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Background. Recently, chronic hepatitis E has been reported in solid organ transplant (SOT) recipients in European countries. Previously, we clarified the prevalence of hepatitis E virus (HEV) infection in Japanese liver transplant recipients and identified 2 chronic hepatitis E patients infected by blood transfusion. However, the rate of HEV infection in recipients of SOTs other than liver in Japan remains unclear, so we conducted a nationwide survey to clarify the prevalence of chronic HEV infection in Japanese heart and kidney transplant recipients. Methods. A total of 99 heart and 2526 kidney transplant recipients in 17 hospitals in Japan were examined for the presence of the IgG class of anti-HEV antibodies as well as for serum HEV RNA. Results. The prevalence of anti-HEV IgG among heart and kidney transplant recipients was 7.07% (7/99) and 4.08% (103/2526), respectively. One heart transplant patient (1.01%) and 11 kidney transplant patients (0.44%) were found to be positive for HEV RNA. The HEV isolates from all viremic patients were typed as genotype 3. Four patients developed chronic hepatitis E after transplantation. Three patients were treated with ribavirin; their liver enzymes normalized, and HEV RNA became negative immediately. Sustained virologic response was achieved in all cases. Conclusions. This is the first nationwide survey of HEV infection in Japanese heart and kidney transplant recipients. The prevalence of anti-HEV IgG and HEV RNA in heart and kidney transplant recipients in Japan was lower than that in European countries. Of note, 42% of viremic transplant patients developed chronic hepatitis.

Although the effect of levocarnitine (L‐carnitine) on hyperammonemia has been reported in patients with liver cirrhosis (LC), its effect on sarcopenia remains to be elucidated. We assessed the effects of L‐carnitine on sarcopenia in patients with LC. We retrospectively evaluated 52 patients with LC who were treated with L‐carnitine for more than 3 months between February 2013 and June 2017. Computed tomography was used to measure the cross‐sectional area of the skeletal muscles at the level of the third lumbar vertebra. The relative change in skeletal muscle index (SMI) per year (ΔSMI/year) was computed in each patient. We evaluated the relationship between ΔSMI/year and various parameters, such as age, sex, liver functional reserve, and dose of L‐carnitine. The median ΔSMI/year for all patients was −0.22%. The ΔSMI/year values in Child‐Pugh classes A, B, and C were not significantly different among the three groups. There was no significant relationship between ΔSMI/year and sex, age, body mass index, and sarcopenia. Multivariate analysis showed that only a high dose of L‐carnitine (odds ratio [OR], 4.812; 95% confidence interval [CI], 1.233‐18.784; P = 0.024) was associated with increased muscle mass. The L‐carnitine high‐dose group included a significantly larger number of patients with increased muscle mass compared with the low‐dose group (OR, 3.568; 95% CI, 1.138‐11.185; P = 0.027). Administration of L‐carnitine led to a significant and gradual reduction in serum ammonia levels. Conclusion: L‐carnitine seems to suppress the progression of sarcopenia dose dependently, and this was noted to be associated with the improvement of hyperammonemia in patients with LC.

Background Pancreatectomy may cause serious pancreatic exocrine insufficiency (PEI), which can lead to some nutritional problems, including new-onset diabetes mellitus (DM) or non-alcoholic fatty liver disease (NAFLD). Recent studies have reported that remnant pancreatic volume (RPV) significantly influences postoperative PEI. However, the specific correlation between RPV and postoperative PEI remains unclear. Here, we compare various pre-, peri-, and postoperative risk factors in a retrospective cohort to address whether preoperatively measured RPV is a predictor of postoperative PEI in pancreatic cancer patients after distal pancreatectomy (DP). Methods Sixty-one pancreatic cancer patients who underwent DP were retrospectively enrolled. Pancreatic volume was measured using preoperative 3D images, which simulated the actual intraoperative pancreatic parenchymal volume. We obtained the 3D-measured RPV and resected pancreatic volume. We calculated the ratio of the RPV to the total pancreatic volume and then divided the cohort into high- and low-RPV ratio groups based on a cut-off value (>0.35, n = 37 and ≤ 0.35, n = 24). Using multivariate analysis, the RPV ratio as well as pre-, peri- and postoperative PEI risk factors were independently assessed. Results The multivariate analysis revealed that a low RPV ratio (odds ratio [OR], 5.911; p = 0.001), a hard pancreatic texture (OR, 3.313; p = 0.023) and TNM stage III/IV (OR, 3.515; p = 0.031) were strong predictors of the incidence of PEI. Conclusions The present study indicates that the RPV ratio is an additional useful predictor of postoperative nutrition status in pancreatic cancer patients.

