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Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.

Organoprotective effects of noble gases are subject of current research. One important field of interest is the effect of noble gases on hepatic regenerative capacity. For the noble gas argon, promising studies demonstrated remarkable experimental effects in neuronal and renal cells. The aim of this study was to investigate the effects of argon on the regenerative capacity of the liver after ischemia/reperfusion injury (IRI). Male, Sprague-Dawley rats underwent hepatic IRI by clamping of the hepatic artery. Expression of hepatoproliferative genes (HGF, IL-1&beta, IL-6, TNF), cell cycle markers (BrdU, TUNEL, Ki-67), and liver enzymes (ALT, AST, Bilirubin, LDH) were assessed 3, 36, and 96 h after IRI. Expression of IL-1&beta, and IL-6 was significantly higher after argon inhalation after 36 h (IL-1&beta, 5.0 vs. 8.7 fold, p = 0.001, IL-6 9.6 vs. 19.1 fold, p = 0.05). Ki-67 was higher in the control group compared to the argon group after 36 h (214.0 vs. 38.7 positive cells/1000 hepatocytes, p = 0.045). Serum levels of AST and ALT did not differ significantly between groups. Our data indicate that argon inhalation has detrimental effects on liver regeneration after IRI as measured by elevated levels of the proinflammatory cytokines IL-1&beta, and IL-6 after 36 h. In line with these results, Ki-67 is decreased in the argon group, indicating a negative effect on liver regeneration in argon inhalation.

Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment. (C) 2018 Elsevier B.V. All rights reserved.

Krüppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)-treated mice. In mice with hepatocyte-specific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and BECLIN1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates autophagy by transcriptional induction of ATG7 and BECLIN1 in a p53-dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of autophagy in hepatocytes.

Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of platelet-mediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses.

Summary In rodents and humans, the liver can efficiently restore its mass after hepatectomy. This is largely attributed to the proliferation and cell cycle re-entry of hepatocytes. On the other hand, bone marrow cells (BMCs) migrate into the liver after resection. Here, we find that a block of BMC recruitment into the liver severely impairs its regeneration after the surgery. Mobilized hematopoietic stem and progenitor cells (HSPCs) in the resected liver can fuse with hepatocytes, and the hybrids proliferate earlier than the hepatocytes. Genetic ablation of the hybrids severely impairs hepatocyte proliferation and liver mass regeneration. Mathematical modeling reveals a key role of bone marrow (BM)-derived hybrids to drive proliferation in the regeneration process, and predicts regeneration efficiency in experimentally non-testable conditions. In conclusion, BM-derived hybrids are essential to trigger efficient liver regeneration after hepatectomy., Graphical Abstract, Highlights • Bone marrow cell migration after liver hepatectomy is key for liver regeneration • Migrated bone marrow cells fuse with hepatocytes • Hybrids are essential for liver regeneration • Mathematical modeling unveils the hybrid function for liver regeneration, Hepatocyte replication is considered the main mechanism of liver regeneration after hepatectomy in mammals. Pedone et al. report that bone marrow cells can migrate into the liver upon resection and fuse with the hepatocytes. The derived hybrids are essential for efficient liver regeneration, which is also predicted by mathematical modeling.

BACKGROUND: An increasing number of patients undergo major liver resection following preoperative chemotherapy. Liver regeneration may be impaired in these patients, predisposing them to postoperative liver dysfunction. The aim of the present study was to evaluate the effects of preoperative chemotherapy on liver regeneration after partial liver resection. METHODS: Patients planned to receive right hepatectomy either with (group B) or without (group A) prior chemotherapy were identified retrospectively from a prospective multi-institutional database created in the conduct of a national randomized controlled trial (RCT). Prior chemotherapy was neither an inclusion nor an exclusion criterion of the trial. Future remnant liver volume (FRLV) was calculated by measuring total functional liver volume and resection specimen on preoperative computed tomography (CT) scans. Remnant liver volume after 7 days (V RLV7days) was measured on scheduled postoperative CT scans. The early regeneration index 7 days after surgery (RI early) was calculated as [(V RLV7days - FRLV) / FRLV] x 100 %. Data are expressed as median (interquartile range). RESULTS: A total of 72 patients were enrolled: 45 in group A and 27 in group B. For the whole group, the liver remnant showed a 58 % (39 %) increase in volume at day 7 (1) day. The RI early was not significantly different between groups A and B, 60 % (36 %) and 50 % (43 %), respectively (p = 0.47). The RI early was significantly lower in patients who had undergone more than six cycles of chemotherapy. CONCLUSIONS: Preoperative chemotherapy does not seem to have a negative impact on early liver regeneration after partial liver resection.

