Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice.

Liver ischemia and reperfusion injury (IRI) is one of the obstacles in liver surgery such as liver resection and transplantation. In this study, we investigated the preventive effect on mouse liver IRI by feeding mice with inulin, which is a heterogeneous blend of indigestible fructose polymer. Mice were fed either a control ordinary diet (CD) or an inulin diet (ID) containing 5% inulin in the CD, for 14 days before the ischemia and reperfusion (IR) maneuver. IR induced-liver damages were significantly ameliorated in the ID group, compared with those in the CD group. Feeding mice with an ID, but not a CD, elevated levels of Bacteroidetes among gut microbiota, and especially increased Bacteroides acidifaciens in mouse feces, which resulted in significant elevation of short-chain fatty acids (SCFAs) in the portal vein of mice. Among SCFAs, propionic acid (PA) was most significantly increased. The microbial gene functions related to PA biosynthesis were much higher in the fecal microbiome of the ID group compared to the CD. However, the action of PA on liver IRI has not been yet clarified. Direct intraperitoneal administration of PA alone prior to the ischemia strongly suppressed liver cell damages as well as inflammatory responses caused by liver IR. Furthermore, PA suppressed the secretion of inflammatory cytokines from peritoneal macrophages stimulated in vitro through TLR-4 with high-mobility group box 1 protein (HMGB-1), known to be released from apoptotic liver cells during the IR insult. The present study shows that PA may play a key role in the inulin-induced amelioration of mouse liver IRI.

Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine Models.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment. METHODS: ALF was induced in C5-knockout (KO, B10D2/oSn) mice and their wild-type (WT) counterparts (B10D2/nSn) through intraperitoneal lipopolysaccharide (LPS) and d-galactosamine (D-GalN) administration. Thereafter, monoclonal anti-C5 antibody (Ab) or control immunoglobulin was administered intravenously. Furthermore, a selective C5a-receptor (C5aR) antagonist was administered to WT mice to compare its efficacy with that of anti-C5-Ab-mediated total C5 inhibition. We clarified the therapeutic effect of delayed anti-C5-Ab administration after LPS/D-GalN challenge. We also assessed the efficacy of anti-C5-Ab in another ALF model, using concanavalin-A. RESULTS: Liver injury was evident 6 hours after LPS/D-GalN administration. C5-KO and anti-C5-Ab treatment significantly improved overall animal survival and significantly reduced serum transaminase and high-mobility group box-1 release with decreased histological tissue damage. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and less infiltration of CD11+/Ly6-G+ cells with lower cytokine/chemokine expression. Furthermore, C5-KO and anti-C5-Ab downregulated tumor necrosis factor-α production by macrophages before inducing marked liver injury. Moreover, single-stranded-DNA cells and caspase activation were reduced, indicating significant attenuation of apoptosis. Anti-C5-Ab treatment protected the liver more effectively than the C5aR antagonist, and its delayed doses were hepatoprotective. In addition, anti-C5-Ab treatment was effective against concanavalin-A-induced ALF. CONCLUSIONS: C5 inhibition effectively suppresses progression to ALF in mice models of fulminant hepatitis, serving as a new potential treatment strategy for ALF.

The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice.

Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.

Up-regulation of FOXO1 and reduced inflammation by ß-hydroxybutyric acid are essential diet restriction benefits against liver injury.

