Wnt/ß-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction.

Background and aims: Wnt/ß-catenin signaling plays an important role in regulating hepatic metabolism. This study is to explore the molecular mechanisms underlying the potential crosstalk between Wnt/ß-catenin and mTOR signaling in hepatic steatosis. Methods: Transgenic mice (overexpress Wnt1 in hepatocytes, Wnt+) mice and wild-type littermates were given high fat diet (HFD) for 12 weeks to induce hepatic steatosis. Mouse hepatocytes cells (AML12) and those transfected to cause constitutive ß-catenin stabilization (S33Y) were treated with oleic acid for lipid accumulation. Results: Wnt+ mice developed more hepatic steatosis in response to HFD. Immunoblot shows a significant increase in the expression of fatty acid synthesis-related genes (SREBP-1 and its downstream targets ACC, AceCS1, and FASN) and a decrease in fatty acid oxidation gene (MCAD) in Wnt+ mice livers under HFD. Wnt+ mice also revealed increased Akt signaling and its downstream target gene mTOR in response to HFD. In vitro, increased lipid accumulation was detected in S33Y cells in response to oleic acid compared to AML12 cells reinforcing the in vivo findings. mTOR inhibition by rapamycin led to a down-regulation of fatty acid synthesis in S33Y cells. In addition, ß-catenin has a physical interaction with mTOR as verified by co-immunoprecipitation in hepatocytes. Conclusions: Taken together, our results demonstrate that ß-catenin stabilization through Wnt signaling serves a central role in lipid metabolism in the steatotic liver through up-regulation of fatty acid synthesis via Akt/mTOR signaling. These findings suggest hepatic Wnt signaling may represent a therapeutic strategy in hepatic steatosis.

Para-aortic lymph nodes and ductal adenocarcinoma of the pancreas: Distant neighbors?

BACKGROUND: Para-aortic lymph nodes in the ductal adenocarcinoma of the pancreatic head are regarded as distant metastases. Chemotherapy is considered the only treatment option if para-aortic lymph nodes metastases are detected preoperatively or intraoperatively. The role of standardized para-aortic lymph node lymphadenectomy during pancreaticoduodenectomy remains controversial. The aim of this study was to evaluate complication profiles and survival. METHODS: All cases of ductal adenocarcinoma of the pancreatic head were evaluated from a prospectively maintained database (n = 289). Para-aortic lymph node lymphadenectomy was routinely performed in all patients with suspected ductal adenocarcinoma of the pancreatic head. Subgroup analysis was performed between patients with histologically positive (+) and negative (-) para-aortic lymph nodes. Patients receiving pancreaticoduodenectomy without para-aortic lymph node lymphadenectomy for other causes served as a control group. RESULTS: A total of 192 patients received para-aortic lymph node lymphadenectomy, of which 41 were positive for para-aortic lymph node metastases. In 97 patients with ductal adenocarcinoma of the pancreatic head, no para-aortic lymph node lymphadenectomy was performed owing to postoperative pancreatic ductal adenocarcinoma diagnosis. Clinicopathologic data were homogenously distributed. Hospital stay and postoperative morbidity demonstrated no significant difference between the 3 subgroups. The median overall survival of 19.63 months (95% confidence interval: 14.57-24.79 months) in para-aortic lymph node- patients was not statistically different when compared with the median overall survival of 18.22 months (95% confidence interval: 12.68-23.75 months) in para-aortic lymph node + patients (log-rank test P = .223). Preoperative computed tomography was a poor predictor for para-aortic lymph node status (sensitivity = 10.3%, specificity = 97.8%). CONCLUSION: This study represents the largest cohort receiving routine para-aortic lymph node lymphadenectomy. Extended lymphadenectomy can be performed safely and, although disease-free survival of para-aortic lymph node+ patients was significantly shorter, overall survival and postrelapse survival were on par with that of para-aortic lymph node- patients. Preoperative computed tomography indicating para-aortic lymph node metastasis should not preclude curative resection.

Variation in complications and mortality following ALPPS at early-adopting centers.

