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Background: The aim of the study was to evaluate the potential advantages of the ultrasonic scalpel compared with the conventional technique in gastric cancer surgery.Methods: Patients with resectable adenocarcinoma of the stomach were randomly assigned to ultrasonic scalpel or conventional technique. We used the HARMONIC FOCUS (Ethicon Endo-Surgery, Inc.) as ultrasonic scalpel.Results: Between February 2010 and December 2010, 60 patients with resectable gastric cancer were enrolled into the study. Operative time was significantly shorter with the ultrasonic arm than with the conventional arm (median 238.5 vs. 300.5 min; P = 0.0004). Blood loss was also significantly lower in the ultrasonic arm than in the conventional arm (median 351.0 vs. 569.5 ml; P = 0.016). Clavien-Dindo grades of postoperative complications were similar in the two groups. From a questionnaire survey of operators, the ultrasonic scalpel significantly reduced the stress of lymph node dissection (3.67 vs. 2.87; P = 0.0006). However, in assisting surgeons, the contributions to surgery, study, and technical improvement of the ultrasonic group were lower than in the conventional group.Conclusions: This study shows that the ultrasonic scalpel is a reliable and safe tool for open gastric cancer surgery. [ABSTRACT FROM AUTHOR]

Postoperative delirium (POD) is one of the most common complications of surgery. This study aimed to identify the risk factors for POD in patients undergoing cholecystectomy for acute cholecystitis. This retrospective study included 77 patients who underwent cholecystectomy for acute cholecystitis between January 2015, and December 2020. Multiple logistic regression analysis was used to identify the factors associated with the development of delirium as the primary endpoint. Patients were divided into POD (n = 18) and non-POD (n = 59) groups and their demographic features and clinical results were compared. A significant model associated with delirium onset was predicted (Nagelkerke's R 2  = 0.382), and the significantly correlated factors were C-reactive protein/albumin ratio (CAR), Subjective Global Assessment (SGA) score, and history of psychiatric disease. The predictive value of CAR for POD was evaluated using ROC analysis; the area under the curve of CAR was 0.731, with a cutoff value of 3.69. CAR, SGA score, and a history of psychiatric disease were identified as factors associated with the development of POD in patients with acute cholecystitis. In particular, the new preoperative evaluation of CAR may be beneficial as an assessment measure of the risk factor for the development of POD., (© 2024. The Author(s).)

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1β (IL-1β) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1β-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.

Pancreatic pseudocysts are surrounded by a non-epithelialized wall confined to the pancreas and localized to the pancreatic tissue or adjacent pancreatic cavity. In contrast, pancreatic cystic tumors occur less frequently than solid lesions and are often detected incidentally on imaging. Regarding the qualitative diagnosis of pancreatic pseudocysts, it is important to differentiate them from neoplastic cysts. We report the case of a 74-year-old woman with a giant hemorrhagic pancreatic pseudocyst and a suspected cystic pancreatic tumor, wherein distal pancreatectomy and splenectomy with lymph node dissection were performed. The patient was discharged 11 days postsurgery, with a good postoperative course. There are no reports of giant pancreatic pseudocysts larger than 10 cm with hematoma contents. The presumptive diagnosis of pseudocysts based on imaging alone may be difficult. Surgical resection is considered when it is difficult to distinguish a giant pancreatic pseudocyst from a cystic neoplasm., Competing Interests: The authors have no conflict of interest to declare., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Baicalein is the main active flavonoid in Scutellariae Radix and is included in shosaikoto, a Kampo formula used for treating hepatitis and jaundice. However, little is known about its hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI), a severe clinical condition directly caused by interventional procedures. We aimed to investigate the hepatoprotective effects of baicalein against HIRI and partial hepatectomy (HIRI + PH) and its potential underlying mechanisms., Methods and Results: Male Sprague-Dawley rats received either baicalein (5 mg/kg) or saline intraperitoneally and underwent a 70% hepatectomy 15 min after hepatic ischemia. After reperfusion, liver and blood samples were collected. Survival was monitored 30 min after hepatic ischemia and hepatectomy. In interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes, the influence of baicalein on inflammatory mediator production and the associated signaling pathway was analyzed. Baicalein suppressed apoptosis and neutrophil infiltration, which are the features of HIRI + PH treatment-induced histological injury. Baicalein also reduced the mRNA expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α). In addition, HIRI + PH treatment induced liver enzyme deviations in the serum and hypertrophy of the remnant liver, which were suppressed by baicalein. In the lethal HIRI + PH treatment group, baicalein significantly reduced mortality. In IL-1β-treated rat hepatocytes, baicalein suppressed TNF-α and chemokine mRNA expression as well as the activation of nuclear factor-kappa B (NF-κB) and Akt., Conclusions: Baicalein treatment attenuates HIRI + PH-induced liver injury and may promote survival. This potential hepatoprotection may be partly related to suppressing inflammatory gene induction through the inhibition of NF-κB activity and Akt signaling in hepatocytes., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

