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis., Aims: We examined whether this genetic variation is associated with host lipids and treatment response., Methods: A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between IFNL3 genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis., Results: Forty patients (40%) had liver steatosis before therapy. Patients with IFNL3 minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and IFNL3 major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, IFNL3 genotype was the most significant predictor, as per multivariate analysis., Conclusions: Our results confirmed that IFNL3 genotype is associated with hepatic steatosis as well as IFN response., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: Recently, Asian dust (AD) has become a serious health problem and several studies have clearly proven that AD can aggravate asthma. However, it remains unclear as to which components of AD have a strong effect on the asthma exacerbation caused by AD exposure. Outdoor fungi can increase emergency department visits and hospitalization for asthma exacerbation and can aggravate asthma symptoms. Therefore, this study was aimed at investigating the relationship between AD and outdoor fungi and determining the potential of fungi to cause airborne particulate matter (PM)-related inflammatory responses., Methods: Airborne PM was collected each day from January 26, 2015 to February 27, 2015. Daily levels of outdoor fungi-associated PM were calculated using a culture-based method. Production of cytokines such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α was assessed in THP1 cells stimulated by the collected airborne PM each day., Results: Daily levels of AD particles were assessed using Light Detection and Ranging and did not correlate with outdoor fungi (r = -0.17, P =  0.94). There was also no association between outdoor fungi and the daily production of IL-6 (r = 0.16, P =  0.37), IL-8 (r = 0.19, P =  0.30), or TNF-α induced by collected PM (r = 0.07, P =  0.70). However, the daily levels of AD particles were significantly associated with IL-6 (r = 0.91, P < 0.0001), IL-8 (r = 0.64, P =  0.0004), and TNF-α (r = 0.72, P  < 0.0001) production., Conclusion: AD did not increase the acute levels of outdoor fungi and outdoor fungi did not affect the cytokine production induced by airborne PM. These results suggest that outdoor fungi do not have any detectable effect on the asthma exacerbation caused by AD exposure.

Hepatocellular carcinoma (HCC) is a predominantly male disease in which the androgen receptor (AR) serves an important pathogenic role in hepatocarcinogenesis. Fatty acid metabolism also contributes to hepatocarcinogenesis and is associated with the prognosis of cancer. The present study aimed to investigate the effects of the AR on fatty acid metabolism-associated gene expression in human hepatoma cell lines. AR-expression plasmids or control plasmids were transiently transfected into the human HCC cell lines Huh7 and HepG2. After 48 h, cellular protein and RNA were extracted and the expression of AR was confirmed by western blotting. Complementary DNA was synthesized and subjected to a quantitative polymerase chain reaction-based array to examine the expression of 84 fatty acid metabolism-associated genes. Overexpression of AR significantly downregulated the expression of 11 fatty acid metabolism-associated genes in Huh7 cells and 35 in HepG2 cells. The overexpression of AR also resulted in the upregulation of 6 fatty acid metabolism genes in HepG2 cells; however, it had no effect in Huh7 cells. Acyl-coenzyme A (CoA) thioesterase 7 and acyl-CoA oxidase 3 were downregulated in both cell lines. In conclusion, upregulation of AR via overexpression led to the disturbance of fatty acid metabolism-associated gene expression in human HCC cells. Therefore, the AR may serve a role in hepatocarcinogenesis via the regulation of hepatocellular fatty acid metabolism.

Infection with hepatitis A virus (HAV) is a major cause of acute hepatitis globally and it is important to identify the mechanisms of HAV replication. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) chaperone and serves a role in unfolded protein response pathways. Previous studies have demonstrated that GRP78 functions as an endogenous antiviral factor. In the present study, two loss-of-function studies using GRP78 were completed to elucidate the role of GRP78 in HAV infection. HAV replication was observed to be enhanced by deficient GRP78 although GRP78-deficiency also led to lower expression of ER stress molecules downstream of GRP78. Therefore, GRP78 appears to be a potential novel defensive molecule against HAV in hepatocytes.

