Poly I:C enhances production of nitric oxide in response to interferon-γ via upregulation of interferon regulatory factor 7 in vascular endothelial cells.

The effect of poly I:C on interferon (IFN)-γ-induced nitric oxide (NO) production in vascular endothelial cells was examined using murine aortic endothelial END-D cells. Poly I:C augmented IFN-γ-induced NO production although it alone did not induce the NO production. Poly I:C augmented the NO production via enhanced expression of an inducible NO synthase protein. Poly I:C did not affect the activation of Janus kinase (JAK) 1/2, and signal transducer and activator of transcription (STAT) 1 in IFN-γ signaling. Moreover, there was no significant difference in the IFN-γ-induced interferon regulatory factor (IRF) 1 expression between the presence and absence of poly I:C. Poly I:C led to the activation of IRF7 in END-D cells. Inhibition of poly I:C signaling by amlexanox, an inhibitor of TANK-binding kinase (TBK) 1 and IκB kinase (IKK) ε, abolished the augmentation of IFN-γ-induced NO production. Therefore, poly I:C was suggested to augment IFN-γ-induced NO production at the transcriptional level via enhanced IRF7 activation.

[A case of colorectal cancer with pelvic recurrence treated by systemic chemotherapy and radiotherapy].

A 63-year-old man who had a history of rectal cancer and was treated with low anterior resection in February 2006, presented with liver metastases in September 2007 and underwent right anterior sectionectomy of the liver. He developed a pelvic wall recurrence with buttock pain in September 2009. This was treated with conventional radiation therapy and Cyber- Knife. The buttock pain was relieved after CyberKnife treatment and the patient received systemic chemotherapy in the outpatient clinic. Subsequently, he developed a left sacral recurrence with buttock pain and gait disturbance in August 2013. Since the tumor was located close to the field previously subjected to radiotherapy, we opted for CyberKnife treatment again. Although the pain subsided, our patient died of lymphangitic carcinomatosis in April 2014, 7 years and 2 months after the surgery. In this case, CyberKnife was effective in treating pelvic recurrence with pain, and thus, may have a significant role to play in the multidisciplinary treatment of metastatic colorectal cancer.

[Four cases of bevacizumab-related gastrointestinal perforation].

We report 4 cases of gastrointestinal perforation associated with systemic administration of bevacizumab. Case 1: A 51- year-old man with colorectal cancer (CRC) received mFOLFOX+bevacizumab (Bev). A small intestinal perforation occurred 7 days after Bev administration (Bev-a) and was successfully treated with omental packing. Case 2: A 50-year-old woman with CRC received capecitabine+Bev. A small intestinal perforation was detected 5 days after Bev-a, and was successfully treated with primary suture and an omental flap. Case 3: A 74-year-old man with CRC received CapeOX+Bev. A duodenal perforation occurred on the same day as Bev-a, but could be treated conservatively. Case 4: A 57-year-old man with lung cancer received DTX+Bev. A small intestinal perforation occurred 13 days after Bev-a, but this could be managed with primary suture and an omental flap. The gastrointestinal perforation presented with mild abdominal pain and was detected within 14 days after Bev-a in each of these 4 cases. Three patients were successfully treated with only minimal surgical procedures and 1 patient could be managed with conservative treatment for a perforated duodenal ulcer.

Effect of L-arginine supplement on liver regeneration after partial hepatectomy in rats.

BACKGROUND: Nitric oxide (NO) has been reported to be a key mediator in hepatocyte proliferation during liver regeneration. NO is the oxidative metabolite of L-arginine, and is produced by a family of enzymes, collective termed nitric oxide synthase (NOS). Thus, administration of L-arginine might enhance liver regeneration after a hepatectomy. Another amino acid, L-glutamine, which plays an important role in catabolic states and is a crucial factor in various cellular and organ functions, is widely known to enhance liver regeneration experimentally. Thus, the present study was undertaken to evaluate the effects of an L-arginine supplement on liver regeneration, and to compared this with supplementation with L-glutamine and L-alanine (the latter as a negative control), using a rat partial hepatectomy model. METHODS: Before and after a 70% hepatectomy, rats received one of three amino acid solutions (L-arginine, L-glutamine, or L-alanine). The effects on liver regeneration of the administered solutions were examined by assessment of restituted liver mass, staining for proliferating cell nuclear antigen (PCNA), and total RNA and DNA content 24 and 72 hours after the operation. RESULTS: At 72 hours after the hepatectomy, the restituted liver mass, the PCNA labeling index and the DNA quantity were all significantly higher in the L-arginine and L-glutamine groups than in the control. There were no significant differences in those parameters between the L-arginine and L-glutamine groups, nor were any significant differences found between the L-alanine group and the control. CONCLUSION: Oral supplements of L-arginine and L-glutamine enhanced liver regeneration after hepatectomy in rats, suggesting that an oral arginine supplement can clinically improve recovery after a major liver resection.