Gastrointestinal decompression is generally applied to a non-strangulated acute small bowel obstruction (NSASBO). Although long tube (LT) placement and administration of Gastrografin through a nasogastric tube (NGT-G) have shown advantages over NGT alone in previous studies, no studies appear to have compared LT and NGT-G. In this multicenter, randomized controlled trial, patients with NSASBO were randomly assigned to receive LT or NGT-G between July 2016 and November 2018 at 11 Japanese institutions. The primary endpoint was non-inferiority of NGT-G compared to LT for non-surgery rate, and the lower limit of the 95% confidence interval for the non-surgery rate (−15%) was set as the lower margin for inferiority of NGT-G compared to LT. In total, 223 patients (LT group, n = 111; NGT-G group, n = 112) were analyzed in the present trial. The non-surgery rate was 87.4% in the LT group and 91.1% in the NGT-G group, with a 3.7% difference between NGT-G and LT (95.3%CI − 5.55 to 12.91; non-inferiority P = 0.00002923). On the other hand, the non-surgery rate with pure NGT-G alone (76.8%) that represents non-cross-over NGT-G without subsequent LT was significantly lower than that with LT (P = 0.039). Median procedure time was significantly shorter with NGT-G (1 min) than with LT (25 min; P

The development of red or near-infrared light (NIR) switchable photochromic molecules is required for an efficient utilization of sunlight and regulation of biological activities. While the photosensitization of photochromic molecules to red or NIR light has been achieved by a two-photon absorption process, the development of a molecule itself having sensitivity to red or NIR light has been now a challenging study. Herein, we developed an efficient molecular design for realizing red or NIR-light-responsive negative photochromism based on binaphthyl-bridged imidazole dimers. The introduction of electron-donating substituents shows the red shift of the absorption band at the visible-light region because of the contribution of a charge-transfer transition. Especially, the introduction of a di(4-methoxyphenyl)amino group (TPAOMe) and a perylenyl group largely shifts the absorption edge of the stable colored form to 900 nm. In addition, because the absorption band of one of the derivatives substituted with TPAOMe covers the whole visible-light region, the colored form shows a neutral gray color. Upon red (660 nm) or NIR-light (790 nm) irradiation, we observed the negative photochromic reaction from the stable colored form to the metastable colorless form. Therefore, the substituted binaphthyl-bridged imidazole dimers constitute the attractive photoswitches within a biological window.

Laugier’s hernia is a rare clinical entity compared with a typical femoral hernia. Therefore, the clinical features, radiological findings, and appropriate treatment strategies remain largely unclear. In this study, we present 15 Laugier’s hernia cases. Additionally, we review the relevant literature and discuss the clinical features, radiological findings, and appropriate treatment strategies pertaining to Laugier’s hernia compared with a typical femoral hernia. Among 1260 hernia patients, we retrospectively enrolled 15 Laugier’s hernia patients (1.19%) and 89 femoral hernia patients (7.06%) who underwent herniorrhaphy and compared the demographic characteristics and radiological findings between the two groups. Regarding the patient characteristics, a significant difference was observed in the presence of pain (p

Aim The aim of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) between 5-fluorouracil (5-FU)-based continuous infusion chemotherapy and low-dose cisplatin (CDDP) monotherapy in patients with advanced hepatocellular carcinoma (HCC). Methods Patients were grouped according to HAIC regimen (5-FU group, n = 317/CDDP group, n = 66). A two-to-one match was created using propensity score analysis (5-FU group, n = 102/CDDP group, n = 51). After matching, response rate (RR) and adverse events as primary end-points, and survival and progression-free survival as secondary end-points, were analyzed. Results In the analysis of primary end-points, the RR in the 5-FU group was significantly higher than in the CDDP group (32.4% vs. 15.7%, P = 0.033). In patients with a Child-Pugh (CP) score of 5-7, the RR in the 5-FU group was significantly higher than that in the CDDP group (36.1% vs. 15.4%, P = 0.020). In those with a CP score of 8-9, there was no significant difference in RR between the two groups (15.8% vs. 16.6%, P = 1.000). The reservoir system-related complications were 9.8% in the 5-FU group, and there was no significant difference in the incidence of grade 3/4 adverse events between the two matched groups (P > 0.05). In terms of secondary end-points, the median survival time was 9.1 and 8.7 months for the 5-FU and CDDP groups, respectively (P = 0.4917). Progression-free survival was 3.9 months for the 5-FU group and 4.9 months for the CDDP group (P = 0.4). Conclusions 5-Fluorouracil-based continuous infusion chemotherapy could be suitable for advanced HCC patients with a CP score of 5-7 considering the treatment response.