The aim of this study was to characterize the treatment response and tolerability of sofosbuvir plus ribavirin therapies in Japanese patients infected with hepatitis C virus (HCV) genotype (GT)-2. This retrospective study analyzed 114 Japanese HCV GT-2 patients treated for 12 weeks with 400 mg of sofosbuvir plus weight-based ribavirin daily. This treatment led to higher sustained virologic response at 12-weeks post-treatment (SVR12) rates in both treatment-naïve and treatment-experienced patients. The efficacy of this treatment in compensated cirrhotics was the same as that in patients with chronic hepatitis. HCV GT-2a infection and lower estimated glomerular filtration rates (eGFR) tended to be associated with SVR12. Of 114 patients, 113 completed the combination of sofosbuvir plus ribavirin for 12 weeks. Seven patients without SVR12 did not have HCV NS5B-S282 mutations. The overall SVR12 rate was 90.4% (103 of 114). More effective therapeutic options with less adverse events are desired to achieve higher SVR rates in HCV GT-2 Japanese patients.

Hepatitis B virus (HBV) surface antigen (HBsAg) loss is one of the treatment goals of chronic HBV infection. Bone marrow stromal cell antigen 2 (BST2) is one of the interferon (IFN)-stimulated genes (ISGs) and inhibits the release of various enveloped viruses. Here we examined the effects of antiviral treatment on HBsAg levels and its intracellular mechanism in HBsAg-producing hepatocytes. In PLC/PRF/5 and Huh1, IFNα-2a treatment decreased HBsAg levels in their conditioned media. Upregulation of interleukin 8 (IL8), toll-like receptor 2 (TLR2) and interferon gamma-induced protein 10 (IP10) mRNAs was associated with the reduction of HBsAg in both PLC/PRF/5 and Huh1. The HBsAg level was upregulated by knockdown of IL8, TLR2 or IP10. Exogenous addition of IL8 enhanced BST2 promoter activity and BST2 mRNA expression. Additionally, knockdown of IL8 could lead to the downregulation of BST2 mRNA. Transfection of poly(I-C) enhanced IL8 and BST2 mRNA expression and inhibited HBsAg secretion from PLC/PRF/5 cells. In conclusion, IL8 might play an important role in the enhancement of BST2 and be involved in HBsAg eradication., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Noninvasive methods to accurately and conveniently evaluate liver fibrosis are desirable. MicroRNA (miR) is one of the candidates. MiRs are small RNAs consisting of 19-25 nucleotides that negatively regulate many target genes at transcriptional levels. Recently, many researchers have focused on circulating miRs in the blood stream as biomarkers. Hepatic miR-122 has been reported to have an association with viral replication and hepatic fibrosis in chronic hepatitis B virus (HBV) and hepatic C virus (HCV) infection., Methods: We measured serum miR-122 levels in HBV- and HCV-infected patients confirmed with liver biopsy. We also investigated a novel liver fibrosis marker Wisteria floribunda agglutinin-positive Mac-2 binding protein [WFA(+)-M2BP]. We evaluated the diagnostic usefulness of these markers in hepatic fibrosis and inflammation of patients with chronic viral infection., Results: The serum miR-122 levels of HBV-infected patients were higher than those of the control subjects. In HBV-infected patients, the serum miR-122 levels of patients with advanced liver fibrosis were significantly lower. Serum WFA(+)-M2BP was significantly higher dependent on both the staging of fibrosis and the grading of inflammatory activity in patients with both HBV and HCV infection. We also observed that higher serum WFA(+)-M2BP levels augmented the prediction of advanced liver fibrosis among HBV-infected patients with lower serum miR-122 levels., Conclusions: A lower serum miR-122 level is a useful predictor of advanced liver fibrosis in HBV-infected patients. Serum WFA(+)-M2BP could predict liver fibrosis in both HBV and HCV infection. The combination of these markers may result in the more accurate evaluation of liver fibrosis in HBV infection.

Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. Here, we discuss the recent data on AR and HCC, and the combination of sorafenib and inhibitors of AR for advanced-HCC patients. Androgen-dependent and androgen-independent AR activation exist in human hepatocarcinogenesis. AR could directly control hepatocarcinogenesis and regulate the innate immune system to influence HCC progression. Combination of sorafenib with AR inhibitors might represent a potential treatment for patients with advanced HCC.