Laparoscopic surgery in the management of hypersplenism and esophagogastric varices: our initial experiences.

BACKGROUND: Owing to recent advances in laparoscopic surgery, devascularization of the upper stomach with splenectomy (Spx) or Hassab's procedure (Has) as well as Spx for patients with portal hypertension have been attempted laparoscopically in some facilities, the results of which have been reported. This article describes the authors' surgical techniques and their results. METHODS: Between August 1999 and August 2010, the authors treated 110 cases of portal hypertension with Spx or Has. Among these patients, 56 who simultaneously underwent additional major operations were eliminated from the study, leaving 54 patients eligible. They included 38 with open surgeries and 16 with laparoscopic surgeries, which consisted of 10 splenectomies and 6 Has operations. The perioperative data for the 2 groups were compared. RESULTS: Purely laparoscopic Spx (L-Spx) was completed for 9 patients. Conversion from laparoscopic to hand-assisted laparoscopic surgery (HALS) was necessary for 1 patient because of poor visualization. Operative time was significantly longer in L-Spx than in the open method. Postoperative hospital stays were shorter for L-Spx. HALS was used for all 6 laparoscopic Has patients. There was no conversion from the laparoscopic to the open method. Operative time was significantly longer for laparoscopic Has than for open Has. Postoperative complication rates were significantly reduced, and postoperative hospital stays were significantly shorter for laparoscopic Has. CONCLUSIONS: Although the data are still preliminary, laparoscopic surgery for patients with portal hypertension may prove to be a successful strategy.

Long-term results of laparoscopic Hassab's procedure for esophagogastric varices with portal hypertension.

INTRODUCTION: Recent reports have shown laparoscopic gastric devascularization and splenectomy (Hassab's procedure) to be a safe and effective treatment for esophagogastric varices with portal hypertension. However, the long-term postoperative results remain unclear. METHODS: Between 2009 and 2015, 17 patients with portal hypertension and esophagogastric varices underwent laparoscopic Hassab's procedure at our institution. Two patients were lost to long-term follow-up (at least 2 years) and excluded. The remaining 15 patients' data and endoscopic findings were retrospectively reviewed. RESULTS: The median postoperative follow-up period was 56 months. The median spleen volume, operation time, blood loss, and length of postoperative hospital stay were 651 (320-1,265) mL, 305 (275-547) minutes, 347 (24-1,131) mL, and 20 (8-41) days, respectively. According to the endoscopic findings 1 year after surgery, the esophagogastric varices disappeared in three patients and improved in 12 patients. The median platelet count was significantly higher 1 year after surgery (19.7 × 104 /dL) than before surgery (5.5 × 104 /dL) (P < .001) and remained stable 2 years after surgery. Two patients died of liver disease. The remaining 13 patients, with a median postoperative follow-up of 57 months, were alive without bleeding from esophagogastric varices. CONCLUSION: Laparoscopic Hassab's procedure is a feasible treatment for esophagogastric varices with portal hypertension in terms of both short- and long-term results.

Peroxisome proliferator-activated receptor α (PPARα) mRNA expression in human hepatocellular carcinoma tissue and non-cancerous liver tissue.