A standardized extract of cultured Lentinula edodes mycelia (ECLM, AHCC ® ) has been shown to have beneficial effects on organ metabolism. ECLM has been indicated to have liver protective properties by suppressing inflammatory responses. The pathogenesis of hepatic ischemia-reperfusion injury is thought to involve the induction of inflammatory mediators. However, whether ECLM affects inflammatory mediators caused by warm hepatic ischemia-reperfusion injury and partial hepatectomy (HIRI+PH) has not been clarified. In this study, we evaluated the protective effects of ECLM against liver damage caused by HIRI+PH. Rats were fed a normal diet (HIRI+PH) or a normal diet with 2% ECLM (HIRI+PH and ECLM) for ten days, then the liver and duodenal ligament were clamped and subjected to 15 min of hepatic ischemia. After 70% hepatectomy, the inflow occlusion was released, and liver and blood samples were collected at 3, 6, and 24 h. The effect of ECLM on mortality induced by 30 min of ischemia and hepatectomy was evaluated. The results showed that ECLM attenuated pathological liver damage, including apoptosis, in the rats treated with HIRI+PH, and decreased serum aminotransferase activity; ECLM decreased mRNA levels of the inflammation-related genes inducible nitric oxide synthase and C-X-C motif chemokine ligand 1, and increased mRNA levels of interleukin 10, an anti-inflammatory cytokine; ECLM increased hepatocyte growth factor mRNA levels and Ki-67 labeled nuclei in the liver at 24 h; ECLM significantly reduced HIRI+PH-induced mortality. In conclusion, ECLM may prevent HIRI+PH-induced liver injury in part by suppressing various inflammatory responses and promoting liver regeneration.

Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1β-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes.

Cleansing foam is a common multicomponent polymeric functional material. It contains ingredients in innumerable combinations, which makes formulation optimization challenging. In this study, we used artificial intelligence (AI) with machine learning to develop a cleansing capability prediction system that considers the effects of self-assembled structures and chemical properties of ingredients. Over 500 cleansing foam samples were prepared and tested. Molecular descriptors and Hansen solubility index were used to estimate the cleansing capabilities of each formulation set. We used five machine-learning models to predict the cleansing capability. In addition, we employed an in silico formulation by generating virtual formulations and predicting their cleansing capabilities using an established AI model. The achieved accuracy was R 2 = 0.770. Our observations revealed that mixtures of cosmetic ingredients exhibit complex interactions, resulting in nonlinear behavior, which adds to the complexity of predicting cleansing performance. Nevertheless, accurate chemical property descriptors, along with the aid of in silico formulations, enabled the identification of potential ingredients. We anticipate that our system will efficiently predict the chemical properties of polymer-containing blends.

The roots of Polygonum multiflorum Thunberg (Polygonaceae) are used as a crude drug Kashu that is considered to improve blood deficiency based on a Kampo concept. Kashu has been included in Kampo formulas, such as Tokiinshi, which is used to treat eczema and dermatitis with itchiness by inhibiting inflammation and facilitating blood circulation in the skin. However, the effects of P. multiflorum roots on erythropoiesis are unclear. Previously, we isolated six phenolic constituents from an ethyl acetate (EtOAc)-soluble fraction of P. multiflorum root extract and identified them as (E)-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside [(E)-THSG], emodin, emodin-8-O-β-D-glucopyranoside, physcion, physcion-8-O-β-D-glucopyranoside, and catechin. To examine whether P. multiflorum roots facilitate erythropoiesis, the EtOAc-soluble fraction was orally administered to healthy ICR mice. When compared with mice fed a standard diet alone (Controls), the mice fed a diet including the EtOAc-soluble fraction exhibited significantly higher serum erythropoietin (Epo) levels. The renal Epo mRNA levels in EtOAc-soluble fraction-administered mice were significantly higher than those in the control mice. Then, we administered roxadustat, which is a drug to treat the patient suffering with renal anemia by specifically inhibiting hypoxia-inducible factor prolyl hydroxylases. Roxadustat slightly increased renal Epo mRNA levels in healthy mice. Administration of (E)-THSG, a major constituent, significantly increased serum Epo levels. It is likely that (E)-THSG may facilitate the process to convert inactive renal Epo-producing cells to active Epo-producing cells. Collectively, it is implied that (E)-THSG in the EtOAc-soluble fraction of P. multiflorum roots may primarily improve blood deficiency of Kampo concept by promoting erythropoiesis., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Abstract: Sepsis after a major hepatectomy is a critical problem. In septic shock, the inflammatory mediator, nitric oxide (NO), is overproduced in hepatocytes and macrophages. The natural antisense (AS) transcripts, non-coding RNAs, are transcribed from a gene that encodes inducible nitric oxide synthase (iNOS). iNOS AS transcripts interact with and stabilize iNOS mRNAs. A single-stranded "sense oligonucleotide" (designated as SO1) corresponding to the iNOS mRNA sequence inhibits mRNA-AS transcript interactions and reduces iNOS mRNA levels in rat hepatocytes. In contrast, recombinant human soluble thrombomodulin (rTM) treats disseminated intravascular coagulopathy by suppressing coagulation, inflammation, and apoptosis. In this study, the combination therapy of SO1 and a low dose of rTM was evaluated for hepatoprotection in a rat septic shock model after partial hepatectomy. Rats underwent 70% hepatectomy, followed by intravenous (i.v.) injection of lipopolysaccharide (LPS) after 48 h. SO1 was injected (i.v.) simultaneously with LPS, whereas rTM was injected (i.v.) 1 h before LPS injection. Similarly to our previous report, SO1 increased survival after LPS injection. When rTM, which has different mechanisms of action, was combined with SO1, it did not interfere with the effect of SO1 and showed a significant increase in survival compared with LPS alone treatment. In serum, the combined treatment decreased NO levels. In the liver, the combined treatment inhibited iNOS mRNA and protein expression. A decreased iNOS AS transcript expression by the combined treatment was also observed. The combined treatment decreased mRNA expression of the inflammatory and pro-apoptotic genes while increasing that of the anti-apoptotic gene. Furthermore, the combined treatment reduced the number of myeloperoxidase-positive cells. These results suggested that the combination of SO1 and rTM has therapeutic potential for sepsis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by the Shock Society.)