BACKGROUND: Various, often conflicting, estimates for post-operative morbidity and mortality following ALPPS have been reported in the literature, suggesting that considerable center-level variation exists. Some of this variation may be related to center volume and experience. METHODS: Using data from seventeen centers who were early adopters of the ALPPS technique, we estimated the variation, by center, in standardized 90-day mortality and comprehensive complication index (CCI) for patients treated between 2012 and 2018. RESULTS: We estimated that center-specific 90-day mortality following treatment with ALPPS varied from 4.2% (95% CI: 0.8, 9.9) to 29.1% (95% CI: 13.9, 50.9), and that center-specific CCI following treatment with ALPPS varied from 17.0 (95% CI: 7.5, 26.5) to 49.8 (95% CI: 38.1, 61.8). Declines in estimated 90-day mortality and CCI were observed over time, and almost all individual centers followed this trend. Patients treated at centers with a higher number of ALPPS cases performed over the prior year had a lower risk of post-operative mortality. CONCLUSION: Despite considerable center-level variation in ALPPS outcomes, perioperative outcomes following ALPPS have improved over time and treatment at higher volume centers results in a lower risk of 90-day mortality. Morbidity and mortality remain concerningly high at some centers.

Platelets Boost Recruitment of CD133+ Bone Marrow Stem Cells to Endothelium and the Rodent Liver-The Role of P-Selectin/PSGL-1 Interactions.

We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133+BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133+BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair.

CD133+ bone marrow stem cells (BMSC) control platelet activation - Role of ectoNTPDase-1 (CD39).

BACKGROUND: We previously demonstrated CD133+ bone marrow stem cells (BMSC) to promote hepatic proliferation for liver regeneration. Here, we evaluated the capacity of CD133+BMSC to utilize platelets for homing to vasculature and concomitant controlling their aggregability upon ADP stimulation. METHODS: CD133+BMSC and platelets were co-cultured along micro endothelial cells under variable flow conditions and tested for homing levels along vasculature. Aggregometry and FACS analysis were utilized to evaluate platelet reactivity following co-incubation ±â€¯CD133+BMSC. RT-PCR and FACS analyses served to characterize ADP degrading ectonucleoside triphosphate diphosphohydrolase-1 (ectoNTPDase-1/CD39) expression on various cell types. RESULTS: Platelets attracted human CD133+BMSC to autologous micro endothelium under shear stress unaffected by ADP stimulation. However, CD133+BMSC inhibited ADP-mediated platelet activation and aggregation. Latter was dependent on ectoNTPDase-1 expression levels. Platelet aggregatory control was increased with CD133+BMSC compared to CD133+PHSC. Different effects of those stem cell subtypes positively correlated with their FACS-detected expression levels of ectoNTPDase-1. CONCLUSION: We provide evidence that CD133+BMSC are capable of controlling ADP-dependent platelet aggregation and activation by direct interaction dependent on cellular expression of ectoNTPDase-1. Whether different capacities of BMSC modulate platelet-depending thrombogenicity at sites of regeneration impact effectiveness and adverse event profiles of regenerative treatment requires further evaluation.

ACGH detects distinct genomic alterations of primary intrahepatic cholangiocarcinomas and matched lymph node metastases and identifies a poor prognosis subclass.

Lymph node metastases (LNM) are an important prognostic factor for patients with intrahepatic cholangiocarcinoma, but underlying genetic alterations are poorly understood. Whole genome array comparative genomic hybridization (aCGH) was performed in 37 tumors and 14 matched LNM. Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA). Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p). LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)]. Unsupervised clustering revealed a poor prognosis subclass with increased alterations significantly associated to tumor differentiation and survival. TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases. Pathway analyses revealed association to cancer-associated pathways. Advanced tumor stage, microvascular/perineural invasion, and microscopic positive resection margin (R1) were significantly correlated to metastases, while N1-status, R1-resection, and poor tumor differentiation were significantly correlated to survival. ACGH identified clear differences between N0 (no LNM) and N1 tumors, while N1 tumors and matched LNM displayed high clonality with exclusive gains in the metastases. A novel subclass with increased CNAs and poor tumor differentiation was significantly correlated to survival.

Augmented Wnt signaling as a therapeutic tool to prevent ischemia/reperfusion injury in liver: Preclinical studies in a mouse model.