Port-site metastasis of hepatocellular carcinoma (HCC) is extremely rare, and only one case has been reported in the English-language literature. Contamination with malignant cells along the needle tract during percutaneous biopsy or radiofrequency ablation is a well-recognized cause of HCC recurrence. Here, we describe a case of port-site metastasis after laparoscopic liver resection of HCC. The patient, who had undergone laparoscopic partial resection of the left lateral segment of the liver 18 months earlier, was diagnosed with HCC. CT showed a nodule in the abdominal wall where the laparoscopic port had been inserted during resection. Local excision was performed, and histological examination revealed HCC consistent with recurrence after laparoscopic resection. The experience described in this report highlights the risk of port-site metastasis of HCC. Imaging for oncologic surveillance after laparoscopic resection must include all port sites., (© 2016 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.

Background: Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown., Methods: The expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured., Results: The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines., Conclusions: The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

Achromobacter xylosoxidans is an environmental bacterium with multi-drug resistance. We isolated Achromobacter xylosoxidans and investigated its susceptibility to 13 drugs. Seventy-eight water samples were collected from rivers and ponds, and 11 samples were swabbed from residential sinks and baths. Nine strains of Achromobacter xylosoxidans were isolated from the 89 samples. Five strains, including 2 that were sampled from residential homes, showed high resistance to multiple aminoglycosides. This indicated that Achromobacter xylosoxidans is widely distributed in various outdoor and indoor environments. Moreover, since these highly resistant bacteria were present in indoor environments, caution should be taken for elderly people living at home. Furthermore, a careful assessment should be made for diagnosing and treating compromised hosts.

We describe a case of acute liver failure (ALF) without hepatic encephalopathy with marked elevation of aminotransferase due to hepatitis A, according to the revised Japanese criteria of ALF. This liver biopsy of the patient showed compatible to acute viral hepatitis and she immediately recovered without intensive care. She had no comorbid disorders. Of interest, phylogenetic tree analysis using almost complete genomes of hepatitis A virus (HAV) demonstrated that the HAV isolate from her belonged to the HAV subgenotype IA strain and was similar to the HAJFF-Kan12 strain (99% nucleotide identity) or FH1 strain (98% nucleotide identity), which is associated with severe or fulminant hepatitis A. Careful interpretation of the association between HAV genome variations and severity of hepatitis A is needed and the mechanism of the severe hepatitis should be explored.

We report a case of unresectable locally advanced pancreatic cancer successfully resected after gemcitabine(GEM)plus nab-paclitaxel(PTX)treatment. A 68-year-old man was referred to our institution with jaundice. We diagnosed pancreatic head cancer using computed tomography(CT)and endoscopic retrograde cholangiopancreatography. We initially diagnosed it as locally advanced unresectable pancreatic cancer because of extensive invasion to the portal vein. GEM plus nab- PTX was administered to the patient as systemic chemotherapy. After 9 courses of chemotherapy, a CT scan revealed that the tumor had significantly reduced in size and range of portal vein invasion. Therefore, we performed pancreaticoduodenectomy with resection of the portal vein and achieved R0 resection. Currently, the patient is alive without recurrence. Therefore, conversion surgery after treatment with GEM plus nab-PTX chemotherapy for unresectable pancreatic cancer should be considered.

Although the interaction between host and hepatitis A virus (HAV) factors could lead to severe hepatitis A, the exact mechanism of acute liver failure caused by HAV infection is not yet fully understood. The effects of metabolic diseases such as dyslipidemia or diabetes mellitus on HAV replication are still unknown. Here, we examined the effects of free fatty acids or high-concentration glucose on HAV replication and the effects on mitogen-activated protein kinase signaling pathway-related genes in human hepatocytes. We discovered a novel effect of free fatty acids or high-concentration glucose on HAV replication in association with a reduction in the expression of glucose-regulated protein 78 (GRP78). We also observed that thapsigargin induced GRP78 expression and inhibited HAV replication. These findings may provide a new interpretation of the relationship between metabolic diseases and severity of hepatitis A and suggest a new understanding of the mechanism of severe HAV infection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Determination of hepatitis C virus (HCV) genotypes plays an important role in the direct-acting agent era. Discrepancies between HCV genotyping and serotyping assays are occasionally observed. Eighteen samples with discrepant results between genotyping and serotyping methods were analyzed. HCV serotyping and genotyping were based on the HCV nonstructural 4 (NS4) region and 5'-untranslated region (5'-UTR), respectively. HCV core and NS4 regions were chosen to be sequenced and were compared with the genotyping and serotyping results. Deep sequencing was also performed for the corresponding HCV NS4 regions. Seventeen out of 18 discrepant samples could be sequenced by the Sanger method. Both HCV core and NS4 sequences were concordant with that of genotyping in the 5'-UTR in all 17 samples. In cloning analysis of the HCV NS4 region, there were several amino acid variations, but each sequence was much closer to the peptide with the same genotype. Deep sequencing revealed that minor clones with different subgenotypes existed in two of the 17 samples. Genotyping by genome amplification showed high consistency, while several false reactions were detected by serotyping. The deep sequencing method also provides accurate genotyping results and may be useful for analyzing discrepant cases. HCV genotyping should be correctly determined before antiviral treatment., Competing Interests: Tatsuo Kanda received research grants from Merck Sharp and Dohme (MSD), Chugai Pharm and Abbvie. The other authors declare no conflict of interest.