The roots of Peucedanum praeruptorum Dunn and Angelica decursiva Franchet et Savatier are designated Zenko , which is a crude drug defined by the Japanese Pharmacopoeia. This crude drug is used as an antitussive and an expectorant and is included in the Kampo formula Jinsoin , which improves cough, fever, and headache. Although the anti-inflammatory effects of this crude drug have been determined, the constituents responsible for this effect remain unknown. To investigate biologically active compounds, rat hepatocytes were used, which produce proinflammatory mediator nitric oxide (NO) in response to proinflammatory cytokine interleukin 1β (IL-1β). A methanol extract of P. praeruptorum roots, which suppressed IL-1β-induced NO production, was fractionated into three crude fractions (ethyl acetate (EtOAc)-soluble, n -butanol-soluble, and water-soluble fractions) based on hydrophobicity. The EtOAc-soluble fraction markedly inhibited NO production. After this fraction was purified, three biologically active compounds were identified as praeruptorins A, B, and E, the contents of which were high. A comparison of their activities indicated that praeruptorin B exhibited the highest potency to inhibit NO production by decreasing inducible NO synthase expression and suppressed the expression of mRNAs encoding proinflammatory cytokines. Collectively, the three praeruptorins may primarily contribute to the anti-inflammatory effects of P. praeruptorum roots., Competing Interests: Hiromu Ozaki and Airi Fujii performed the experiments as graduate students of the Graduate School of Life Sciences, Ritsumeikan University. Kaito Nakamura and Takanori Maesako performed this study as undergraduate students of the College of Life Sciences, Ritsumeikan University. The authors declare no conflicts of interest.

Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric oxide synthase (iNOS) as an early inflammatory response to hepatic ischaemia reperfusion injury (HIRI) in mouse- and rat-liver models. A systematic search of studies was performed within three databases. Studies meeting the inclusion criteria were subjected to qualitative and quantitative synthesis of results. We performed a meta-analysis of studies grouped by different HIRI models and ischaemia times. Additionally, we investigated a possible correlation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) regulation with iNOS expression. Of 124 included studies, 49 were eligible for the meta-analysis, revealing that iNOS was upregulated in almost all HIRIs. We were able to show an increase of iNOS regardless of ischemia or reperfusion time. Additionally, we found no direct associations of eNOS or NO with iNOS. A sex gap of primarily male experimental animals used was observed, leading to a higher risk of outcomes not being translatable to humans of all sexes.

Background: Omeprazole (OMZ) is a proton pump inhibitor that is used to reduce gastric acid secretion, but little is known about its possible liver protective effects. This study investigated whether OMZ has beneficial effects in rat septic models of LPS-induced liver injury after D-galactosamine (GalN) treatment and 70% hepatectomy (PH), and to determine the mechanisms of OMZ in an in vitro model of liver injury., Methods: In the in vivo models, the effects of OMZ were examined 1 h before treatments in both models on survival, nuclear factor (NF)-κB activation, histopathological analysis, and proinflammatory mediator expression in the liver and serum. In the in vitro model, primary cultured rat hepatocytes were treated with IL-1β in the presence or absence of OMZ. The influence of OMZ on nitric oxide (NO) product and inducible NO synthase (iNOS) induction and on the associated signaling pathway was analyzed., Results: OMZ increased survival and decreased tumor necrosis factor-alpha, iNOS, cytokine-induced neutrophil chemoattractant 1, IL-6, and IL-1β mRNA expression, and increased IL-10 mRNA expression in the livers of both GaIN/LPS- and PH/LPS-treated rats. Necrosis and apoptosis were inhibited by OMZ in GaIN/LPS rats, but OMZ had no effects on necrosis in PH/LPS rats. OMZ inhibited iNOS induction partially through suppression of NF-κB signaling in hepatocytes., Conclusions: OMZ inhibited the induction of several inflammatory mediators, resulting in the prevention of LPS-induced liver injury after GalN liver failure and PH, although OMZ showed different doses and mechanisms in the two models., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