BACKGROUND: Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism in the liver. It is unclear, however, how this receptor changes in liver cancer tissue. On the other hand, mouse carcinogenicity studies showed that PPARα is necessary for the development of liver cancer induced by peroxisome proliferators, and the relationship between PPARα and the development of liver cancer have been the focus of considerable attention. There have been no reports, however, demonstrating that PPARα is involved in the development of human liver cancer. METHODS: The subjects were 10 patients who underwent hepatectomy for hepatocellular carcinoma. We assessed the expression of PPARα mRNA in human hepatocellular carcinoma tissue and non-cancerous tissue, as well as the expression of target genes of PPARα, carnitine palmitoyltransferase 1A and cyclin D1 mRNAs. We also evaluated glyceraldehyde 3-phosphate dehydrogenase, a key enzyme in the glycolytic system. RESULTS: The amounts of PPARα, carnitine palmitoyltransferase 1A and glyceraldehyde 3-phosphate dehydrogenase mRNA in cancerous sections were significantly increased compared to those in non-cancerous sections. The level of cyclin D1 mRNA tends to be higher in cancerous than non-cancerous sections. Although there was a significant correlation between the levels of PPARα mRNA and cyclin D1 mRNA in both sections, however the correlation was higher in cancerous sections. CONCLUSION: The present investigation indicated increased expression of PPARα mRNA and mRNAs for PPARα target genes in human hepatocellular carcinoma. These results might be associated with its carcinogenesis and characteristic features of energy production.

Risk factors for surgical site infection after hepatectomy for hepatocellular carcinoma.

BACKGROUND/AIMS: Clarification of risk factors for surgical site infection (SSI) after hepatectomy for hepatocellular carcinoma (HCC) is important for improvement of surgical outcome. METHODOLOGY: The incidences of SSI under various states were evaluated in 171 patients who underwent hepatectomy for HCC. Univariate and logistic regression analysis were performed to identify risk factors for SSI. The relation between postoperative hepatic failure and SSI was also evaluated. Data were analyzed using Stat View 5.0. RESULTS: SSI occurred in 36 patients (21%). Of the 36 patients with SSI, organ/space SSI occurred in 27. Bile leakage occurred in 22 patients, of which 18 patients had accompanying organ/space SSI. Postoperative hepatic failure occurred in 6 patients, and 5 of these 6 patients also had organ/ space SSI. The postoperative mortality rate was significantly higher in the patients with organ/space SSI (3 of 27 patients, 11%) than in those without organ/space SSI (1 of 144 patients, 0.7%). Logistic regression analysis revealed bile leakage and blood loss to be independent right factors for occurrence of organ/space SSI. CONCLUSIONS: Bile leakage frequently causes organ/space SSI after hepatectomy. Organ/space SSI is closely related to postoperative hepatic failure and death. Prevention of bile leakage is important to improve the surgical outcome of hepatectomy for HCC.

General rules for recording endoscopic findings of esophagogastric varices (2nd edition).

General rules for recording endoscopic findings of esophageal varices were initially proposed in 1980 and revised in 1991. These rules have widely been used in Japan and other countries. Recently, portal hypertensive gastropathy has been recognized as a distinct histological and functional entity. Endoscopic ultrasonography can clearly depict vascular structures around the esophageal wall in patients with portal hypertension. Owing to progress in medicine, we have updated and slightly modified the former rules. The revised rules are simpler and more straightforward than the former rules and include newly recognized findings of portal hypertensive gastropathy and a new classification for endoscopic ultrasonographic findings.

Results of laparoscopic liver resection: retrospective study of 68 patients.

BACKGROUND: Although an increasing number of reports and publications have dealt with the laparoscopic approach to liver resection, this procedure remains uncommon, and its feasibility, safety and effectiveness are still not established. There are few reports of the advantages of this approach on postoperative recovery. METHODS: From December 1997 to March 2007, laparoscopic hepatic resection were performed in 68 patients. RESULTS: There were 52 malignant tumors (36 hepatocellular carcinomas, three intrahepatic cholangiocarcinomas, one cystadenocarcinoma, liver metastases from ten colorectal carcinomas and two other organs) and 16 benign lesions among our 68 patients. Fifteen patients with hepatocellular carcinoma had cirrhosis. The mean tumor size was 3.1 +/- 1.8 cm (range 1.0-14.0 cm), and the tumors were located in every liver segment except segment I. Liver resection was anatomical in 17 patients and consisted of a lobectomy in four patients and a lateral segmentectomy in 13 patients. Non-anatomical resections were performed in 51 patients. The operative time was 214 +/- 93 min. Mean blood loss was 393 +/- 564 g. A hand-assisted laparoscopic method or mini-laparotomy method was required in 35 patients (51.4%). Operative complications occurred mainly in our early cases and included three patients (4.4%) with operative bleeding, 2 of whom (2.9%) requiring a conversion to open surgery. Postoperative complications occurred in seven patients (10.0%), and two of then eventually required a re-operation. The mean hospital stay was 17 days. There were no complications in the more recent cases. CONCLUSIONS: The laparoscopic approach for liver tumors is feasible, if the indication is carefully selected. The safety of this procedure depends on the surgical experience of the surgeon and team and the availability of the necessary technology.