Partial liver resection is a well established treatment for patients with liver tumors. It is associated with significant morbidity and some mortality, even in high volume centers. Less invasive modalities are currently available and deserve a place in the armamentarium of liver surgeons. This review discusses the role of thermoablation as a treatment modality for liver tumors. The minimal invasive possibility of percutaneous ablation is a great advantage. The limitation of ablation is the high incidence of ablation site recurrences. The inflammatory response is associated with the initiation of cancer at sites of chronic inflammation. There is also accumulating evidence that progression of tumors is also enhanced by an ongoing inflammatory response. The common denominator probably is angiogenesis. The paper supplies data about the interrelationship between inflammation, angiogenesis and tumor growth. Ablation of liver tumors is associated with a low inflammatory response, especially if it is performed percutaneous and thus deserves to be considered in patients with liver tumors.

Item does not contain fulltext Caveolae are a subtype of cholesterol-enriched lipid microdomains/rafts that are routinely detected as vesicles pinching off from the plasma membrane. Caveolin-1 is an essential component of caveolae. Hepatic caveolin-1 plays an important role in liver regeneration and lipid metabolism. Expression of caveolin-1 in hepatocytes is relatively low, and it has been suggested to also reside at other subcellular locations than the plasma membrane. Recently, we found that the peroxisomal membrane contains lipid microdomains. Like caveolin-1, hepatic peroxisomes are involved in lipid metabolism. Here, we analyzed the subcellular location of caveolin-1 in rat hepatocytes. The subcellular location of rat hepatocyte caveolin-1 was analyzed by cell fractionation procedures, immunofluorescence, and immuno-electron microscopy. Green fluorescent protein (GFP)-tagged caveolin-1 was expressed in rat hepatocytes. Lipid rafts were characterized after Triton X-100 or Lubrol WX extraction of purified peroxisomes. Fenofibric acid-dependent regulation of caveolin-1 was analyzed. Peroxisome biogenesis was studied in rat hepatocytes after RNA interference-mediated silencing of caveolin-1 and caveolin-1 knockout mice. Cell fractionation and microscopic analyses reveal that caveolin-1 colocalizes with peroxisomal marker proteins (catalase, the 70 kDa peroxisomal membrane protein PMP70, the adrenoleukodystrophy protein ALDP, Pex14p, and the bile acid-coenzyme A:amino acid N-acyltransferase BAAT) in rat hepatocytes. Artificially expressed GFP-caveolin-1 accumulated in catalase-positive organelles. Peroxisomal caveolin-1 is associated with detergent-resistant microdomains. Caveolin-1 expression is strongly repressed by the peroxisome proliferator-activated receptor-alpha agonist fenofibric acid. Targeting of peroxisomal matrix proteins and peroxisome number and shape were not altered in rat hepatocytes with 70%-80% reduced caveolin-1 levels and in livers of caveolin-1 knockout mice. CONCLUSION: Caveolin-1 is enriched in peroxisomes of hepatocytes. Caveolin-1 is not required for peroxisome biogenesis, but this unique subcellular location may determine its important role in hepatocyte proliferation and lipid metabolism. 01 mei 2010

BackgroundlAims. Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of this study was to investigate the effects of IPC and INT on ischemia reperfusion injury in aged livers.Methods. A rat model of segmental hepatic ischemia (45 min) and reperfusion (60 min) was used. Bile flow, as an indicator of early hepatocyte damage and dynamic liver function, plasma concentrations of bilirubin, liver marker enzymes, and liver histology were assessed.Results. In young rats (8-13 weeks), IPC regimes of 10 min clamping and 10 min reperfusion, and 5 min clamping and 30 min reperfusion, restored bile flow to 23 and 42%, respectively, of the initial value, compared to 14 and 88% for continuous clamping and controls, respectively. An M regime of three cycles of alternating 15 min perfusion and 15 min clamping gave a substantially greater (70%) restoration of bile flow. In aged rats (20-24 months), the IPC regimes did not give any restoration of bile flow. By contrast, the INT regime restored bile flow to 68%. Plasma bilirubin concentrations were lowest in the INT groups, whereas alanine transaminase concentrations for the IPC and INT groups compared with the continuous clamping groups showed no significant differences.Conclusions. In young rats, INT is more effective than IPC in restoring the immediate consequences of IP-induced damage to hepatocytes and liver function after ischemia-reperfusion. In aged rats INT, but not IPC, reverses hepatocyte damage and restores liver function. INT may promote better hepatocyte and liver function than IPC following the surgical resection of aged livers. (c) 2009 Elsevier Inc. All rights reserved.