In the present era of organ transplantation with critical organ shortage, various strategies are employed to expand the pool of available allografts for kidney transplantation (KT). Even though, the use of allografts from extended criteria donors (ECD) could partially ease the shortage of organ donors, ECD organs carry a potentially higher risk for inferior outcomes and postoperative complications. Dynamic organ preservation techniques, modulation of ischemia-reperfusion and preservation injury, and allograft therapies are in the spotlight of scientific interest in an effort to improve allograft utilization and patient outcomes in KT. Preclinical animal experiments are playing an essential role in translational research, especially in the medical device and drug development. The major advantage of the porcine orthotopic auto-transplantation model over ex vivo or small animal studies lies within the surgical-anatomical and physiological similarities to the clinical setting. This allows the investigation of new therapeutic methods and techniques and ensures a facilitated clinical translation of the findings. This protocol provides a comprehensive and problem-oriented description of the porcine orthotopic kidney auto-transplantation model, using a preservation time of 24 hours and telemetry monitoring. The combination of sophisticated surgical techniques with highly standardized and state-of-the-art methods of anesthesia, animal housing, perioperative follow up, and monitoring ensure the reproducibility and success of this model.

Background: Few chemotherapies are available for neuroendocrine tumors, especially for highly malignant neuroendocrine cancers. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 selectively replicates in tumor cells and shows cytotoxicity against tumor cells without damaging surrounding normal tissues. We examined the antitumor effect of T-01 to explore novel treatments for patients with neuroendocrine tumors., Methods: The cytotoxicity of T-01 was tested in two human and one murine neuroendocrine tumor cell lines in vitro . Mouse models with subcutaneously implanted human neuroendocrine tumor QGP1 cells were used to investigate T-01 efficacy in vivo ., Results: T-01 showed cytotoxicity against the three cell lines in vitro . In xenograft models, the growth of tumors derived from QGP1 cells was inhibited by T-01 compared with control group. Although weight loss of mice was observed with tumor growth in the control group, it was suppressed by T-01 administration. The antitumor effects of T-01 were dependent on virus concentration and frequency of administration., Conclusions: T-01 effectively inhibits tumor cell proliferation in a poorly differentiated NEC mouse model. These results suggest that the third-generation oncolytic HSV-1 may serve as a novel treatment for patients with neuroendocrine tumors., Competing Interests: CONFLICTS OF INTEREST All authors hereby declare that there is no potential or actual personal, financial, or political interest related to this study.

Background: Ischemia-reperfusion (IR) injury of the small intestine is a serious problem in abdominal aortic aneurysm surgery or small intestine transplantation. Active hexose correlated compound (AHCC) is a popular anti-inflammatory drug in complementary and alternative medicine. The aim of this study was to examine whether pretreatment with AHCC reduces intestinal IR injury., Methods: Rats were given a normal diet (IR group) or normal diet supplemented with 2% AHCC (IR + AHCC group) ad libitum for 10 d. After 1 d of fasting, the superior mesenteric artery was occluded by clipping for 45 min. Intestinal and blood samples were collected for 1-6 h after reperfusion. The messenger RNA (mRNA) and protein levels of inflammatory factors were analyzed., Results: The IR + AHCC group had reduced mucosal abrasion and significantly increased mucosal thickness of the intestinal tissues 6 h after reperfusion, compared with the IR group. AHCC decreased mRNA expression of inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant 1 and interleukin 6 in the mucosa of the small intestine. AHCC also decreased expression of iNOS protein. Serum levels of cytokine-induced neutrophil chemoattractant 1 and tumor necrosis factor α were decreased in the IR + AHCC group compared with the IR group. Electrophoretic mobility shift assay of mucosal nuclear extracts revealed that AHCC inhibited the activation of nuclear factor kappa B. AHCC also inhibited the expression of iNOS antisense transcript, which stabilizes iNOS mRNA., Conclusions: Our findings suggest that AHCC reduces expression of inflammatory mediators, in part, by inhibiting nuclear factor kappa B activation. AHCC may have anti-inflammatory effect in patients with intestinal IR injury., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/aims: The proton pump inhibitor lansoprazole (LPZ) is clinically used to reduce gastric acid secretion, but little is known about its possible hepatoprotective effects. This study aimed to investigate the hepatoprotective effects of LPZ and its potential mechanisms using in vitro and in vivo rat models of liver injury., Methods: For the in vitro model of liver injury, primary cultured rat hepatocytes were treated with interleukin-1β in the presence or absence of LPZ. The influence of LPZ on inducible nitric oxide synthase (iNOS) induction and nitric oxide (NO) production and on the associated signaling pathways was analyzed. For the in vivo model, rats were treated with D-galactosamine (GalN) and lipopolysaccharide (LPS). The effects of LPZ on survival and proinflammatory mediator expression (including iNOS and tumor necrosis factor-α) in these rats were examined., Results: LPZ inhibited iNOS induction partially through suppression of the nuclear factor-kappa B signaling pathway in hepatocytes, thereby reducing potential liver injury from excessive NO levels. Additionally, LPZ increased survival by 50% and decreased iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 mRNA expression in the livers of GalN/LPS-treated rats. LPZ also inhibited nuclear factor-kappa B activation by GalN/LPS., Conclusions: LPZ inhibits the induction of several inflammatory mediators (including cytokines, chemokines, and NO) partially through suppression of nuclear factor-kappa B, resulting in the prevention of fulminant liver failure. The therapeutic potential of LPZ for liver injuries warrants further investigation.