Liver ischemia and reperfusion injury (IRI) is a major challenge in liver surgery. Diet restriction reduces liver damage by increasing stress resistance; however, the underlying molecular mechanisms remain unclear. We investigated the preventive effect of 12-h fasting on mouse liver IRI. Partial warm hepatic IRI model in wild-type male C57BL/6 mice was used. The control ischemia and reperfusion (IR) group of mice was given food and water ad libitum, while the fasting IR group was given water but not food for 12 h before ischemic insult. In 12-h fasting mice, serum liver-derived enzyme level and tissue damages due to IR were strongly suppressed. Serum ß-hydroxybutyric acid (BHB) was significantly raised before ischemia and during reperfusion. Up-regulated BHB induced an increment in the expression of FOXO1 transcription factor by raising the level of acetylated histone. Antioxidative enzyme heme oxigenase 1 (HO-1), a target gene of FOXO1, then increased. Autophagy activity was also enhanced. Serum high-mobility group box 1 was remarkably lowered by the 12-h fasting, and activation of NF-κB and NLRP3 inflammasome was suppressed. Consequently, inflammatory cytokine production and liver injury were reduced. Exogenous BHB administration or histone deacetylase inhibitor administration into the control fed mice ameliorated liver IRI, while FOXO1 inhibitor administration to the 12-h fasting group exacerbated liver IRI. The 12-h fasting exerted beneficial effects on the prevention of liver IRI by increasing BHB, thus up-regulating FOXO1 and HO-1, and by reducing the inflammatory responses and apoptotic cell death via the down-regulation of NF-κB and NLRP3 inflammasome.

Preventive Effect of Antioxidative Nutrient-Rich Enteral Diet Against Liver Ischemia and Reperfusion Injury.

BACKGROUND: Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver surgery. This study is aimed to compare the preventive effect of an antioxidative nutrient-rich enteral diet (Ao diet) with an ordinal enteral diet (control diet) against liver IRI. METHODS: The Ao diet was an ordinary diet comprising polyphenols (catechin and proanthocyanidin) and enhanced levels of vitamins C and E. Male C57BL/6 mice were fed the Ao or control diet for 7 days before ischemic insult for 60 minutes, followed by reperfusion for 6 hours. The levels of inflammatory cytokines, chemokines, and antioxidant enzymes and oxidative stress were evaluated. RESULTS: After 7 days of pretreatment with the Ao diet, the serum levels of vitamins C and E in mice were markedly elevated. The levels of serum aspartate aminotransferase and alanine aminotransferase, as well as the scores of liver necrosis caused by ischemia and reperfusion, were significantly lower in the Ao diet group than in the control diet group. The gene expression levels of inflammatory cytokines and chemokines, such as interleukin-6 and CXCL1, were significantly lower in the Ao diet group. In the liver, the levels of antioxidant enzymes superoxide dismutase 1 (SOD1) and SOD2 were significantly higher and the malondialdehyde levels were significantly lower in the Ao diet group. Cell adhesion molecule expression was significantly lower, and neutrophil and macrophage infiltration was less in the Ao diet group. CONCLUSIONS: Antioxidative nutrient supplementation to an ordinary enteral diet may mitigate liver IRI by causing an antioxidant effect and suppressing inflammation.

New laparoscopic procedure for left-sided pancreatic cancer-artery-first approach laparoscopic RAMPS using 3D technique.

BACKGROUND: For left-sided pancreatic ductal adenocarcinoma (PDAC), radical antegrade modular pancreatosplenectomy (RAMPS) is a reasonable surgical approach for tumor-free margin resection and systemic lymph node clearance. In pancreaticoduodenectomy for PDAC, the superior mesenteric artery (SMA)-first approach (or the "artery-first approach") has become the standard procedure. With improvements in laparoscopic instruments and techniques, some surgeons attempted to apply laparoscopic RAMPS (L-RAMPS) for carefully selected patients with left-sided PDAC. However, owing to several technical difficulties in this procedure, its application remains uncommon. Moreover, the artery-first approach in L-RAMPS has not been reported. Here, we developed the artery-first approach L-RAMPS for left-sided PDAC and have presented the same in this report. CASE PRESENTATION: Between June 2014 and July 2015, 16 patients with left-sided PDAC were referred to our division for pancreatic resection. The following technique was used for performing L-RAMPS on 3 of the 16 patients (19%). Six trocars were placed. After opening the omental bursa, only the middle segment of the pancreas was initially separated from both the left renal vein and the SMA. We termed this procedure as the "artery-first approach using a dome-shaped dorsomedial dissection (3D) technique." This 3D technique enabled the interruption of the entire arterial supply to the specimen while preserving the venous drainage through the splenic vein for preventing venous congestion. The technique also contributed to the early detection of no tumor infiltration into the SMA and the early determination of posterior dissection plane. After pancreatic neck transection, the splenic artery and vein were divided. Finally, the pancreatic tail and spleen were dissected in a right-to-left direction. All operations were completed without any intraoperative complications. The median blood loss and retrieved lymph node count were 75 mL and 37, respectively, which were superior to those reported by other previous studies on L-RAMPS. All resection margins were free of carcinoma. No severe postoperative complications were observed. CONCLUSIONS: The artery-first approach L-RAMPS using 3D technique is safe and feasible to perform. The significance of our proposed procedure is minimal blood loss and precise lymphadenectomy. Therefore, this novel technique may become the preferred treatment for left-sided PDAC in selected cases.