Background. Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibitor, and assessed the effect on liver regeneration and urinary AMP activity.Methods. Mice were subjected to sham operations, 67% hepatectomy, or 67% hepatectomy plus treatment with the broad-spectrum AMP inhibitor Marimastat. Urine collected preoperatively and for 8 d postoperatively was tested for MMP-2 and MMP-9 activity using zymography. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, TNF-alpha, IL-6, and hepatocyte growth factor levels were measured. Liver sections were analyzed by CD31 immunohistochemistry and microvessel density. Mitotic index and proliferating cell nuclear antigen labeling index were determined.Results. The mean regenerating liver weight on postoperative day 8 was 0.72 +/- 0.01 grams for the hepatectomy Marimastat group, and 0.83 +/- 0.02 grams for the hepatectomy control group (P Conclusions. The broad-spectrum AMP-inhibitor Marimastat inhibits liver regeneration. Microvessel density is reduced at day 4. Furthermore, urinary MMP-9 is elevated during liver regeneration, and this effect is not observed when regeneration is inhibited by the broad-spectrum AMP-inhibitor Marimastat. (C) 2008 Elsevier Inc. All rights reserved.

BackgroundLiver metastases of colorectal cancer occur frequently, but only 10-20% are eligible for liver surgery. Recent new developments changed the concepts of treating patients with colorectal liver metastases.AimTo describe the available modalities that can result in increasing resectability rate.MethodsPotentials and drawbacks of portal vein embolization, radiofrequency ablation (RFA), trans-ablated tumour hepatectomy, neoadjuvant chemotherapy and the approach to patients with extrahepatic metastases are described.ResultsPortal vein embolization is a well-established technique to increase the volume of the future liver remnant. RFA should be applied if partial liver resection alone cannot make the liver tumour-free. Neoadjuvant chemotherapy in patients with unresectable liver metastases can result in secondary resectability rates of 15-40%. Hepatotoxicity can lead to a higher complication rate after partial liver resection. A limited number of extrahepatic tumour localizations should be resected as well.ConclusionsA more aggressive approach to patients with colorectal liver metastases improves resectability rate and survival. Unfortunately, these new options have not been thoroughly evaluated in randomized controlled trials. For some of these modalities, the currently available results are so promising that it might be difficult to start such trials in the future.

BackgroundThyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3',5-Triiodo-L-thyronine (T-3). T-3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T-3 pre-conditioning in the liver of brain-dead rats.MethodsBrain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T-3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed.ResultsBrain-dead animals treated with T-3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1 beta) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T-3 compared to vehicle-treated animals.ConclusionT-3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T-3 hormone therapy in the management of brain-dead donors.

The aim of the present study was to assess the influence of quercetine (QE) on liver regeneration after partial hepatectomy (PH) in rats. A total of 24 male Wistar albino rats were divided into three groups: sham-operated (SH), PH and PH+QE; each group contain 8 animals. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day i. p., for 7 days starting 3 days prior to hepatectomy operation. At 7 days after resection, liver samples were collected. The malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were estimated in liver homogenates. Moreover, histopathological examination, mitotic index (MI), proliferating cell nuclear antigen labelling, proliferation index (PI), transferase-mediated dUTP nick end-labelling assay, apoptotic index (AI) were evaluated at 7 days after hepatectomy. As a result, QE significantly increased MI, PI, and significantly decreased AI in PH rats. Additionally, QE remarkably inhibited the elevation of MDA, restored impaired antioxidant SOD activity and GSH level, and also attenuated hepatic vacuolar degeneration and sinusoidal congestion. These results suggested that QE treatment had a beneficial effect on liver regenerative capacity of the remnant liver tissue after hepatectomy, probably due to its antioxidative, antiapoptotic and proliferative property.