Non-linear photoresponses against excitation light intensity are important for the development of attractive photofunctional materials exhibiting high spatial selective photoswitching that is not affected by weak background light. Biphotochromic systems composed of two fast photochromic units have the potential to show a stepwise two-photon absorption process in which the optical properties can be non-linearly controlled by changing the excitation light conditions. Herein, we designed and synthesized novel bisnaphthopyran derivatives containing fast photoswitchable naphthopyran units. The bisnaphthopyran derivatives show a stepwise two-photon-induced photochromic reaction upon UV light irradiation accompanied by a drastic color change due to a large change in the molecular structure between the one-photon product and the two-photon product. Consequently, the color of the bisnaphthopyran derivatives can be non-linearly controlled by changing the excitation intensity. This characteristic photochromic property of the biphotochromic system provides important insight into advanced photoresponsive materials.

Photocontrol of mechanical motions of small objects has attracted much attention to develop mesoscopic remote actuators. For this purpose, photoinduced morphological changes of molecules, molecular aggregates, and crystals have been extensively studied in the field of chemistry and materials science. Here, we propose direct use of momenta of light (i.e. radiation force) to control the motion of small objects, through photochromic reactions of pyranoquinazoline (PQ) derivatives. PQ is colorless in visible wavelength region while it is in closed form and undergoes photochemical ring-opening reactions to form colored isomers upon UV light irradiation; the open-ring isomers return to the colorless closed isomers mainly through the thermal back reaction. In the experiment, individual polymer microparticles with diameters of 7 μm incorporating PQ were trapped by optical tweezers. When the trapped microparticle was irradiated with UV light, the microparticle was pushed along the axis of light propagation about a...

Aim As second-line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second-line chemotherapy. Methods Patients (n = 160) with advanced HCC, Child-Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child-Pugh A liver function and ECOG PS 0-1 at progression as candidates for second-line chemotherapy and those who had tolerated sorafenib (≥400 mg/day for ≥20 of the last 28 days of treatment) as candidates eligible for regorafenib treatment. Results Among all 160 patients, median overall survival was 10 months, and median progression-free survival was 3.5 months. Among the 147 patients with PD, 74 (50.3%) were candidates for second-line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second-line chemotherapy (8.8 months) was statistically longer (P = 0.0002) than that of the non-candidates (3.6 months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin >3.5 g/dL (OR, 3.3; P = 0.005) at sorafenib initiation. Conclusion Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment.

Background and aim Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies. Methods The subjects were 391 HAIC and 431 sorafenibs administered at our hospital and related hospitals. In this case, cases that satisfy the following three conditions were targeted: (i) no extrahepatic metastasis, (ii) Child-Pugh A, and (ii) not having received treatment of both HAIC and sorafenib during the course. As a result, 150 cases of HAIC and 134 cases of sorafenib were analyzed this time. Results Univariate and multivariate analyses were performed for the HAIC and sorafenib groups. TACE refractory status and MVI were factors contributing to overall survival (OS). Therefore, this study divided all cases according to those variables. The median survival time of MVI-positive and non-TACE refractory cases was significantly better with HAIC (13 months) versus sorafenib (6 months). However, in MVI-negative and TACE refractory cases, the median survival time of HAIC (8 months) was significantly poorer than for sorafenib (20 months). Conclusion Transcatheter arterial chemoembolization refractory status with HAIC and MVI with sorafenib were factors for poor prognosis. In particular, HAIC was significantly better than sorafenib as primary treatment in MVI and non-TACE refractory cases. It is necessary to consider these factors in treatment selection.

Objective: To compare the outcome of hepatic arterial infusion chemotherapy combined with radiotherapy (HAIC + RT) versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombosis (PVTT). Methods: This retrospective study included 108 HCC patients with PVTT of the main trunk or first branch and Child-Pugh ≤7. Sixty-eight received HAIC + RT and 40 received sorafenib. Patients were then assigned to the HAIC + RT group (n = 36) and the sorafenib group (n = 36) through case-control matching. The decision to treat with HAIC + RT or sorafenib was left to the attending physician. Results: The median overall, progression-free, and postprogression survival were significantly longer in the HAIC + RT group than in the sorafenib group (9.9 vs. 5.3, p = 0.002; 3.9 vs. 2.1, p = 0.048; and 3.7 vs. 1.9 months, p = 0.02, respectively). Multivariate analysis identified HAIC + RT (hazard ratio = 2.02; 95% confidence interval, 1.14–3.57; p = 0.01) as a significant and independent determinant of overall survival. Conclusions: In patients with advanced HCC and major PVTT, survival was significantly longer in those treated with HAIC + RT than with sorafenib.