Liver necrosis shortly after pancreaticoduodenectomy with resection of the replaced left hepatic artery.

BACKGROUND: Surgeons, in general, underestimate the replaced left hepatic artery (rLHA) that arises from the left gastric artery (LGA), compared with the replaced right hepatic artery (rRHA), especially in standard gastric cancer surgery. During pancreaticoduodenectomy (PD), preservation of the rRHA arising from the superior mesenteric artery (SMA) is widely accepted to prevent critical postoperative complications, such as liver necrosis, bile duct ischemia, and biliary anastomotic leakage. In contrast, details of complication onset following rLHA resection remain unknown. We report two cases of postoperative liver necrosis shortly after rLHA resection during PD for advanced gastric cancer. CASE PRESENTATION: Both cases had advanced gastric cancer with infiltration of the pancreatic head. In case 1, the rLHA comprised segment 2/3 artery (A2 + A3), which arose from the LGA. The rRHA originated from the SMA, and the segment 4 artery (A4) was a branch of the rRHA. We conducted PD with combined en bloc resection of both the rLHA and rRHA, and anastomosis between the distal and proximal stumps of the rRHA and LGA, respectively. The divided A2 + A3 was not reconstructed. In case 2, the rLHA comprised segment 2 artery (A2) only, which arose from the LGA. The segment 3/4 artery and the RHAs originated from the proper hepatic artery. We undertook PD with combined en bloc resection of A2 without vascular reconstruction. In both patients, serious necrosis of the lateral segment of the liver occurred within 6 days after PD. Case 1 recovered with conservative management, whereas case 2 required lateral segmentectomy of the liver. Pathologically, the necrotic area in case 2 was apparently circumscribed and confined to segment 2 of the liver, potentially implicating rLHA resection during PD as causing hepatic necrosis. CONCLUSIONS: During PD, rLHA resection can cause serious liver necrosis. Therefore, this artery should be preserved as far as oncologically acceptable. In cases that require rLHA resection during PD due to tumor conditions, surgeons should carefully monitor postoperative course while keeping in mind the possible necessity of urgent hepatectomy.

The use of transureteroureterostomy during ureteral reconstruction for advanced primary or recurrent pelvic malignancy in the era of multimodal therapy.

PURPOSE: Cancerous involvement of a ureter is sometimes encountered in pelvic surgery for malignancy. We usually perform transureteroureterostomy (TUU) in cases of unilateral lower ureteral cancerous involvement. We report the outcomes in patients treated with TUU in our institute. METHODS: We retrospectively reviewed the medical records of 11 patients who underwent TUU between June 2006 and September 2015. RESULTS: The primary disease was colon cancer in five patients, rectal cancer in four, and uterine cervical cancer and ovarian cancer in one patient each. Early postoperative complications relevant to TUU occurred in four patients; however, three patients were managed conservatively and recovered quickly. Only one patient developed ureteral obstruction, which resulted from anastomotic hematoma. Follow-up periods ranged from 5 to 78 months with a median of 28 months. The median estimated glomerular filtration rate before and after TUU was 59 ml/min (range, 31-90 ml/min) and 62.0 ml/min (range, 43-127 mL/min), respectively. No patients experienced worsening of their renal function or recurrent urinary tract infection. CONCLUSIONS: Short-term outcomes are good and long-term renal function is maintained following TUU. TUU is considered a feasible technique for ureteral reconstruction for pelvic malignancy, and TUU has great potential in the era of multimodal therapy.