Increasing evidence links metabolic signals to cell proliferation, but the molecular wiring that connects the two core machineries remains largely unknown. E2Fs are master regulators of cellular proliferation. We have recently shown that E2F2 activity facilitates the completion of liver regeneration after partial hepatectomy (PH) by regulating the expression of genes required for S-phase entry. Our study also revealed that E2F2 determines the duration of hepatectomy-induced hepatic steatosis. A transcriptomic analysis of normal adult liver identified "lipid metabolism regulation" as a major E2F2 functional target, suggesting that E2F2 has a role in lipid homeostasis. Here we use wild-type (E2F2+/+) and E2F2 deficient (E2F2-/-) mice to investigate the in vivo role of E2F2 in the composition of liver lipids and fatty acids in two metabolically different contexts: quiescence and 48-h post-PH, when cellular proliferation and anabolic demands are maximal. We show that liver regeneration is accompanied by large triglyceride and protein increases without changes in total phospholipids both in E2F2+/+ and E2F2-/- mice. Remarkably, we found that the phenotype of quiescent liver tissue from E2F2-/- mice resembles the phenotype of proliferating E2F2+/+ liver tissue, characterized by a decreased phosphatidylcholine to phosphatidylethanolamine ratio and a reprogramming of genes involved in generation of choline and ethanolamine derivatives. The diversity of fatty acids in total lipid, triglycerides and phospholipids was essentially preserved on E2F2 loss both in proliferating and non-proliferating liver tissue, although notable exceptions in inflammation-related fatty acids of defined phospholipid classes were detected. Overall, our results indicate that E2F2 activity sustains the hepatic homeostasis of major membrane glycerolipid components while it is dispensable for storage glycerolipid balance. Fil: Maldonado, Eduardo N.. Universidad del Pais Vasco; España Fil: Delgado, Igotz. University Of The Basque Country (upv/ehu). Department Of Chemical And Environmental Engineering, Polytechnic School; España Fil: Furland, Natalia Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); Argentina Fil: Buqué, Xabier. Universidad del Pais Vasco; España Fil: Iglesias, Ainhoa. Universidad del Pais Vasco; España Fil: Aveldaño, Marta Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Investigaciones Bioquímicas Bahía Blanca (i); Argentina Fil: Zubiaga, Ana. Universidad del Pais Vasco; España Fil: Fresnedo, Olatz. Universidad del Pais Vasco; España Fil: Ocho, Begoña. Universidad del Pais Vasco; España

Background: Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome. Methods: Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-β and β-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out. Results: High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-β at transcription and protein level was observed, whereas for β-catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis. Conclusions: SERPINB3 is overexpressed in the subset of the most aggressive HCCs.

To establish the tolerance of liver tissue to single high-dose intraoperative irradiation, the histopathological changes in the canine liver after single high-dose intraoperative irradiation were investigated by means of radionuclide imaging and light microscopy, Intraoperative irradiation at doses of 0, 10, 20, 25 or 30 Gy was applied to a part of the liver of 25 beagles. Radionuclide imaging using Tc-99m-sulfur colloid was performed at several times during follow-up. Elective humane killing was done 3 months and 1, 2, 3 and 5 years after irradiation, Light microscopy was used to identify histopathological alterations. There was no morbidity or mortality during a maximal followup of 5 years. In 40% of the animals, a region of diminished uptake was observed at the irradiation site, The regions of diminished uptake of the radiopharmaceutical agent became smaller with time. Light microscopic examination revealed severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1 to 2 years after irradiation. At 3 and 5 years, vascular changes with endothelial proliferation and focal arteriolar hyalinosis were observed, This study demonstrates that intraoperative irradiation of a part of the liver in the canine model can be applied safely. Light microscopy confirmed that histological damage was not always accompanied by diminished uptake of the radiopharmaceutical agent at the irradiation site. (C) 2000 by Radiation Research Society.