Roles of naofen, a novel WD-repeat-2 protein, in the CCl4-treated livers--a possible relationship to cell proliferation.

Naofen (GenBank accession no. EF613262), a newly found intracellular protein in the WD-repeat-2 protein family, has been cloned as an anti-verotoxin II antibody immunoreactive substance, and the nucleotide- and amino acid-sequences have been clarified. The present study was undertaken to evaluate the roles of naofen especially in carbon tetrachloride (CCl4-induced cirrhosis model of rats, also in partial hepatectomy. Naofen mRNA expressions were observed from the early phases of cirrhosis development and during regenerative phases after partial hepatectomy, more remarkable in the former. Naofen immunoreactive fragments located in the vascular endothelial cells and peri-vascular spaces in normal livers especially in Glisson's areas, being strongly stained in the connective tissues 8 weeks after starting CCl4-injections, besides in the cytoplasm of hepatocytes in pseudo-lobules. In contrast, partial hepatectomy caused a small increase of naofen expressions in the whole hepatocytes, and significantly in the endothelial cells of portal veins and hepatic arterioles. Furthermore, in parallel to the degree of naofen mRNA and protein expressions, the rates of double-nuclei cells to total hepatocytes in the Glisson's areas increased in both cirrhosis and partial hepatectomy, suggesting a relationship between naofen expression and mitosis. In in-vitro studies with cell lines, vascular endothelial growth factor, a cell proliferation stimulant, increased the naofen mRNA expressions in HepG(2) cell lines, whereas paclitaxel, a cytotoxic anti-cancer drug, diminished them in NRK52E, both concentration-dependently. These results indicated that naofen immunoreactive fragments play an important role in the cell proliferation, relevant for analyzing the regenerative phases during cirrhosis developments and after partial hepatectomy.

Hand-assisted laparoscopic hepatectomy for tumors located in posterior segment.

BACKGROUND/AIMS: In spite of recent advances in laparoscopic surgery, laparoscopic approach is still not a standard option for the tumors located in the posterior segment of the right hepatic lobe mainly due to its technical difficulties and the risk for injuring major adjacent vessels. METHODOLOGY: In order to evaluate the feasibility of laparoscopic posterior segment hepatectomy (LPSH) compared to open posterior segment hepatectomy (OPSH), we retrospectively reviewed a total of 46 laparoscopic hepatectomies and 169 open hepatectomies. Among them, three patients underwent LPSH and seven patients underwent OPSH for tumors located in the posterior segment of the right hepatic lobe. RESULTS: Although duration of operation showed a trend toward being longer in LPSH, LPSH was not accompanied by significant increase of blood loss. Furthermore, LPSH had a trend to result in earlier recovery of the patients, including shorter hospital stay and earlier start of walking or meal. CONCLUSIONS: In conclusion, our data suggested that LPSH could be as safe and feasible as OPSH for tumors located in the posterior segment.

[A case of lumbar metastases from rectal cancer successfully treated by UFT plus oral leucovorin (LV) therapy].

A 63-year-old man had undergone a low anterior resection for rectal cancer with multiple liver metastases. Oral UFT (450 mg/day) administration alone was started after the operation. After 6 months post operatively, the patient was diagnosed as anastomosis recurrence because of ileus by abdominal X-ray. Transverse loop colostomy was performed by emergency surgery. After surgery, he suffered from paraplegia for lumbar vertebrae metastases. UFT+LV therapy was started. After chemotherapy a significant reduction of the lymph node and liver metastases and an apparent decrease in CEA and CA19-9 were observed. The patient left the hospital and showed no signs of tumor exacerbation for three months. The patient died of aggravation of primary disease afterwards. The therapy was safe and effective, and has successfully maintained the quality of life (QOL) of this patient.

The SHAP-hyaluronan complex in serum from patients with chronic liver diseases caused by hepatitis virus infection.