Successful laparoscopic treatment of a giant solitary fibrous tumor of the mesorectum: A case report and literature review.

A solitary fibrous tumor is a ubiquitous mesenchymal fibroblastic tumor that was previously considered limited to the pleural cavity. Here, we report a rare case of a large solitary fibrous tumor of the mesorectum, which was successfully resected laparoscopically. A 56-year-old woman was referred to our hospital for a giant pelvic mass. Pelvic MRI showed a well-circumscribed mass, 12 cm in diameter, with heterogeneous signal intensity on T2 -weighted images. It was diagnosed as a benign mesorectal tumor of unknown origin. We successfully resected the entire tumor laparoscopically. Histological examination revealed it to be an extrapleural solitary fibrous tumor. For large tumors in the pelvis, the laparoscopic approach is preferable in terms of intraoperative hemorrhage, as long as they do not invade surrounding tissues.

Clinical efficacy of liver resection after downsizing systemic chemotherapy for initially unresectable liver metastases.

BACKGROUND: This study sought to clarify the clinical benefits of liver resection after downsizing systemic chemotherapy for initially unresectable colorectal liver metastases (CLM). METHODS: Survival and clinical characteristics of CLM patients who underwent resection between January 2001 and December 2013 were retrospectively assessed. The study cohort of 88 patients with limited liver disease who underwent curative liver resection comprised 34 with initially resectable synchronous disease (synchronous group), 38 with initially resectable metachronous disease (metachronous group), and 16 with initially unresectable converted disease (conversion group). RESULTS: The median duration of follow-up for the overall study population was 33 (1-98) months. Overall survival (OS) in the conversion group was not significantly different from that in the other groups. However, disease-free survival (DFS) in the conversion group was significantly shorter than that in the synchronous group. The median DFS was 19.1 months in the synchronous group, 16.6 months in the metachronous group, and 15.3 months in the conversion group. Most patients in the conversion group had recurrence shortly after liver resection in the remnant liver with or without metastases at other sites, but many could undergo repeat hepatectomy or resection of the metastases at other sites. CONCLUSIONS: Although the converted patients tended to have recurrence shortly after liver resection, survival could be prolonged by repeat hepatectomy or resection of metastases at other sites. Liver resection after downsizing chemotherapy appears to be efficacious for patients with initially unresectable CLM and may result in long-term outcomes equivalent to those of patients with initially resectable CLM.

[A case of rupture of post-gastrectomy afferent loop obstruction due to invasion by pancreatic cancer].

A 77-year-old man with history of distal gastrectomy with Billroth II reconstruction for peptic ulcer disease performed 55 years ago was admitted to our hospital for diarrhea and abdominal pain. Abdominal computed tomography revealed a dilatation of the afferent loop and the duodenum, and a low density mass located in the body of the pancreas, which invaded the gastro-jejunal anastomosis site as well as the celiac axis and the superior mesenteric artery. Judging from these findings, we diagnosed this case as acute afferent loop obstruction due to an unresectable pancreatic cancer. Endoscopic decompression of the afferent loop was unsuccessful. After a while, the patient complained a severe abdominal pain, and an emergency surgery was performed under the diagnosis of rupture of the afferent loop. At laparotomy, a perforation of the jejunum located at a 15 cm anal side from Ligament of Treitz was found, and Braun's anastomosis was performed using the perforated site. The patient was treated with chemotherapy and survived for 15 months after the operation. Prompt decompression of afferent loop should be performed for preventing a rupture in case of acute obstruction of the afferent loop.