The Wnt signaling pathway has established biological roles in liver development, regeneration, and carcinogenesis. Given the common need for cellular energy utilization in each of these processes, we hypothesized that Wnt signaling would directly regulate hepatocyte mitochondrial function. Mice were engineered to overexpress Wnt1 in hepatocytes under the control of a tetracycline analogue. Wnt1 and wild-type mice underwent ischemia/reperfusion injury (IRI) to induce oxidative mitochondrial injury. Alpha mouse liver 12 (AML12) hepatocytes were exposed to Wnt agonists for in vitro hypoxia/reoxygenation (H-R) experiments. We observed stabilized mitochondrial membrane potential and reduced levels of hepatocyte apoptosis involving the mitochondrial pathway in Wnt1 mice compared to controls following IRI. Wnt1 mice also demonstrated increased mitochondrial DNA copy number, as well as an increased tricarboxylic acid cycle activity and adenosine triphosphate levels indicating that mitochondrial function is preserved by Wnt1 overexpression following IRI. AML12 cells treated by Wnt3a or the glycogen synthase kinase 3ß inhibitor LiCl exposed to H-R demonstrated decreased reactive oxygen species and reduced apoptosis compared to controls. Increased nucleus-localized PGC-1α and phosphorylated SIRT1 was observed in both Wnt1+ mice as well as AML12 cells treated with Wnt3a or LiCl. Activated Wnt signaling protects hepatocytes against oxidative injury and apoptosis through mitochondrial stabilization and preserved oxidative phosphorylation function. Mechanistically, these effects are accompanied by an increase in phosphorylated SIRT1 and nucleus-localized PGC-1α. These findings expand the understanding of Wnt signaling biology in hepatocytes and suggest the potential for the therapeutic application of Wnt pathway manipulation in a variety of clinical applications including organ transplantation.

HGF and SDF-1-mediated mobilization of CD133+ BMSC for hepatic regeneration following extensive liver resection.

BACKGROUND: The molecular mechanisms of haematopoietic stem cells (HSC) mobilization and homing to the liver after partial hepatectomy (PH) remain largely unexplored. METHODS: Functional liver volume loss and regain was determined by computerized tomography (CT) volumetry in 30 patients following PH. Peripheral HSC mobilization was investigated by fluorescence-activated cell sorting (FACS) analyses and cytokine enzyme-linked immunosorbent assay assays. Migration of purified HSC towards hepatic growth factor (HGF) and stroma-derived factor-1 (SDF-1) gradients was tested in vitro. Mice after 70% PH were examined for HSC mobilization by FACS and cytokine mRNA expression in the liver. FACS-sorted HSC were administered after PH and hepatocyte proliferation was evaluated by immunohistochemical staining for Ki67. RESULTS: Impaired liver function was noted after extended hepatic resection when compared to smaller resections. Patients with large liver resections were characterized by significantly higher levels of peripheral HSC which were positively correlated with the extent of resected liver volume and its regain after 3 weeks. Increased plasma levels of HGF, SDF-1 and insulin like growth factor (IGF-1) were evident within the first 6 hours post resection. Migration assays of human HSC in vitro showed a specific target-demonstrated migration towards recombinant HGF and SDF-1 gradients in a concentration and specific receptor (c-Met and CXCR4) dependent manner. The evaluation of peripheral human alpha foetoprotein expression demonstrated pronounced stemness following increased CD133(+) HSC in the course of liver regeneration following PH. Our human data were further validated in a murine model of PH and furthermore demonstrated increased hepatocyte proliferation subsequent to CD133(+) HSC treatment. CONCLUSION: HGF and SDF-1 are required for effective HSC mobilization and homing to the liver after hepatic resection. These findings have significant implications for potential therapeutic strategies targeting chemotactant modulation and stem cell mobilization for liver protection and regeneration.

"Cherry picking", a multiple non-anatomic liver resection technique, as a promising option for diffuse liver metastases in patients with neuroendocrine tumours.

INTRODUCTION: Liver metastases of GEP-NETs are a known major prognostic factor with a strong effect on patients' survival. To date, various treatment options are available, whereas surgery remains the only curative option. Because large liver resections often cannot be performed due to insufficient remnant liver volume, a special operative technique, "cherry picking" (multiple nonanatomic liver resections), can be used as a tissue-preserving procedure. METHODS: Of 91 patients with various GEP-NETs, 16 patients were identified with synchronous or metachronous multifocal, bilobular liver metastases (>10). All were treated with "cherry picking." Patient records were reviewed retrospectively and clinical data and pathology results were analyzed. RESULTS: Mean survival after primary tumour resection was 82.8 versus 41.2 months after liver surgery. All 16 patients are still alive. Mean recurrence-free survival after primary tumour operation was 49.8 versus 24.6 months after liver surgery. Complications of cherry picking included two postoperative biliary leakages and three small hepatic abscesses (conservative/interventional approach 25 % (n = 4), surgical approach 6.25 % (n = 1). There was no postoperative mortality. Initial hormonal symptoms (5/16 patients) completely disappeared postoperatively in 2 patients and were significantly decreased in 3 patients. CONCLUSIONS: The tissue-preserving surgical technique "cherry picking" has developed due to improved imaging techniques and increased knowledge in liver anatomy, which has helped to make this approach safer and easier. Highly selected patients with multiple bilobular liver metastases of GEP-NET can benefit from this special surgical approach, also applicable for recurrent metastases.