Our previous study suggested that the serum-derived hyaluronan associated protein (SHAP)-hyaluronan (HA) complex in the sera of patients with rheumatoid arthritis is useful as a marker that directly correlates with the degree of inflammation. Here, we have investigated the serum levels of the SHAP-HA complex in patients at various clinical stages of chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) caused by infection with the hepatitis C or hepatitis B virus. Both serum levels of the SHAP-HA complex and HA in those patients were significantly higher than those of the controls and increased in the order of CH

Regulation of branched-chain amino acid metabolism and pharmacological effects of branched-chain amino acids.

Significant evidence of the pharmacological and physiological effects of branched-chain amino acids (BCAA) has accumulated, attracting the interest of not only clinicians but also basic medical researchers. We summarize here the characteristic features of BCAA catabolism, focusing on the initial two enzymes in the pathway, branched-chain aminotransferase and branched-chain alpha-keto acid dehydrogenase complex. In addition, we describe a unique characteristic of the valine catabolic pathway. Finally, we present evidence obtained in animal studies that indicates that BCAA treatment may be appropriate for liver cirrhosis, but not acute liver failure.

Apoptosis induced by culturing MH134 cells in the presence of porcine skin gelatin in vitro.

Porcine skin (PS) gelatin showed antitumor effect in vitro on MH134 murine hepatoma cells. We analyzed the effect of PS gelatin on MH134 cells compared to the effect of Bovine bone (BB) gelatin, 5-Fluorouracil (5-FU) and 7-ethyl-10-hydroxycamptothecin (SN-38). We previously suggested that PS gelatin induces apoptosis in MH134 cells using flow cytometric analysis. We performed agarose gel electrophoresis and electron microscopic studies to ascertain apoptosis. Agarose gel electrophoresis showed the typical DNA ladder pattern and electron microscopic findings revealed characteristic features in the case of apoptosis on PS gelatin. SN-38 also showed DNA ladder pattern and ultrastructural changes in apoptosis. 5-FU didn't show DNA ladder pattern but electron microscope revealed changes in necrosis. On the other hand, BB gelatin didn't induce apoptosis or necrosis.

[A case of giant hepatocellular carcinoma treatable with radio frequent ablation therapy after effective UFT administration].

A 71-year-old man was diagnosed with giant hepatocellular carcinoma (HCC) and hepatitis C cirrhosis at a nearby hospital. Image diagnosis showed no other metastasis, but the tumor was very huge with daughter nodules in the bilateral lobe of the liver. He was thus treated by oral administration of UFT (300 mg/day). Two months later, the giant liver tumor had shrunk remarkably, and the daughter tumors had disappeared. Eight months later, the levels of serum AFP and PIVKA-II had also reduced remarkably. Twelve months following the first treatment, the levels of both serum AFP and PIVKA-II began increasing again, and he was referred to our hospital. CT showed 2 liver tumors, 1 of which showed viability with moderately differentiated hepatocellular carcinoma and the other evidencing necrosis histologically. Radio frequency ablation therapy was performed for 2 tumors by open laparotomy. It was considered that administration of UFT is a useful and safe therapy for far advanced HCC.

Pifithrin-α, a pharmacological inhibitor of p53, downregulates lipopolysaccharide-induced nitric oxide production via impairment of the MyD88-independent pathway.

The effect of pifithrin (PFT)-α, a pharmacological inhibitor of p53, on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. PFT-α inhibited the production of NO but not tumor necrosis factor (TNF)-α in response to LPS. PFT-α inhibited LPS-induced NO production via reduced expression of an inducible NO synthase (iNOS). Moreover, PFT-α inhibited LPS-induced iNOS expression in p53-silenced cells. PFT-α inhibited the production of interferon (IFN)-ß, characteristic of the MyD88-independent pathway of LPS signaling, whereas it did not affect the activation of nuclear factor (NF)-κB and mitogen-activated protein kinases in the MyD88-dependent pathway. PFT-α inhibited poly I:C-induced NO production whereas it did not inhibit IFN-ß-induced NO production. Further, PFT-α reduced the expression of IFN regulatory factor 3 that leads to the IFN-ß production in the MyD88-independent pathway. The most upstream event impaired by PFT-α was the reduced expression of TNF receptor-associated factor (TRAF) 3 in the MyD88-independent pathway. PFT-α also reduced the in vivo expression of iNOS in the livers of mice injected with LPS. Taken together, PFT-α was suggested to inhibit LPS-induced NO production via impairment of the MyD88-independent pathway and attenuated LPS-mediated inflammatory response.