The Prognostic Impact of Leucine-Rich α-2-Glycoprotein-1 in Cholangiocarcinoma and Its Association With the IL-6/TGF-ß1 Axis.

BACKGROUND: Leucine-rich α-2-glycoprotein-1 (LRG) has been found to participate in the development of various cancers through its involvement in TGF-ß1-induced epithelial-mesenchymal transition (EMT) and/or angiogenesis and can be induced by inflammatory cytokines, such as IL-6. As we previously showed the implication of IL-6/TGF-ß axis in EMT of cholangiocarcinoma cells, we herein explored the prognostic impact of LRG in postoperative intrahepatic cholangiocarcinoma (ICC) and assessed the association between tumor LRG and factors such as TGF-ß1, IL-6, and the tumor microvessel density. METHODS: We determined the expression of LRG, IL-6, TGF-ß1, and CD31 in cancer tissues from 50 ICC patients by immunohistochemistry and analyzed their association with the prognosis. RESULTS: The LRG expression was closely associated with recurrence-free survival (RFS) and overall survival (OS) in postoperative ICC. A multivariate Cox regression model indicated that LRG as an independently associated with poor RFS (hazard ratio = 2.4339, P = 0.0354) and OS (hazard ratio = 2.8892, P = 0.0268). The LRG expression was significantly associated with the expression of TGF-ß1 (P = 0.0003) and IL-6 (P = 0.0164). CONCLUSIONS: The upregulation of LRG in tumors was an independent prognostic factor in patients with postoperative ICC. LRG was closely associated with the TGF-ß1 expression and seems to be an important member of the IL-6/TGF-ß1 axis.

Dynamic contrast-enhanced ultrasound (DCE-US) for the characterization of hepatocellular carcinoma and cholangiocellular carcinoma.

PURPOSE: In a prospective study, we compared the different perfusion kinetics of HCC and ICC using dynamic contrast-enhanced ultrasound (DCE-US). MATERIALS AND METHODS: Patients with proven HCC and ICC were included. Three-minute video clips of CEUS examinations (CPS - low MI mode) after a bolus injection of 1.2 ml SonoVue were recorded and analyzed with quantification software (VueBox). Parameters for the arterial contrast enhancement [rise time (RT), time-to-peak (TTP)] towards portal venous contrast enhancement [mean transit time (local) (mTTl) and fall time (FT)] were quantified. Furthermore, contrast wash-out after peak enhancement (PE) (40 s, 80 s, 100 s and 120 s after PE) was compared between HCC and ICC. RESULTS: 43 patients with proven HCC (n = 23 HCC; cirrhosis n = 16) and ICC (n = 20 ICC; Cirrhosis n = 6) were examined. No statistical difference of the arterial DCEUS parameters was found between HCC and ICC. Contrast enhancement of the portal venous and late phases showed significantly lower values in the ICC group indicating early wash-out of the contrast agent: mTTl (p = 0.0209): HCC 118.4 s (SD±â€Š88.4); ICC 64.8 s (SD±â€Š49.7). FT (p = 0.0433): HCC 42.5 s (SD±â€Š27.7); ICC 27.7 s (SD±â€Š16.2). The percental loss of intensity at a definite time point after PE was significantly higher in ICC than in HCC lesions. CONCLUSION: DCE-US is able to detect and quantify differences in perfusion kinetics between HCC and ICC. Whereas arterial contrast enhancement patterns may overlap between HCC and ICC, a timed characterization of wash-out kinetics may offer an additional tool to characterize HCC and ICC. The presence of a rapid loss of signal intensity in the early portal venous phase is significantly higher in ICC than in HCC lesions.

Tumor size predicts vascular invasion and histologic grade among patients undergoing resection of intrahepatic cholangiocarcinoma.