Eosinophils secrete IL-4 to facilitate liver regeneration.

The liver is a central organ for the synthesis and storage of nutrients, production of serum proteins and hormones, and breakdown of toxins and metabolites. Because the liver is susceptible to toxin- or pathogen-mediated injury, it maintains a remarkable capacity to regenerate by compensatory growth. Specifically, in response to injury, quiescent hepatocytes enter the cell cycle and undergo DNA replication to promote liver regrowth. Despite the elucidation of a number of regenerative factors, the mechanisms by which liver injury triggers hepatocyte proliferation are incompletely understood. We demonstrate here that eosinophils stimulate liver regeneration after partial hepatectomy and toxin-mediated injury. Liver injury results in rapid recruitment of eosinophils, which secrete IL-4 to promote the proliferation of quiescent hepatocytes. Surprisingly, signaling via the IL-4Rα in macrophages, which have been implicated in tissue repair, is dispensable for hepatocyte proliferation and liver regrowth after injury. Instead, IL-4 exerts its proliferative actions via IL-4Rα in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver.

Wnt/ß-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3.

Numerous liver diseases are associated with extensive oxidative tissue damage. It is well established that Wnt/ß-catenin signaling directs multiple hepatocellular processes, including development, proliferation, regeneration, nutrient homeostasis, and carcinogenesis. It remains unexplored whether Wnt/ß-catenin signaling provides hepatocyte protection against hepatotoxin-induced apoptosis. Conditional, liver-specific ß-catenin knockdown (KD) mice and their wild-type littermates were challenged by feeding with a hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce chronic oxidative liver injury. Following the DDC diet, mice with ß-catenin-deficient hepatocytes demonstrate increased liver injury, indicating an important role of ß-catenin signaling for liver protection against oxidative stress. This finding was further confirmed in AML12 hepatocytes with ß-catenin signaling manipulation in vitro using paraquat, a known oxidative stress inducer. Immunofluorescence staining revealed an intense nuclear FoxO3 staining in ß-catenin-deficient livers, suggesting active FoxO3 signaling in response to DDC-induced liver injury when compared with wild-type controls. Consistently, FoxO3 target genes p27 and Bim were significantly induced in ß-catenin KD livers. Conversely, SGK1, a ß-catenin target gene, was significantly impaired in ß-catenin KD hepatocytes that failed to inactivate FoxO3. Furthermore, shRNA-mediated deletion of FoxO3 increased hepatocyte resistance to oxidative stress-induced apoptosis, confirming a proapoptotic role of FoxO3 in the stressed liver. Our findings suggest that Wnt/ß-catenin signaling is required for hepatocyte protection against oxidative stress-induced apoptosis. The inhibition of FoxO through its phosphorylation by ß-catenin-induced SGK1 expression reduces the apoptotic function of FoxO3, resulting in increased hepatocyte survival. These findings have relevance for future therapies directed at hepatocyte protection, regeneration, and anti-cancer treatment.

Notch 1 tumor expression is lacking in highly proliferative pancreatic neuroendocrine tumors.

To date, very little is known about the development of benign organic hyperinsulinism and its metastatic potential. Typical morphologic, biochemical, or genetic differentiations for benign or malign tumor course of insulinomas do not exist. As signaling pathways may affect pancreatic cancer development and the maintenance of the neoplastic phenotype, the purpose of this study was to examine the role of Notch1 expression in organic hyperinsulinism. We examined 32 well-differentiated pancreatic endocrine tumors (wd PET); 11 wd PET of unknown behavior (wd PET ub); and 15 wd pancreatic endocrine cancer (wd PEC) for Notch1 expression by immunohistochemistry. Demographic data, clinical data, and follow-up of all patients were analyzed. Islets of the Langerhans show the strongest Notch1 staining in nearly 90 %. Positive Notch1 staining was absent in the acinar of the pancreas. In patients with a wd PET more than every second tumor (56.3 %/n = 18/32) demonstrated a negative Notch1 staining. The other 14 patients were positive for Notch1. Tumors of unknown behavior (wd PET ub) and malignant insulinomas had no signs of Notch expression in contrast to benign insulinomas. Considering the clinical and histomorphological tumor behavior, no correlation between Notch1 expression and clinical data was found. The missing Notch expression in the malignant tumor course might be used as a potential predictive marker, but further studies are needed to investigate the underlying molecular mechanism.

SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas.

The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.

ß-Catenin regulates hepatic mitochondrial function and energy balance in mice.

BACKGROUND & AIMS: Wnt signaling regulates hepatic function and nutrient homeostasis. However, little is known about the roles of ß-catenin in cellular respiration or mitochondria of hepatocytes. METHODS: We investigated ß-catenin's role in the metabolic function of hepatocytes under homeostatic conditions and in response to metabolic stress using mice with hepatocyte-specific deletion of ß-catenin and their wild-type littermates, given either saline (sham) or ethanol (as a model of binge drinking and acute ethanol intoxication). RESULTS: Under homeostatic conditions, ß-catenin-deficient hepatocytes demonstrated mitochondrial dysfunctions that included impairments to the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) and decreased production of adenosine triphosphate (ATP). There was no evidence for redox imbalance or oxidative cellular injury in the absence of metabolic stress. In mice with ß-catenin-deficient hepatocytes, ethanol intoxication led to significant redox imbalance in the hepatocytes and further deterioration in mitochondrial function that included reduced OXPHOS, fatty acid oxidation (FAO), and ATP production. Ethanol feeding significantly increased liver steatosis and oxidative damage, compared with wild-type mice, and disrupted the ratio of nicotinamide adenine dinucleotide. ß-catenin-deficient hepatocytes also had showed disrupted signaling of Sirt1/peroxisome proliferator-activated receptor-α signaling. CONCLUSIONS: ß-catenin has an important role in the maintenance of mitochondrial homeostasis, regulating ATP production via the tricarboxylic acid cycle, OXPHOS, and fatty acid oxidation; ß-catenin function in these systems is compromised under conditions of nutrient oxidative stress. Reagents that alter Wnt-ß-catenin signaling might be developed as a useful new therapeutic strategy for treatment of liver disease.

Intestinal involvement during 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced chronic liver injury in a mouse model.

PURPOSE: Although a physiologic relationship between intestinal mucosal integrity and hepatic function has been previously described, the effect of primary liver disease on intestinal mucosal homeostasis has not been previously well documented. In the current study, we studied the effects of chronic liver injury as a primary injury on enterocyte turnover (proliferation and apoptosis) in a mouse model. METHODS: The liver toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet was used to induce chronic cholestatic liver injury in mice. Livers and intestine were harvested after 3 weeks of dietary treatment of histologic analysis and a determination of cell proliferation (immunohistochemistry for Ki67), or apoptosis (immunohistochemistry for caspase-3), as well as a determination of Wnt/ß-catenin signaling activity. RESULTS: All DDC-fed animals exhibited histologic evidence of liver damage that was associated with the expansion of atypical ductal proliferation near the periportal areas and increased oxidative stress. In the intestine, DDC-induced liver damage was associated with decreased villus height, decreased enterocyte proliferation, and increased cell apoptosis compared with control animals. There was also evidence for decreased ß-catenin expression by immunostaining in crypt and villus cells of DDC-fed mice compared with control animals. CONCLUSION: Primary liver injury and cholestasis is associated with intestinal mucosal hypoplasia. Decreased cell proliferation and increased cell apoptosis may be responsible for decreased intestinal epithelial cell mass. The observed decrease in cell turnover is accompanied by an alteration in Wnt/ß-catenin signaling.

Wnt-ß-catenin signaling protects against hepatic ischemia and reperfusion injury in mice.