Primary retroperitoneal serous adenocarcinoma (PRSA) is a rare malignancy of which only seven cases have been reported in the literature. The clinical features and outcomes of PRSA are not well understood. We herein report a case of PRSA with liver metastasis in a 74-year-old woman who was treated with surgical excision. The tumor cells were positive for estrogen receptor, Wilms tumor 1, PAX8, p53, and cytokeratin AE1/AE3. The final diagnosis was PRSA and liver metastasis. The pathological features of PRSA resemble those of ovarian serous carcinoma, which suggests that a combination of surgical excision with adjuvant chemotherapy may be the best option.

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited, as was the case for contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Natural antisense transcripts (asRNAs) that do not encode proteins are transcribed from rat, mouse, and human genes, encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide (NO). In septic shock, NO is excessively produced in hepatocytes and macrophages. The iNOS asRNA interacts with and stabilizes iNOS mRNA. We found that single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence reduced iNOS mRNA levels by interfering with the mRNA-asRNA interactions in rat hepatocytes. The iNOS sense oligonucleotides that were substituted with phosphorothioate bonds and locked nucleic acids efficiently decreased the levels of iNOS mRNA and iNOS protein. In this study, the gene expression patterns in the livers of two endotoxemia model rats with acute liver failure were compared. Next, we optimized the sequence and modification of the iNOS sense oligonucleotides in interleukin 1β-treated rat hepatocytes. When a sense oligonucleotide was simultaneously administered with d-galactosamine and bacterial lipopolysaccharide (LPS) to rats, their survival rate significantly increased compared to the rats administered d-galactosamine and LPS alone. In the livers of the sense oligonucleotide-administered rats, apoptosis in the hepatocytes markedly decreased. These results suggest that natural antisense transcript-targeted regulation technology using iNOS sense oligonucleotides may be used to treat human inflammatory diseases, such as sepsis and septic shock., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Constitutional indocyanine green (ICG) excretory defect is extremely rare. The indocyanine green retention rate at15 min (ICGR15) is important for estimating hepatic functional reserve and selection of the appropriate surgical procedure before hepatectomy is performed. Because of the rarity of constitutional ICG excretory defect, its clinical features are not well understood. We report here evaluation and treatment of a patient with such a disorder., Presentation of Case: An 83-year-old man was admitted to hospital with the diagnosis of resectable hepatocellular carcinoma. The preoperative indocyanine green (ICG) retention rate at 15 min was greater than 76.2%. Despite this finding, Child-Pugh classification and 99m Tc-galactosyl human serum albumin (GSA) liver scintigraphy didn't show any abnormal findings, and there was no background disease. Therefore, we diagnosed him with constitutional ICG excretory defect and performed partial hepatectomy. For patients requiring hepatectomy with this disease the indications and procedure for surgery should be considered. These should be based on liver function tests such as GSA liver scintigraphy., Conclusions: Constitutional ICG excretory defect is an extremely rare disorder. At present, the indications for surgery for this condition should be comprehensively considered. Findings of liver function tests, such as a general liver function test and GSA liver scintigraphy, are important for treating this disorder., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Primary hepatic neuroendocrine carcinomas are extremely rare. Because of the rarity of PHNEC, its clinical features and treatment outcomes are not well understood. A proper diagnosis and the correct therapeutic approach therefore remain clinically challenging., Case Presentation: A 67-year-old man was admitted to our department because of a liver tumor. Computed tomography revealed a single liver tumor 50 mm in diameter and located in the S3 region. Biopsy and imaging findings resulted in a diagnosis of primary hepatic neuroendocrine carcinoma. Left lateral segmentectomy was performed. Immunohistochemically, the tumor cells were positive for synaptophysin, chromogranin A, and CD56. Ki-67 was positive in > 90% of the tumor cells. The final diagnosis was primary hepatic neuroendocrine carcinoma. The patient suffered two episodes of lymph node recurrence. Nonetheless, the tumor was excised to prolong survival. Thus, after lymphadenectomy, he received adjuvant chemotherapy for 6 months. Two years after surgery, the patient remains alive and in good general condition., Conclusions: In most cases, primary hepatic neuroendocrine carcinoma, while extremely rare, has a poor prognosis. At present, surgical resection is a priority for curative treatment, but in patients with recurrence, combined therapies are recommended.