The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) undergoing surgical resection is controversial. We sought to define the incidence of major and microscopic vascular invasion relative to ICC tumor size, and identify predictors of microscopic vascular invasion in patients with ICC ≥5 cm. A total of 443 patients undergoing surgical resection for ICC between 1973 and 2011 at one of 11 participating institutions were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. As tumor sized increased, the incidence of microscopic vascular invasion increased: <3 cm, 3.6 %; 3-5 cm, 24.7 %; 5-7 cm, 38.3 %; 7-15 cm, 32.9 %, ≥15 cm, 55.6 %; (p < 0.001). Increasing tumor size was also found to be associated with worsening tumor grade. The incidence of poorly differentiated tumors increased with increasing ICC tumor size: <3 cm, 9.7 %; 3-5 cm, 19.8 %; 5-7 cm, 24.2 %; 7-15 cm, 21.1 %; >15 cm, 31.6 % (p = 0.04). The presence of perineural invasion (odds ratio [OR] = 2.98) and regional lymph node metastasis (OR = 4.43) were independently associated with an increased risk of microscopic vascular invasion in tumors ≥5 cm (both p < 0.05). Risk of microscopic vascular invasion and worse tumor grade increased with tumor size. Large tumors likely harbor worse pathologic features; this information should be considered when determining therapy and prognosis of patients with large ICC.

[A case of curative resection after downsizing chemotherapy in initially unresectable locally advanced intrahepatic cholangiocarcinoma].

This case report describes an 83-year-old man with intrahepatic cholangiocarcinoma who was referred by a local hospital. Abdominal computed tomography (CT) showed a large tumor in hepatic segments 4, 5, and 8 involving the right hepatic vein and inferior vena cava, which is normally indicative of an unresectable locally advanced tumor. After systemic chemotherapy with gemcitabine and cisplatin, the observed decrease in the level of tumor marker suggested that the cancer was responding to treatment, while radiological findings showed the main tumor shrunk without the presence of distant metastases. Thus, hepatic left trisectionectomy with bile duct resection was performed after portal vein embolization. Pathological examination revealed negative margins (R0). Eighteen months after surgery, the patient is free of disease and shows no signs of recurrence. An initially unresectable, locally advanced biliary tract cancer may be down sized by chemotherapy, which makes radical resection possible, at least in a proportion of patients. This approach provides longer survival and may have a potential for disease eradication as a new multidisciplinary approach for patients with unresectable locally advanced biliary tract cancer.

[Hepatic inferior vena cava resection and vascular prosthesis reconstruction for locally advanced intrahepatic cholangiocarcinoma - a case report].

A 61-year-old woman was referred to our hospital because of jaundice and general itching. Computed tomography (CT) scan demonstrated that the tumor was located in the caudate lobe of the liver with hilar invasion and involved the hepatic inferior vena cava (IVC) and the right renal artery and vein. The patient was diagnosed with locally advanced intrahepatic cholangiocarcinoma, for which she underwent right hemihepatectomy with right caudate lobectomy, portal vein resection, hepatic IVC resection, extrahepatic bile duct resection, and right nephrectomy. IVC was reconstructed using vascular prosthesis by expanded polytetrafluoroethylene (ePTFE)-ringed graft. The patient's postoperative course was uneventful. The patient was treated with gemcitabine for postoperative chemotherapy, and 3 years after the operation, she died due to recurrence resulting from peritoneal dissemination. Although the thrombosis-related vascular prosthesis obstruction had occurred 2 years after the operation, no clinical symptom were noted, such as lower leg edema or renal dysfunction, during the postoperative course. Hepatic IVC prosthesis reconstruction for locally advanced cancer with extensive IVC invasion can be a useful surgical procedure for improving the resection rate and maintaining quality of life (QOL) in such cases.

[A case of curatively resected intrahepatic cholangiocarcinoma with hepatic artery and portal vein reconstruction].