Objective: To evaluate the impact of hepatitis C virus (HCV) eradication on the clinical outcome of patients with HCV-related advanced hepatocellular carcinoma (HCC) treated with sorafenib. Methods: A total of 58 HCV-related advanced HCC patients with Child-Pugh grade A disease who were treated with sorafenib were enrolled in this retrospective cohort study. Of these, 27 patients were HCV RNA negative as a result of previous antiviral therapy (sustained viral response [SVR] group), while the remaining 31 were HCV RNA positive (non-SVR group). Results: The response rate, disease control rate and median time to progression in the SVR group (6, 46.0%, and 3.8 months, respectively) were similar to those in the non-SVR group (3, 51.5%, and 2.7 months, respectively). On the other hand, the median time to treatment failure (TTTF), post-progression survival (PPS), and overall survival (OS) were significantly longer in the SVR group than in the non-SVR group (9.7, 8.5, and 15 months vs. 5.9, 5.2, and 9.3 months; p = 0.023, 0.02, and 0.014, respectively). On multivariate analysis, SVR was identified as a significant and independent determinant of PPS (p = 0.009), TTTF (p = 0.028), and OS (p = 0.01). Conclusion: HCV eradication before sorafenib treatment for HCV-related advanced HCC could prolong PPS and TTTF and improve OS.

BACKGROUND AND AIM The most important prognostic factor for non-alcoholic steatohepatitis (NASH) is liver fibrosis. The aim of this study is to examine clinical parameters involved in pathological progression in NASH patients who underwent repeated liver biopsy and to analyze the response to treatment with respect to NASH-related single nucleotide polymorphisms (SNPs). We performed longitudinal analysis of genetic and clinical factors associated with progression of NASH. METHODS Eighty NASH patients who had undergone serial liver biopsies were enrolled in this retrospective cohort study. Histological exacerbation was determined based on non-alcoholic fatty liver disease activity score (NAS) and liver fibrosis. RESULTS About 22.5% had progression of fibrosis, 22.5% had improvement of fibrosis, and 55.0% had no change. NAS increased in 12.5%, decreased in 61.3%, and remained stable in the remaining 26.3%. We examined factors associated with histological progression versus non-progression. Poor response of alanine aminotransferase (ALT) levels, increase in HbA1c levels, and presence of the tumor necrosis factor risk allele in the rs1799964 SNP were identified as independent risk factors contributing to histological progression in NASH patients. In addition, we found that the histological progression rate varies with ALT response, HbA1c levels, and rs1799964 genotype. CONCLUSIONS In this study, we clarified the serum ALT level and the clinical significance of HbA1c to evaluate the progression of fibrosis in Japanese NASH patients. Furthermore, the tumor necrosis factor SNP was more likely to be involved in the response than PNPLA3 SNP. By simultaneously evaluating three factors, it is possible to estimate the risk of histological progression more accurately.

Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.

Background In patients with advanced hepatocellular carcinoma (HCC), evidence is unclear as to whether hepatic arterial infusion chemotherapy (HAIC) or sorafenib is superior. We performed a prospective, open-label, non-comparative phase II study to assess survival with HAIC or HAIC converted to sorafenib. Methods Fifty-five patients were prospectively enrolled. Patients received HAIC as a second course if they had complete response, partial response, or stable disease (SD) with an alpha fetoprotein (AFP) ratio 1 and a DCP ratio > 1 or disease progression. The primary endpoint was the 1-year survival rate. Secondary endpoints were the 2-year survival rate, HAIC response, survival rate among HAIC responders, progression-free survival, and adverse events. Results Of the 55 patients in the intent-to-treat population, the 1-year and 2-year survival rates were 64.0 and 48.3%, respectively. After the first course of HAIC, one (1.8%) patient showed complete response, 13 (23.6%) showed partial response, 30 (54.5%) had SD, and 10 (18.1%) patients had progressive disease. Twenty-three patients (41.8%) had SD with AFP ratios 1 and DCP ratios > 1. Thirty-seven patients (68.5%) were responders and 17 (30.9%) were non-responders to HAIC. In responders, the 1-year and 2-year survival rates were 78 and 62%, respectively. Conclusion Given the results of this study, this protocol deserves consideration for patients with advanced HCC. This trial was registered prospectively from December 12. 2012 to September 1. 2016.

We propose combined solder-TSVs and microbumps for cost reduction of 3-D integration. In this study, we find that crystal orientation of solder TSVs are oriented in the same direction by EBSD and TSVs are filled with single solder grain, i.e. grain boundaries are not observed at TSVs. We investigate the dependence of the cooling rate.

While there have been numerous reports about colovesical fistulas and ruptured intestinal diverticula, there have been far fewer reports about vesicointestinal fistulas caused by Meckel’s diverticula. Most Meckel’s diverticula are asymptomatic. Furthermore, they seldom cause vesicointestinal fistulas, and the associated complications are non-specific. Thus, their preoperative diagnosis is difficult. We experienced a case in which a vesicointestinal fistula was caused by a Meckel’s diverticulum and was treated with laparoscopic surgery. A 46-year-old male was referred to our hospital after exhibiting hematuria. Cystoscopy revealed a fistula between the small intestine and bladder. Contrast-enhanced computed tomography and magnetic resonance imaging showed a diverticulum in the ileum and a fistula between the ileum and bladder, which passed through the diverticulum. A Meckel’s diverticulum was suspected. We conducted a laparoscopic operation. We dissected the Meckel’s diverticulum with an automatic suturing device and removed it together with part of the ileum. The patient’s postoperative course was good. We experienced a case in which a vesicointestinal fistula was caused by a Meckel’s diverticulum and was successfully treated with laparoscopic surgery. In selected cases of Meckel’s diverticulum, the dissection of the diverticulum with an automatic suturing device is appropriate.