Background: Anticancer agents and operating procedures have been developed for hepatocellular carcinoma (HCC) patients, but their prognosis remains poor. It is necessary to develop novel diagnostic and therapeutic strategies for HCC to improve its prognosis. Lactosome is a core-shell-type polymeric micelle, and enclosing labeling or anticancer agents into this micelle enables drug delivery. In this study, we investigated the diagnostic and therapeutic efficacies of indocyanine green (ICG)-loaded lactosome for near-infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) for HCC., Methods: The human HCC cell line HuH-7 was treated with ICG or ICG-lactosome, followed by PDT, and the cell viabilities were measured (in vitro PDT efficiency). For NIF imaging, HuH-7 cells were subcutaneously transplanted into BALB/c nude mice, followed by intravenous administration of ICG or ICG-lactosome. The transplanted animals were treated with PDT, and the antineoplastic effects were analyzed (in vivo PDT efficiency)., Results: PDT had toxic effects on HuH-7 cells treated with ICG-lactosome, but not ICG alone. NIF imaging revealed that the fluorescence of tumor areas in ICG-lactosome-treated animals was higher than that of contralateral regions at 24 h after injection and thereafter. PDT exerted immediate and continuous phototoxic effects in the transplanted mice treated with ICG-lactosome., Conclusions: Our results demonstrate that ICG-lactosome accumulated in xenograft tumors, and that PDT had antineoplastic effects on these malignant implants. NIF imaging and PDT with ICG-lactosome could be useful diagnostic and/or therapeutic strategies for HCC.

Amino acids can exert protective effects on the liver either when administered as a medication or following an operation. In this study, we examined the protective effects of amino acids on the liver using in vitro and in vivo models by studying their influence on the induction of inducible nitric oxide synthase (iNOS) and nitric oxide production as a liver injury marker in cultured hepatocytes and liver-protective effects in d-galactosamine and lipopolysaccharide (GalN/LPS)-treated rats, respectively. Primary cultured rat hepatocytes were treated with interleukin (IL)-1β in the presence or absence of Elental® amino acid component (EleAA; 17 amino acids). Rats were pretreated with either EleAA or a diet containing selected amino acids followed by GalN/LPS injection. Survival rate and mRNA expression were analyzed. EleAA inhibited iNOS induction through reduction of mRNA synthesis and stability in cultured hepatocytes, indicating prevention of liver injury, but did not show a liver-protective effect in GalN/LPS rats. Among EleAA, Lys, Trp, His, and Arg (4AA) markedly decreased nitric oxide production and inhibited nuclear factor-κB (NF-κB) activation. In GalN/LPS rats, 4AA (3% of each amino acid in diet) increased survival rate by 50% and decreased mRNA expression of iNOS, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 in the liver. 4AA reduced NF-κB activation induced by GalN/LPS. 4AA inhibited the expression of inflammatory mediators, in part through inhibition of NF-κB activation in cultured hepatocytes and GalN/LPS-treated rats. The results suggest that EleAA has therapeutic potential for organ injuries including liver., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: We conducted a phase I study of sorafenib and intermittent hepatic arterial infusion chemotherapy using cisplatin for unresectable hepatocellular carcinoma., Methods: Sorafenib was administered continuously, whereas cisplatin was administered once every 3 weeks. We estimated the safety and efficacy., Results: Fifteen patients were enrolled into this study. The dose-limiting toxicities occurred at sorafenib 800 mg and cisplatin 20 mg/m 2 . The recommended dose was at sorafenib 400 mg and cisplatin 30 mg/m 2 . The disease control rate was 73.3%., Conclusions: This treatment is feasible for unresectable hepatocellular carcinoma. Further evaluation of the regimen in a randomized controlled trial is warranted.