We report a case of curatively resected intrahepatic cholangiocarcinoma (ICC) with hepatic artery (HA) and portal vein (PV) reconstruction. A 25-year-old man was diagnosed with ICC. Computed tomography (CT) showed that the tumor had invaded the left and common hepatic duct, the right and left HA, and the main branch of the PV. Because the posterior HA was tumor free, we performed a left trisegmentectomy, PV and HA resection and reconstruction, and a hepatocholangiojejunostomy. Pathological examination revealed a tumor classification of T3, N1, M0, Stage IVB. The patient was discharged on postoperative day 59 and gemcitabine (1,000 mg/m²) was administered as adjuvant chemotherapy. However, abdominal CT revealed peritoneal metastasis 8 months after the surgery. A gemcitabine, cisplatin, and TS-1 (GCS) regimen was selected as treatment, and the patient is alive 13 months after surgery.

Vascular biology of the biliary epithelium.

Cholangiocytes are involved in a variety of processes essential for liver pathophysiology. To meet their demanding metabolic and functional needs, bile ducts are nourished by their own arterial supply, the peribiliary plexus. This capillary network originates from the hepatic artery and is strictly arranged around the intrahepatic bile ducts. Biliary and vascular structures are linked by a close anatomic and functional association necessary for liver development, normal organ physiology, and liver repair. This strong association is finely regulated by a range of angiogenic signals, enabling the cross talk between cholangiocytes and the different vascular cell types. This review will briefly illustrate the "vascular" properties of cholangiocytes, their underlying molecular mechanisms and the relevant pathophysiological settings.

Improvement of ischemic cholangiopathy in three patients with hereditary hemorrhagic telangiectasia following treatment with bevacizumab.

The ischemic biliary phenotype of hereditary hemorrhagic telangiectasia (HHT) is rare but distinct, with progressive biliary tree ischemia usually resulting in an irreversible secondary sclerosing cholangiopathy. When clinically severe, liver transplant is often indicated. We report three patients with marked HHT associated biliary disease, in whom prolonged anti-vascular endothelial growth factor therapy (bevacizumab) notably reversed imaging evidence of biliary disease and clinically obviated need for liver transplantation during the first year of follow-up.

Computed tomography virtual endoscopy with angiographic imaging for the treatment of type IV-A choledochal cyst.

Type IV-A choledochal cysts (CCs) are a congenital biliary anomaly which involve dilatation of the extrahepatic and intrahepatic bile ducts. We present the case of a 30-year-old woman with type IV-A CC, on whom three-dimensional computed tomography (3D CT) and virtual endoscopy were performed. 3D CT revealed partial dilatation in the posterior branch of the intrahepatic bile duct and a relative stricture between it and the extrahepatic bile duct. Virtual endoscopy showed that this stricture was membrane-like and separated from the surrounding blood vessels. Based on these image findings, complete cyst resection, bile duct plasty for the stricture, and hepaticojejunostomy were safely performed. To the best of our knowledge, there are no reports of imaging by virtual endoscopy of the biliary tract which show the surrounding blood vessels running along the bile duct.

Protection of the intrahepatic biliary tree by contemporaneous portal and arterial reperfusion: results of a prospective randomized pilot study.

Sequential portal and arterial revascularization (SPAr) is the most common method of graft reperfusion at liver transplantation (LT), contemporaneous portal and arterial revascularization (CPAr) was used to reduce arterial ischemia to the bile ducts. Aim of this pilot study is to prospectively compare SPAr (group 1 #38) versus CPAr (group 2 #42) in 80 consecutive LTs. Biliary anastomosis was always duct to duct [T-tube in 21 % of cases (p = 0.83) in both groups]. CPAr had longer warm ischemia 61 ± 10 versus 39 ± 13 min, p < 0.0001, while SPAr had longer arterial ischemia 96 ± 39 min (p = 0.0001). No PNF while DGF was encountered in 10 versus 5 % (p = 0.32). One-year graft and patient's survival were respectively 87 versus 93 % and 83 versus 88 % in groups 1 and 2 (p = 0.31 and p = 0.39). At a median follow-up of 19 ± 8 versus 17 ± 8 months (p = 0.24), biliary complications were 28 %, being 39 % in group 1 and 19 % in group 2 (p = 0.04). Anastomotic stenoses were present in 11 versus 12 % (p = 0.84), biliary leakage in 5 versus 5 % (p = 0.72) and intrahepatic non-anastomotic biliary strictures in 23 versus 0 % (p = 0.0008) in groups 1 and 2. CPAr is safe and feasible and reduces the incidence of intrahepatic biliary strictures by decreasing the duration of arterial ischemia to the intrahepatic bile ducts.