A 75-year-old woman was referred to our hospital with suspected leukemia. Complete blood count demonstrated WBC 3,810/µl with 26% blasts, Hb of 11.7 g/dl and Plt of 18.0×10 4 /µl. Bone marrow aspiration revealed blasts (86.3%) with expressions of CD34, CD7, TdT, CD33, and CD117. MPO was negative. Chromosomal analysis of the bone marrow showed isolated trisomy 10 in all leukemic cells (20/20). Swelling of superficial lymph nodes was also observed. Cervical lymph node biopsy revealed leukemic blasts which had the same phenotype as those in the bone marrow except that proliferation of Langerhans cell-like cells (LCs) was observed in the paracortex. LCs had pale cytoplasm and grooved nuclei, and were positive for both CD1a and S100 protein. Trisomy 10 was detected in both the leukemic blasts and the LCs by fluorescence in situ hybridization. This rare case strongly suggests leukemic cells to differentiate into LCs.

Objective The 6-min walk test (6MWT) is a simple test that is used to examine the exercise tolerance and outcomes in patients with chronic obstructive pulmonary disease (COPD). Although the 6MWT is useful for assessing exercise tolerance, it is difficult to evaluate time-dependent parameters such as the walking pattern. A modified 6MWT has been devised to assess the walking pattern by calculating the number of steps per second (NSPS). This study was performed to investigate walking pattern of COPD patients in the modified 6MWT before and after a single inhalation of the short-acting β 2 -agonist procaterol. Methods Nine male COPD patients participated in this study. The 6MWT was performed before and after the inhalation of procaterol hydrochloride. A digital video recording of the 6MWT was made. After the 6MWT, the number of steps walked by the subject in each 5-s period was counted manually with a hand counter while viewing the walking test on the video monitor. Results After the inhalation of procaterol, the 6-min walking distance increased significantly in comparison to baseline (p<0.01). The mean NSPS was also significantly increased after the inhalation of procaterol in comparison to baseline (p<0.01). The walking pattern was displayed on a graph of time versus NSPS, and the walking pace was shown by a graph of time versus cumulative steps. Conclusion The analysis of the COPD patients' walking test performance and their walking pattern and pace in the 6MWT may help to evaluate the effects of drug treatment.

Background: Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+)-M2BP) is a novel non-invasive marker of liver fibrosis. The goal of the study was to investigate whether the novel serum biomarker WFA(+)-M2BP or other non-invasive markers are useful for the prediction of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH), autoimmune hepatitis (AIH), and primary biliary cholangitis (PBC)., Methods: We examined a significant correlation between serum WFA(+)-M2BP levels and histological staging of fibrosis in several chronic liver diseases, such as NASH, AIH, and PBC., Results: WFA(+)-M2BP could not predict hepatic fibrosis in these patients. We also showed that the level of platelet counts is a useful predictor of hepatic fibrosis progression in patients with NASH, AIH, and PBC. There was a significant correlation between staging of fibrosis and grading of activity in the liver in all groups except for AIH patients., Conclusion: Platelet counts can predict hepatic fibrosis in patients with NASH, AIH, or PBC. Clinicians should pay attention to the grading of liver activity in the use of WFA(+)-M2BP.