BACKGROUND & AIMS: Ischemia and reperfusion injury are common causes of oxidative tissue damage associated with many liver diseases and hepatic surgery. The Wnt-ß-catenin signaling pathway is an important regulator of hepatic development, regeneration, and carcinogenesis. However, the role of Wnt signaling in the hepatocellular response to ischemia-reperfusion (I/R) injury has not been determined. METHODS: Hepatic injury following ischemia or I/R was investigated in hepatocyte-specific, ß-catenin-deficient mice, as well as Wnt1-overexpressing and wild-type (control) mice. RESULTS: Wnt-ß-catenin signaling was affected by the cellular redox balance in hepatocytes. Following ischemia or I/R, mice with ß-catenin-deficient hepatocytes were significantly more susceptible to liver injury. Conversely, mice that overexpressed Wnt1 in hepatocytes were resistant to hepatic I/R injury. Hypoxia inducible factor (HIF)-1α signaling was reduced in ß-catenin-deficient liver but increased in hepatocytes that overexpressed Wnt1 under hypoxia and following I/R, indicating an interaction between ß-catenin and HIF-1α signaling in the liver. The mechanism by which Wnt signaling protects against liver injury involves the role of ß-catenin as a transcriptional coactivator of HIF-1α signaling, which promotes hepatocyte survival under hypoxic conditions. CONCLUSIONS: Cellular redox balance affects Wnt-ß-catenin signaling, which protects against hypoxia and I/R injury. These findings might be used to develop strategies for protection of hepatocytes, regeneration of liver, and inhibition of carcinogenesis.

Unusual histological findings after partial pancreaticoduodenectomy including benign multicystic mesothelioma, adenomyoma of the ampulla of Vater, and undifferentiated carcinoma, sarcomatoid variant: a case series.

INTRODUCTION: The standard operation for carcinoma of the pancreatic head is a partial pancreaticoduodenectomy. Unusual histological findings may occasionally occur in the surgical specimen. We present three unusual histologic diagnoses after pancreaticoduodenectomy. CASE PRESENTATIONS: In the first case, an 86-year-old Caucasian woman was admitted with abdominal pain and nausea. Preoperative evaluation showed a 3 cm cystic lesion in the head of the pancreas. Pathology revealed a benign multicystic mesothelioma. In the second case, a 45-year-old Caucasian man complained of nausea, vomiting and general malaise for several months. Endoscopic retrograde cholangiopancreatographic examination and a computed tomography scan showed a stenosis of the distal bile duct secondary to a mass in the head of the pancreas and duodenum. Histology showed an adenomyoma of the ampulla. In the third case, a 59-year-old Caucasian man presented with chronic alcoholic pancreatitis. A computed tomography scan revealed a 3.5 cm lesion in the head of the pancreas with cystic and solid components. Pathology showed an undifferentiated carcinoma, sarcomatoid variant. CONCLUSION: Partial pancreaticoduodenectomy is usually performed for ductal adenocarcinomas, neuroendocrine tumors or chronic pancreatitis. Compared to the majority of the above diagnoses, the three cases in our study are very rare. Benign multicystic mesothelioma is a very rare tumor that originates from the peritoneum. Although it demonstrates a benign clinical behaviour, it frequently recurs after resection. Adenomyoma of the bile duct or ampullary region is a very unusual, benign, localized lesion characterized by adenomyomatous hyperplasia. Undifferentiated carcinoma, sarcomatoid variant, is an aggressive tumor and is characterized by spindle cells. As the lesions were suspicious for carcinoma, partial pancreaticoduodenectomy was justified in all three patients. The histologic diagnosis after partial pancreaticoduodenectomy may differ from the preoperative and intraoperative findings. These cases demonstrate that a definitive diagnosis may only be obtained by a pathologic examination of the surgical specimen.

Extrahepatic intraductal ectopic hepatocellular carcinoma: bile duct filling defect.

BACKGROUND: Obstructive jaundice caused by an intraductal hepatocellular carcinoma is a rare initial symptom. We report a rare case of an extrahepatic icteric type hepatocellular carcinoma. METHODS: A 75-year-old patient was admitted to our hospital because of obstructive jaundice 3 months after resection of multilocular hepatocellular carcinoma. A postoperative bile leakage was treated by placement of a decompressing stent in the common bile duct. Endoscopic retrograde choledochoscopy showed extended blood clots filling the bile duct system and computed tomography revealed a local swelling in the common extrahepatic bile duct. The level of alpha-fetoprotein (AFP) was only slightly elevated but that of CA19-9 was dramatically increased. Cholangiography showed an intraductal filling defect typical of a cholangiocellular carcinoma. RESULTS: Bile duct brushing cytology showed no cholangiocellular carcinoma but hepatocellular carcinoma cells in the extrahepatic bile duct. An extrahepatic bile duct resection was performed. Histological examination confirmed the diagnosis of extrahepatic intraductal growth of hepatocellular carcinoma. CONCLUSION: Ectopic hepatocellular carcinoma is a rare but important differentially diagnosed of extrahepatic bile duct filling defect.