The aim of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) between 5-fluorouracil (5-FU)-based continuous infusion chemotherapy and low-dose cisplatin (CDDP) monotherapy in patients with advanced hepatocellular carcinoma (HCC).Patients were grouped according to HAIC regimen (5-FU group, n = 317/CDDP group, n = 66). A two-to-one match was created using propensity score analysis (5-FU group, n = 102/CDDP group, n = 51). After matching, response rate (RR) and adverse events as primary end-points, and survival and progression-free survival as secondary end-points, were analyzed.In the analysis of primary end-points, the RR in the 5-FU group was significantly higher than in the CDDP group (32.4% vs. 15.7%, P = 0.033). In patients with a Child-Pugh (CP) score of 5-7, the RR in the 5-FU group was significantly higher than that in the CDDP group (36.1% vs. 15.4%, P = 0.020). In those with a CP score of 8-9, there was no significant difference in RR between the two groups (15.8% vs. 16.6%, P = 1.000). The reservoir system-related complications were 9.8% in the 5-FU group, and there was no significant difference in the incidence of grade 3/4 adverse events between the two matched groups (P 0.05). In terms of secondary end-points, the median survival time was 9.1 and 8.7 months for the 5-FU and CDDP groups, respectively (P = 0.4917). Progression-free survival was 3.9 months for the 5-FU group and 4.9 months for the CDDP group (P = 0.4).5-Fluorouracil-based continuous infusion chemotherapy could be suitable for advanced HCC patients with a CP score of 5-7 considering the treatment response.

Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies.The subjects were 391 HAIC and 431 sorafenibs administered at our hospital and related hospitals. In this case, cases that satisfy the following three conditions were targeted: (i) no extrahepatic metastasis, (ii) Child-Pugh A, and (ii) not having received treatment of both HAIC and sorafenib during the course. As a result, 150 cases of HAIC and 134 cases of sorafenib were analyzed this time.Univariate and multivariate analyses were performed for the HAIC and sorafenib groups. TACE refractory status and MVI were factors contributing to overall survival (OS). Therefore, this study divided all cases according to those variables. The median survival time of MVI-positive and non-TACE refractory cases was significantly better with HAIC (13 months) versus sorafenib (6 months). However, in MVI-negative and TACE refractory cases, the median survival time of HAIC (8 months) was significantly poorer than for sorafenib (20 months).Transcatheter arterial chemoembolization refractory status with HAIC and MVI with sorafenib were factors for poor prognosis. In particular, HAIC was significantly better than sorafenib as primary treatment in MVI and non-TACE refractory cases. It is necessary to consider these factors in treatment selection.

Hepatitis E caused by hepatitis E virus (HEV) is a serious public health concern in developing countries where HEV is mainly transmitted through contaminated water. Recently, in industrialized countries, autochthonous hepatitis E, a porcine zoonosis, has been increasingly recognized. In Japan, the number of national notifications of acute hepatitis E has increased since the introduction of anti-HEV IgA antibody measurement, covered by the national health insurance program, in 2011. In the past three years, we examined five patients of acute hepatitis or acute-on-chronic liver failure caused by HEV infection who presented various clinical courses in the southern area of Ibaraki prefecture in Japan. Of these patients, 78-year-old and 63-year-old male patients presented acute hepatitis E and recovered by only bed rest. The latter patient had a history of consuming grilled or undercooked pork and shellfish prior to the onset of hepatitis E. Among the five patients examined, the infection route was detected only in this patient. Of note, a 65-year-old female patient presented severe hepatitis associated with painless thyroiditis. The patient was diagnosed with probable autoimmune hepatitis and was successfully treated with prednisolone (40 mg/day). Lastly, 58-year-old and 62-year-old male patients, both of whom had a history of diabetes mellitus and alcoholic liver disease, developed acute-on-chronic liver failure, and the latter patient with pre-existing liver cirrhosis died due to liver failure. Thus, patients with clinical HEV infection who display multiple underlying diseases can develop acute-on-chronic liver failure. In conclusion, HEV infection manifests the diverse clinical courses.