HOLANGIOCYTES C are the epithelial cells which line the intrahepatic biliary tree, a network of interconnecting ducts of increasing diameter from the duct of Hering to the extrahepatic bile ducts (l-6). Cholangiocytes determine the final bile composition through a series of secretory and absorptive processes regulated by a number of hormones and neuropeptides (2-5). The intrahepatic bile ducts are the target of damage in a group of chronic cholestatic liver diseases recently classified as Vanishing Bile Duct Syndromes (4,7-9). These diseases are characterized by the progressive disappearance of intrahepatic bile ducts, which leads to a severe ductopenic condition in the terminal stages (79). The residual bile ducts tend to proliferate as a compensatory mechanism (8). Thus, the course of these diseases is characterized by a balance between damage (loss) of bile ducts and compensatory proliferation of the residual ducts. The terminal decompensated stages are characterized by the inefficacy of proliferation to balance for the loss of intrahepatic bile ducts. Therefore, a therapeutic strategy designed to support efficacious cholangiocyte proliferation could delay progression to ductopenia. This represents a challenge for the future. The aim of this review is to focus on current knowledge of the regulation and dysregulation of cholangiocyte proliferation.

OBJECTIVE: To monitor liver regeneration following partial hepatectomy, liver cell proliferation can be measured by assaying in vivo [H-3]thymidine incorporation into liver cell DNA. We hypothesized that [H-3]thymidine incorporation into whole liver tissue parallels [H-3]thymidine incorporation into liver cell DNA, both in high proliferating and low proliferating liver. STUDY DESIGN: Liver cell proliferation in rats after partial hepatectomy or a sham operation was studied by measuring incorporation of [H-3]thymidine into various fractions of liver tissue on days 1, 2, 3, 4 and 10 after surgery. RESULTS: [H-3]thymidine incorporation into whole with DNA-specific [H-3]thymidine incorporation into regenerating (r > .80, P .69, P

Purpose: The histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT) were investigated in order to establish the tolerance of liver tissue to IORT, thus providing a framework for clinical IORT treatment of patients with metastatic disease to the liver. Materials and methods: Following partial resection of the liver, IORT in doses of 10, 20, 25, or 30Gy was applied to the resection plane and a non-surgically manipulated part of the liver of 25 beagles. Results: There were no postoperative complications, and no morbidity or mortality during a maximal follow-up of 5 years. Dogs were killed at. 3 months, and 1, 2, 3 and 5 years folloning IORT. Light microscopic examination revealed capsular thickening, severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1-2 years following IORT. At 3-5 years, however, only mild parenchymal changes were found that:consisted of slight periportal fibrosis, an incidental portal-central fibrous septum and vascular changes with endothelial proliferation and focal arteriolar hyalinosis. Conclusions: This study demonstrated that following partial hepatic resection, IORT to the liver in the canine model can be applied safely, without short- or long-term treatment morbidity. Although doses up to 30Gy resulted in severe local tissue damage 1-2 years following IORT, these changes were largely reversible due to hepatic regeneration.

To determine whether the expression of transforming growth factor alpha (TGF-alpha), its receptor (epidermal growth factor receptor [EGFr]), p53 nuclear protein, and proliferation influences prognosis of patients with liver metastases, a study was performed in 45 liver metastases and 33 corresponding primary colorectal carcinomas in patients referred for liver surgery. The expression of TGF-alpha, EGFr, p53 nuclear protein, and proliferation rate was correlated with clinicopathological characteristics and survival after partial liver resection. In liver metastases, TGF-alpha expression was low in 42%, intermediate in 35%, and high in 23%. TGF-alpha expression was higher in liver metastases derived from lymph node-positive primary carcinomas, in synchronous and in irresectable liver metastases compared with those derived from lymph node-negative primary carcinomas, metachronous, and resectable liver metastases. Nuclear p53 expression was found in 83% of primary tumors and 71% of liver metastases. p53 expression did not correlate with the various clinicopathological characteristics. Ki67 expression was not associated with clinicopathological characteristics in primary and metastatic tumors. In the 38 patients in whom a partial liver resection was performed, median survival was 25 months in patients with a higher TGF-alpha expression in the metastasis than in the primary tumor and 60 months in patients with comparable or lower TGF-alpha expression in the metastasis than in the primary tumor (P = .036). Median survival after liver resection was 21 months in patients with p53-negative liver metastases and 58 months in patients with p53-positive metastases (P = .043). By multivariate analysis, p53 and EGFr expression on liver metastases were the best predictors of disease-free survival after partial liver resection, with relative risks of 2.38 and 3.33, respectively. In patients with colorectal liver metastases, referred for liver surgery, a higher TGF-alpha expression is associated with unfavorable tumor characteristics, whereas p53 and absence of EGFr expression is associated with a better survival after partial liver resection.