Background/aims: Genipin is a component of Japanese traditional herbal medicine (Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate liver cells, followed by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by iNOS have been implicated as one of the factors in liver injury. Thus it is essential to inhibit iNOS induction for the prevention of liver injury. In this study, we examined IL-1β-stimulated hepatocytes as a simple "in vitro liver injury model" to investigate liver protective effects of genipin., Methods: Primary cultured rat hepatocytes were treated with IL-1β in the presence or absence of genipin. The induction of NO production and iNOS, and its signaling pathway were analyzed., Results: In IL-1β-stimulated hepatocytes, genipin inhibited the production of NO dose- and timedependently, and reduced the levels of iNOS protein and its mRNA expression. Genipin also reduced mRNA expressions of TNF-α and IL-6. Genipin inhibited two essential signaling pathways for iNOS induction, IκB degradation/NF-κB activation and type I IL-1 receptor upregulation. Transfection experiments revealed that genipin decreased the expression of iNOS mRNA through both inhibitions of the promoter activation and mRNA stabilization. Delayed administration of genipin after IL-1β addition also inhibited iNOS induction., Conclusion: Genipin influenced the induction of inflammatory mediators, iNOS and TNF-α, in part through the inhibition of NF-κB activation in hepatocytes. Genipin may have therapeutic potential for organ injuries including liver., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Japanese herbal medicine, Kampo saireito, is used for treatments in patients with digestive diseases, including chronic hepatitis and cirrhosis. However, few studies demonstrate scientific evidence for liver-protective effects of saireito. In inflamed liver, proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate the induction of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production. Excessive levels of NO synthesized by iNOS have been implicated as one of the factors in liver injury, so it is essential to reduce the induction of iNOS for the prevention of liver injury. In this study, we examined IL-1β-stimulated hepatocytes as a simple "in vitro injury model" to investigate liver-protective effects of saireito., Method: Primary cultured rat hepatocytes were treated with IL-1β in the presence or absence of saireito. The induction of NO production and iNOS and its signaling pathway were analyzed., Results: Saireito inhibited the production of NO dose and time dependently and reduced the expression of iNOS messenger RNA (mRNA) and its protein. Saireito had no effect on IκB degradation but inhibited the translocation of nuclear factor (NF)-κB to the nucleus and its DNA binding. Saireito also inhibited the activation of Akt, resulting in the reduction of type I IL-1 receptor (IL-1RI) mRNA and protein expression., Conclusion: These findings demonstrate that saireito suppresses iNOS gene expression through the inhibition of NF-κB and IL-1RI-dependent pathways, leading to the reduction of NO production. Saireito may have therapeutic potential for organ injuries, including liver., (© 2015 American Society for Parenteral and Enteral Nutrition.)

Background: Aberrant signaling mediated by the mammalian target of rapamycin (mTOR) occurs at high frequency in hepatocellular carcinoma (HCC), indicating that mTOR is a candidate for targeted therapy. mTOR forms two complexes called mTORC1 (mTOR complexed with raptor) and mTORC2 (mTOR complexed with rictor). There are minor studies of the expression kinetics of mTORC1 and mTORC2 in HCC., Methods: We studied 62 patients with HCC who underwent curative resection. We used univariate and multivariate analyses to identify factors that potentially influence disease and overall survival after hepatectomy. The mRNA and protein levels of mTOR, rictor and raptor in cancer and non-cancer tissues were analyzed using quantitative RT-PCR, immunohistochemistry and Western blotting., Results/conclusion: High ratio of the levels of rictor and raptor mRNAs in tumors was identified as independent prognostic indicators for disease-free survival. Low and high levels of preoperative serum albumin and mTOR mRNA in the tumor, respectively, were identified as independent indicators of overall survival. HCC is likely to recur early after hepatic resection in patients with high levels of mTOR and rictor mRNAs and high rictor/raptor ratios in cancer tissues. We conclude that analysis of mTOR expression in cancer tissues represents an essential strategy to predict HCC recurrence after curative treatment.