As second-line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second-line chemotherapy.Patients (n = 160) with advanced HCC, Child-Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child-Pugh A liver function and ECOG PS 0-1 at progression as candidates for second-line chemotherapy and those who had tolerated sorafenib (≥400 mg/day for ≥20 of the last 28 days of treatment) as candidates eligible for regorafenib treatment.Among all 160 patients, median overall survival was 10 months, and median progression-free survival was 3.5 months. Among the 147 patients with PD, 74 (50.3%) were candidates for second-line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second-line chemotherapy (8.8 months) was statistically longer (P = 0.0002) than that of the non-candidates (3.6 months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin3.5 g/dL (OR, 3.3; P = 0.005) at sorafenib initiation.Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment.

Benzo-annulated chromenes, i.e., naphthopyrans, are well-known photochromic molecules that undergo photochemical ring-opening reactions to form two colored open-ring isomers, the transoid-cis and transoid-trans forms, upon light irradiation. Though the transoid-cis form returns thermally to the uncolored closed form, the fading rate of the transoid-trans form is extremely slow because of its higher thermal stability. This slow fading behavior of the transoid-trans form is responsible for the persistence of residual color for several minutes to hours, and prevents the application of such molecules to fast photoswitching materials. We have found a new simple and versatile strategy to substantially reduce the amount of the undesirable long-lived colored transoid-trans form by introducing an alkoxy group at the 1-position of azino-fused chromenes, i.e., 8H-pyranoquinazolines. The alkoxy group effectively reduces the formation of the transoid-trans form due to C-H···O intramolecular hydrogen bonding in the transoid-cis form. Moreover, the introduction of a condensed aromatic ring at the 3-position was found to be effective to increase the photosensitivity of the ring-opening reaction. This strategy can also be applied for naphthopyran derivatives and is useful for the development of fast photoresponsive photochromic lenses and fast photoswitching applications such as dynamic holographic materials and molecular actuators.

We propose combined solder-TSVs and microbumpsfor cost reduction of 3-D integration. Conventional via-last TSV technology requires microbump formation. We eliminate the microbump process for low cost 3-D process. In our process, TSVs and microbumps are formed simultaneously with solder. We demonstrate this process by fabricating daisy chain chips with 20-µm-pitch TSVs. The TSVs are 7-µm diameter, 20-µm deep, and a total number of 39,000 per chip. Its electrical characteristics are 1.05 ± 0.64 Ω/TSV (3σ, n=20).

Although it occurs worldwide, hepatitis E virus (HEV) infection in developed countries is generally foodborne. HEV infection is subclinical in most individuals. Although fulminant liver failure may occur, progression to chronic hepatitis is rare. This study describes a 41-year-old man with liver cirrhosis caused by non-alcoholic steatohepatitis and hepatocellular carcinoma within the Milan criteria. His liver function was classified as Child-Pugh grade C. Living donor liver transplantation (LDLT) was performed, and he was discharged from the hospital on postoperative day (POD) 22. However, his alanine aminotransferase concentration began to increase on POD 60 and HEV infection was detected on POD 81. Retrospective assessments of stored blood samples showed that this patient became positive for HEV RNA on POD 3. The liver donor was negative for anti-HEV antibodies and HEV RNA. However, the platelet concentrate transfused into the liver recipient the day after LDLT was positive for HEV RNA. The patient remained positive for HEV infection for 10 months. Treatment with 800 mg/day ribavirin for 20 weeks reduced HEV RNA to an undetectable level. In conclusion, this report describes a patient infected with HEV through a blood transfusion after LDLT, who progressed to chronic hepatitis probably due to his immunosuppressed state and was treated well with ribavirin therapy.

We report a case of advanced gastric cancer that responded completely to S-1 neoadjuvant chemotherapy. An 80-year-old female complained of nausea. A gastroscopy and CT scan revealed advanced gastric cancer with lymph node metastasis (cT4b [diaphragm], cN3a, cM0, cStage III C). S-1 (100 mg/body/day) was administered orally for 14 consecutive days followed by a 7-day interval. After 2 courses of monotherapy, we conducted a total gastrectomy with D2 lymph node dissection. Histological findings revealed that there were no cancer cells in either the primary tumor or the lymph nodes. This meant that the resected lesions were pathologic Grade 3. Our report suggests that S-1 may have a potent therapeutic effect as a neoadjuvant chemotherapy for advanced gastric cancer especially in older patients.

Photofunctional compounds have emerged as critically important materials for both fundamental studies and industrial applications. Control of the thermal decoloration speed to within several seconds while sustaining satisfactory photochromic colorability is an important challenge for the application of such materials to photochromic lenses and smart windows. Photochromic naphthopyran derivatives are utilized for photochromic lenses because of their high durability and easily controllable colorability. However, the residual color imparted by the long-lived transient species upon ceasing light irradiation remains a hindrance to practical applications. In this study, a strategy is demonstrated for on-demand control of the thermal decoloration speed of the transient colored species of naphthopyran derivatives. The increase in the ring-size of the alkylenedioxy moiety on the naphthopyrans accelerates the thermal back-reaction independently of the maximum-absorption wavelength of the colored isomer, leading to the realization of yellow-, red-, and blue-photochromic naphthopyrans with similar thermal fading speeds. This novel molecular design provides a strategy for the future development of advanced photoresponsive materials.