The acute phase response is an orchestrated response to tissue injury, infection or inflammation. A prominent feature of this response is the induction of acute phase proteins, which are involved in the restoration of homeostasis. Cytokines are important mediators of the acute phase response. Uncontrolled and prolonged action of cytokines is potentially harmful, therefore mechanisms exist which limit the activity of cytokines; these include soluble cytokine receptors and receptor antagonists. The cytokine signal is transmitted into the cell via membrane-bound receptors. Different intracellular signalling pathways are activated by different cytokine-receptor interactions. Eventually, cytokine-inducible transcription factors interact with their response elements in the promotor region of acute phase genes and transcription is induced. Systemic inflammation results in a systemic acute phase response. However, local inflammatory or injurious processes in the liver may also induce an acute phase response, for example after partial hepatectomy and during hepatic fibrosis. The acute phase proteins induced in these conditions probably act to limit proteolytic and/or fibrogenic activity and tissue damage. The possible function of the acute phase protein alpha 2-macroglobulin in hepatic fibrosis is discussed in some detail. (C) 1997 by John Wiley & Sons, Ltd.

Trials 13, 54 (2012). doi:10.1186/1745-6215-13-54, Published by BioMed Central, London

Partial liver resection is a well established treatment for patients with liver tumors. It is associated with significant morbidity and some mortality, even in high volume centers. Less invasive modalities are currently available and deserve a place in the armamentarium of liver surgeons. This review discusses the role of thermoablation as a treatment modality for liver tumors. The minimal invasive possibility of percutaneous ablation is a great advantage. The limitation of ablation is the high incidence of ablation site recurrences. The inflammatory response is associated with the initiation of cancer at sites of chronic inflammation. There is also accumulating evidence that progression of tumors is also enhanced by an ongoing inflammatory response. The common denominator probably is angiogenesis. The paper supplies data about the interrelationship between inflammation, angiogenesis and tumor growth. Ablation of liver tumors is associated with a low inflammatory response, especially if it is performed percutaneous and thus deserves to be considered in patients with liver tumors.

Background: Plasma interleukin-6 (IL-6) levels increase during liver resection. The source of this IL-6 is hitherto unclear. It has been demonstrated that the hepatosplanchnic area takes up IL-6 but the role of the gut and liver is unknown. The aim of the present study was to investigate the role of the gut and liver in IL-6 homeostasis during liver surgery. Methods: Before and after partial hepatectomy, IL-6 was measured in blood sampled from the radial artery, and the hepatic and portal vein. Blood flow was measured to assess IL-6 fluxes (flow times AV-differences) across the gut, liver and hepatosplanchnic area. Results: In 22 patients undergoing liver resection, IL-6 release from the gut after transection was 90.9 (30.1) ng/min (P < 0.001), whereas net IL-6 uptake by the liver equalled 83.4 (41.7) ng/min (P < 0.01). Overall hepatosplanchnic flux was 7.3 (43.5) ng/min after transection and did not differ significantly from zero. Overall hepatosplanchnic flux was 87.8 (41.5) ng/min in the major resection group and -59.8 (67.5) ng/min in the minor resection group (P < 0.05). Discussion: The gut releases IL-6 and the liver takes up IL-6 before and after liver resection. The loss of IL-6 uptake as a result of a small functional remnant liver could lead to higher IL-6 levels after surgery.

Background Liver metastases of colorectal cancer occur frequently, but only 10-20% are eligible for liver surgery. Recent new developments changed the concepts of treating patients with colorectal liver metastases. Aim To describe the available modalities that can result in increasing resectability rate. Methods Potentials and drawbacks of portal vein embolization, radiofrequency ablation (RFA), trans-ablated tumour hepatectomy, neoadjuvant chemotherapy and the approach to patients with extrahepatic metastases are described. Results Portal vein embolization is a well-established technique to increase the volume of the future liver remnant. RFA should be applied if partial liver resection alone cannot make the liver tumour-free. Neoadjuvant chemotherapy in patients with unresectable liver metastases can result in secondary resectability rates of 15-40%. Hepatotoxicity can lead to a higher complication rate after partial liver resection. A limited number of extrahepatic tumour localizations should be resected as well. Conclusions A more aggressive approach to patients with colorectal liver metastases improves resectability rate and survival. Unfortunately, these new options have not been thoroughly evaluated in randomized controlled trials. For some of these modalities, the currently available results are so promising that it might be difficult to start such trials in the future.