Background: Recent evidence indicates that alpha-lipoic acid (α-LA) has a variety of liver-protective effects through the suppression of inflammatory mediators including tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). However, there are few reports that α-LA markedly enhanced the survival rate in animal models of liver injury with more than 90% death. The aim of this study was to investigate the beneficial effects of α-LA in a rat model of acute liver injury and to clarify the mechanisms of α-LA action., Methods: Rats were treated with d-galactosamine and lipopolysaccharide (GalN and LPS) to induce acute liver injury. α-LA (100 mg/kg) was administered intraperitoneally 1 h before GalN and LPS injection. Inflammatory mediators including TNF-α and iNOS were analyzed., Results: A single injection of α-LA improved the survival rate by more than 80%. α-LA prevented serum transaminase increases, histopathologic changes, and apoptosis in the liver. In the serum, α-LA decreased TNF-α production and increased interleukin (IL)-10 production. In the liver, α-LA reduced TNF-α and IL-6 messenger RNA (mRNA) but enhanced IL-10 mRNA. α-LA decreased the expression of iNOS mRNA and its antisense transcript, leading to the reduction of iNOS protein expression and resulting in the inhibition of nitric oxide production. An electrophoretic mobility shift assay revealed that α-LA reduced the activation of nuclear factor-kappa B induced by GalN and LPS., Conclusions: α-LA inhibited the induction of inflammatory mediators, such as TNF-α and iNOS, in part through the inhibition of nuclear factor-kappa B activation and enhanced the induction of IL-10. α-LA may have therapeutic potential for use in the prevention of acute liver injury., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Pyroglutamyl leucine (pyroGlu-Leu), which is a peptide isolated from wheat gluten hydrolysate, has been reported to be a hepatoprotective compound in acute liver failure. In inflamed liver, proinflammatory cytokines including interleukin (IL)-1β and tumor necrosis factor (TNF)-α stimulate the induction of inducible nitric oxide synthase (iNOS). Excess production of nitric oxide (NO) by iNOS is an inflammatory biomarker in liver injury. We examined proinflammatory cytokine-stimulated hepatocytes as a simple "in vitro inflammation model" to determine liver protective effects of pyroGlu-Leu and its mechanisms of action. We hypothesized that pyroGlu-Leu inhibits the induction of iNOS gene expression, resulting in the attenuation of hepatic inflammation. Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured cells were treated with IL-1β in the presence or absence of pyroGlu-Leu. The induction of iNOS and its signaling pathway were analyzed. IL-1β stimulated the enhancement of NO production in hepatocytes and this effect was inhibited by pyroGlu-Leu. pyroGlu-Leu decreased the expression of iNOS protein and its mRNA. Transfection experiments with iNOS-luciferase constructs revealed that pyroGlu-Leu inhibited both of iNOS promoter transactivation and its mRNA stabilization. pyroGlu-Leu also decreased the expression of an iNOS gene antisense transcript, which is involved in iNOS mRNA stability. However, pyroGlu-Leu had no effects on IκB degradation and NF-κB activation. Results demonstrate that pyroGlu-Leu inhibited the induction of iNOS gene expression at transcriptional and post-transcriptional steps through IκB/NF-κB-independent pathway, leading to the prevention of NO production. pyroGlu-Leu may have therapeutic potential for liver injury through the suppression of iNOS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We report a novel technique of laparoscopic hepatectomy (lap-HT) performed at our hospital and the outcomes.Lap -HT was performed in 90 cases at our hospital, including 38 cases of anatomical resection of the liver.After mobilization of the right lobe with the patient in the half-lateral position, we resected the liver tissue using cavitron ultrasonic surgical aspirator (CUSA) and AquamantysTM Bipolar®.This surgical instrument is useful for laparoscopic anatomical resection of the liver because it is based on vessel sealing technology.In the 90 cases in which lap-HT was performed, the mean duration of surgery and mean blood loss were 332.9 minutes and 381 mL, respectively. The mean duration of hospitalization after surgery was 12.1 days, and postoperative complications were noted in 5 cases(5.6%). Comparison of the clinical factors and short-term performance of the surgery between liver cirrhosis patients who underwent open hepatectomy and lap-HT revealed that blood loss was significantly lower and the hospital stay duration was significantly shorter in patients who underwent lap-HT. Our findings suggest that laparoscopic anatomical resection of the liver can be safely performed using this novel technique and surgical instrument.

The patient was a 55-year-old man who had been diagnosed as having liver metastases (S3, S4, S5, S6, and S7) from sigmoid colon cancer in March 2010. In June 2010, he underwent sigmoid colon cancer resection, followed by local ablation therapy for the liver tumors( S4, S5, and S6) and hepatic segmentectomy( S3 and S7). Subsequently, adjuvant chemotherapy with S-1 and oxaliplatin( SOX) was initiated. After 6 courses, hepatic metastasis from colon cancer recurred. Thus, primary treatment with SOX plus bevacizumab for advanced metastatic colorectal cancer was initiated. However, progressive disease was diagnosed after 10 postoperative courses of chemotherapy, and therefore, chemotherapy with irinotecan and S-1 (IRIS) plus panitumumab was initiated as secondary treatment. Tumor marker levels reduced with this treatment, and diagnostic imaging indicated a partial response. We report herein a case of a patient who was successfully treated with IRIS plus panitumumab. This therapeutic regimen is useful as second-line treatment because it has the advantage of not requiring a pump for administration and treatment can be tailored to an individual patient's condition, for example, according to pathology and the patient's lifestyle needs.

A 76-year-old woman was diagnosed as having hepatocellular carcinoma( HCC), and partial hepatectomy was performed in 2007. Transarterial chemoembolization (TACE) was performed for recurrent HCCs in 2009. Ileocecal resection was performed for peritoneal dissemination of HCC localized in the ileocecal area, and sorafenib therapy was initiated in October 2009. TACE was performed for recurrent HCCs in December 2009 and March 2010. Positron emission tomography( PET) revealed a solitary intrahepatic recurrent HCC and left ovarian metastasis, and partial hepatectomy and left ovariectomy were performed in June 2010. Multiple lung metastases were detected, and systemic chemotherapy with cisplatin was initiated in February 2011. The lung metastatic tumors disappeared after 3 courses of treatment. The patient is disease free at 2 years after treatment. We encountered a case of advanced recurrent HCC is which complete response (CR) was achieved with multimodality therapy using sorafenib and surgical treatment.