Background and aims The feature of blood glucose dynamics in patients with chronic liver disease (CLD) is marked blood glucose fluctuations. However, the detail of blood glucose dynamics is not well known. The aim of the present study was to evaluate glycemic fluctuations by continuous glucose monitoring (CGM). Materials and methods A total of 105 CLD patients with type 2 diabetes mellitus (T2DM) were enrolled in this study. Various parameters of glycemic variability were evaluated. The association of these parameters with liver functional reserve was examined. The parameters were also evaluated according to glycated hemoglobin A1c (HbA1c) levels. Results and discussion Data of all patients showed that mean blood glucose (MBG) levels and the difference between highest and lowest blood glucose (ΔBG) increased significantly with worsening of liver functional reserve (P < 0.001 and P = 0.005, respectively). Although many of the cases were being treated for diabetes, postprandial hyperglycemia was seen in 92% of patients. Nocturnal hypoglycemia was seen in 22% of patients. In non-anemic patients with HbA1c levels of < 7.0%, the percentage of patients with mean amplitude of glycemic excursion (MAGE) of ≥ 77.4 mg/dL and that of MBG levels of > 145 mg/dL were higher in liver cirrhosis (LC) patients than in chronic hepatitis (CH) patients. In them, homeostasis model assessment for insulin resistance (HOMA-IR) of > 2.5 and LC were significantly associated with the increase in MAGE. LC was also significantly associated with increased MBG levels. Conclusion The CGM systems were useful in finding hidden abnormalities of blood glucose fluctuations in CLD patients with T2DM, especially in non-anemic CLD patients with HbA1c levels of < 7.0%.

The anti-hepatitis E virus (HEV) immunoglobulin (Ig) M antibody response is generally regarded as a useful marker for diagnosing primary infection. However, in some cases, this antibody is not detected during the acute phase of infection. An 81-year-old man with stable membranous nephropathy who presented with asymptomatic acute liver dysfunction came to our hospital. HEV RNA of genotype 3 was detected in his serum, and he was diagnosed with acute hepatitis E. According to an enzyme-linked immunosorbent assay, high-level positivity for anti-HEV IgG and IgA antibodies was observed, but the assay was negative for IgM antibody throughout the clinical course of infection. The patient was not immunosuppressed. We further investigated the presence of IgM antibody using two other polyclonal antibodies against human IgM as secondary antibodies and another recombinant ORF2 protein of genotype 3 as an immobilized antigen. IgM was weakly detected in the serum during the acute phase only by the test with the antigen of genotype 3. Multi-genotype antigens can detect a slight IgM antibody response; however, anti-HEV IgA is more useful in diagnosing primary HEV infection, particularly in cases with a low IgM antibody response.

Results: Infrequent intrahepatic total HBVDNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV-specific T cell responses were similar between “anti-HBc alone” individuals and HBV resolvers (Figure 1). Circulating HBV-memory B cell responses were detected in all “anti-HBc alone” individuals, consistent with an HBsAgspecific memory pool. After one HBV vaccine dose, increased antiHBs antibody levels were observed, accompanied by an expansion of HBsAg-specific memory B cells (P =0.0226) (Figure 2). Conclusions: “Anti-HBc alone” individuals showed HBV-specific T cell and memory B cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection.