The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-κB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-α and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death–promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.

To establish the tolerance of liver tissue to single high-dose intraoperative irradiation, the histopathological changes in the canine liver after single high-dose intraoperative irradiation were investigated by means of radionuclide imaging and light microscopy, Intraoperative irradiation at doses of 0, 10, 20, 25 or 30 Gy was applied to a part of the liver of 25 beagles. Radionuclide imaging using Tc-99m-sulfur colloid was performed at several times during follow-up. Elective humane killing was done 3 months and 1, 2, 3 and 5 years after irradiation, Light microscopy was used to identify histopathological alterations. There was no morbidity or mortality during a maximal followup of 5 years. In 40% of the animals, a region of diminished uptake was observed at the irradiation site, The regions of diminished uptake of the radiopharmaceutical agent became smaller with time. Light microscopic examination revealed severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1 to 2 years after irradiation. At 3 and 5 years, vascular changes with endothelial proliferation and focal arteriolar hyalinosis were observed, This study demonstrates that intraoperative irradiation of a part of the liver in the canine model can be applied safely. Light microscopy confirmed that histological damage was not always accompanied by diminished uptake of the radiopharmaceutical agent at the irradiation site. (C) 2000 by Radiation Research Society.

OBJECTIVE: To monitor liver regeneration following partial hepatectomy, liver cell proliferation can be measured by assaying in vivo [H-3]thymidine incorporation into liver cell DNA. We hypothesized that [H-3]thymidine incorporation into whole liver tissue parallels [H-3]thymidine incorporation into liver cell DNA, both in high proliferating and low proliferating liver. STUDY DESIGN: Liver cell proliferation in rats after partial hepatectomy or a sham operation was studied by measuring incorporation of [H-3]thymidine into various fractions of liver tissue on days 1, 2, 3, 4 and 10 after surgery. RESULTS: [H-3]thymidine incorporation into whole with DNA-specific [H-3]thymidine incorporation into regenerating (r > .80, P .69, P

Purpose: The histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT) were investigated in order to establish the tolerance of liver tissue to IORT, thus providing a framework for clinical IORT treatment of patients with metastatic disease to the liver. Materials and methods: Following partial resection of the liver, IORT in doses of 10, 20, 25, or 30Gy was applied to the resection plane and a non-surgically manipulated part of the liver of 25 beagles. Results: There were no postoperative complications, and no morbidity or mortality during a maximal follow-up of 5 years. Dogs were killed at. 3 months, and 1, 2, 3 and 5 years folloning IORT. Light microscopic examination revealed capsular thickening, severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1-2 years following IORT. At 3-5 years, however, only mild parenchymal changes were found that:consisted of slight periportal fibrosis, an incidental portal-central fibrous septum and vascular changes with endothelial proliferation and focal arteriolar hyalinosis. Conclusions: This study demonstrated that following partial hepatic resection, IORT to the liver in the canine model can be applied safely, without short- or long-term treatment morbidity. Although doses up to 30Gy resulted in severe local tissue damage 1-2 years following IORT, these changes were largely reversible due to hepatic regeneration.

The liver was among the first organs in which connexin proteins have been identified. Hepatocytes harbor connexin32 and connexin26, while non-parenchymal liver cells typically express connexin43. Connexins give rise to hemichannels, which dock with counterparts on adjacent cells to form gap junctions. Both hemichannels and gap junctions provide pathways for communication, via paracrine signaling or direct intercellular coupling, respectively. Over the years, hepatocellular gap junctions have been shown to regulate a number of liver-specific functions and to drive liver cell growth. In the last few years, it has become clear that connexin hemichannels are involved in liver cell death, particularly in hepatocyte apoptosis. This also holds true for hemichannels composed of pannexin1, a connexin-like protein recently identified in the liver. Moreover, pannexin1 hemichannels are key players in the regulation of hepatic inflammatory processes. The current paper provides a concise overview of the features of connexins, pannexins and their channels in the liver. ispartof: FRONTIERS IN PHYSIOLOGY vol:4 ispartof: location:Switzerland status: published