Objective: Chemoresistance associating CD44-positive cancer stem cells may presents a crucial problem in treating pancreatic cancer. Among the various isoforms of CD44, valiant 9 (CD44v9) have revealed especially implicated in tumor growth, invasion, and metastasis. Interaction of CD44v9 with the cystine transporter subunit xCT provide the ability of cancer cells to defend themselves against reactive oxygen species, mediating chemoresistance. Sulfasalazine (SSZ), which is a specific inhibitor of xCT-mediated cystine transport,could be a new therapeutic weapon fight against cancer stem cells. However, the extent of this remains unclear, suggesting the need for a histological evaluation of CD44v9 expression in clinical pancreatic cancer and the anti-tumor effect on pancreatic cancer of SSZ. Therefore, In this study, we analyze the expression of CD44v9 in a pancreatic cancer surgical specimen and examine the anti-tumor effect of SSZ and altered expression of CD44v9 by administration of GEM (GEM) with tumorgrafts. Methods: Experiment 1: A total of 70 clinical primary ductal adenocarcinoma of the pancreas were applied for immunohistochemical evaluation of CD44v9 expression. Randomly picked up 10 fields for each cases were analyzed for intensity of membrane staining and the percentage of stained cancer cells per field, followed by summing the scores using our own scoring system. Experiment 2: Three lines of created tumorgrafts from clinical pancreatic cancer. We administered GEM to the tumorgrafts and also scored the clinical specimens’ immunohistochemical evaluation by CD44v9. In addition, using one line, we divided the mice into two groups, a GEM group and a GEM + SSZ group, and repeated as above to determine the effect on GEM of SSZ. Results: Experiment 1: There was no correlation for prognosis. It was found that CD44v9-positive cells are present in high numbers. Experiment 2: In 1 line, which increased CD44v9-positive cell after GEM treatment,the GEM group showed tumor regression of 85% and the GEM+SSZ group showed tumor regression of 90%. Discussion: Result in Experiment 1 is reasonable, therefore, to consider the significance of the treatment target CD44vv9 as likely to be very high. Further, there was one line of tumorgrafts used, but not all percentages of CD44v9-positive cells increased markedly by GEM administration. This suggests the possibility that CD44v9 may be regarded as a marker of GEM resistance. In addition, a small but insignificant tumor regression effect on GEM of SSZ was found. We present evidence that for pancreatic cancer as well as other carcinomas, CD44v9-positive cells may be regarded as one of the markers of chemo resistance. Furthermore, since SSZ shows the antitumor effects of plus for GEM, we suggest that SSZ treatment is a possibility for a new treatment option. Citation Format: Tomohiro Kurokawa, Tatsuya Oda, Yuki Inagaki, Ryoichi Miyamoto, Yoshimasa Akashi, Nobuhiro Ohkohchi. CD44v9 expression in clinical pancreatic cancer and the gemcitabine plus sulfasalazine therapy against chemoresistant pancreatic cancer murine model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 195. doi:10.1158/1538-7445.AM2014-195

Objective: Histopathological characteristics of pancreatic carcinoma are the presence of abundant stroma that prevent mAb diffusion and consequently hampers mAb from direct attacking cancer cells. With a strong conviction that additional tool that improve mAb penetration and diffusion in dense fibroblastic solid cancer should indispensable for better therapeutic effect, we focused and employed the simple but strongest modalities, heat. Heat might increase tumor blood flow and tumor vessel permeability, leading enhanced accumulation of anticancer mAb. In this study, we aimed the increased accumulation of mAb in mouse pancreatic subcutaneous models and also boosted antitumor effects by applying moderate heat. Methods: Heat generation was completed by hot bathtub method for subcutaneous tumor in nude mice leg. Three human pancreatic cell of different stromal amount were employed (abundant: Capan-1, moderate: BxPC-3, and scant: MIAPaCa-2). At the timing of each tumors growth up to 70mm3, Cetuximab (1 mg/kg) was systematically administrated via caudal vein, subsequently applying heat to tumors for 30 min at three different temperatures of 25°C (control temperature), 37°C (intraabdominal organs), or 41°C (hyperthermia) (n = 5 each). The amount of accumulated Cetuximab were quantified by the fluorescent intensity of Alexa 488 against anti-human IgG at 24 hr, followed by figuring up the intensity of one cancer cell by dividing the total intensity value by the number of a cancer cell nuclei stained with DAPI. Enhanced antitumor effects, among irradiating various heat doses, were evaluated by the tumor volume over time. Results: In Capan-1, the fluorescent intensity per a cancer cell at 25°C, 37°C, 41°C were 675, 1130, 2332 respectively. Similarly, those in BxPC-3 were 673, 1347, 1573, and in MIAPaCa-2 were 1632, 1921, 1949, respectively. In Capan-1 and BxPC-3, the mean tumor growth on day 40 were significantly inhibited at 37°C group (934, 189 mm3), and 41°C group (491, 121 mm3) in compared with 25°C group (1385, 470 mm3) respectively. In MIAPaCa-2, however, that on day 50 was not inhibited at 37 degrees group (109 mm3), and 41 group (151 mm3) as compared with 25 group (123 mm3). Discussion: We demonstrated that hyperthermia actually contributed to measurable add-on antitumor effect for two among three pancreatic cancer models. Intending to provide more add-on effect, we are now evaluating the combined effects of hyperthermia plus applying a cyclic tumor-penetrating peptide (iRGD), which improved anticancer mAb penetration to cancer cells by binding to integrin αv/β3 or β5 and to neuropillin-1 on cancer cells. We suggested that this novel combined strategy would remarkably contribute to the enhanced accumulation of anticancer mAb in tumors and to the enhanced antitumor effects. Citation Format: Ryoichi Miyamoto, Tatsuya Oda, Shinji Hashimoto, Yoshimasa Akashi, Tomohiro Kurokawa, Yuki Inagaki, Nobuhiro Ohkohchi. Hyperthermia improves Cetuximab accumulation in pancreatic cancer mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2014-2663