Liver tumor characterization--comments and illustrations regarding guidelines.

Contrast-enhanced ultrasound (CEUS) is a well established diagnostic imaging technique for a variety of indications and applications. One of the most important applications is in the liver where it is frequently a first-line technique for the detection and diagnosis (characterization) of focal liver lesions (FLLs). In this setting the accurate differentiation of benign lesions from malignant lesions is critical to ensure that the patient undergoes the appropriate therapeutic option. In this article the role of CEUS in the characterization of FLLs is described on the basis of recently published guidelines, in particular in terms of the enhancement patterns of the most common FLLs, e. g. hemangioma, focal nodular hyperplasia, hepatocellular adenoma and their differentiation from malignant lesions.

Liver tumor characterization--review of the literature.

Multicenter trials to assess contrast-enhanced ultrasound (CEUS) for the imaging of focal liver lesions (FLLs) have included more than 1000 patients. This article reviews the published literature pertaining to these trials to determine the role of CEUS in the characterization of FLL.

Contrast-enhanced ultrasound (CEUS) in the diagnostic algorithm of hepatocellular and cholangiocellular carcinoma, comments on the AASLD guidelines.

Contrast-enhanced ultrasound (CEUS) has long been present in important guidelines and recommendations for the diagnostic work-up of focal liver lesions in patients with cirrhosis. These guidelines have included the guidelines of the American Association for the Study of Liver Diseases (AASLD) 2005, the Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma, the recommendations of the Japanese Society of Hepatology, and the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines 2004, 2008 and 2012 (in preparation). Recently, the AASLD removed CEUS from their guidelines in part because of the perceived possibility of false-positive hepatocellular carcinoma (HCC) diagnosis in patients with intrahepatic cholangiocarcinoma (ICC), and in part because CEUS is not available in the USA. This latter factor means that published results are not entirely applicable to a North American population. The present manuscript discusses the diagnostic algorithm of hepatocellular carcinoma and provides information on the differential diagnosis between HCC and ICC.

Covered metallic stent for ischemic hilar biliary stricture.

Compared with surgery, endoscopic treatment is safe and highly effective for a postoperative hilar benign bile duct stricture (BDS). However, the long-term outcome of conventional placement of a single biliary stent for hilar benign BDS is generally poor. Although the placement of multiple biliary stents is preferred, multiple stenting in a BDS is difficult. Alternatively, single or multiple stent placement above the papilla ('inside stent') or fully-covered self-expandable metallic stents (SEMS) are feasible approaches for benign BDS. Nevertheless, controversy remains regarding whether and how to perform endoscopic biliary drainage for a hilar benign BDS. In patients with hilar benign BDS, endoscopic biliary drainage can be performed by placing conventional plastic stents across the papilla, plastic stents above the papilla or fully-covered SEMS. Individualized treatment should be considered. We report the placement of a fully-covered SEMS for a hilar benign biliary stricture after extended left hepatectomy.

Intrahepatic cholangiocarcinomas in cirrhosis are hypervascular in comparison with those in normal livers.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinomas (ICCs) are usually adenocarcinomas with fibrotic and hypovascular stroma. Intrahepatic cholangiocarcinomas in cirrhosis and precirrhotic liver (ICC-cirrhosis) are increasingly being diagnosed, and can display hypervascular enhancement resembling a hepatocellular carcinoma on dynamic imaging. METHODS: In this study using ICC-cirrhosis (71 cases), ICC with non-specific reactive changes (ICC-reactive) (72 cases) and the cholangiocarcinoma component of combined hepatocellular cholangiocarcinoma (HCC-ICC) (30 cases), we tried to compare the tumour vasculature. RESULTS: It was found that ICC-cirrhosis and the cholangiocarcinoma component of HCC-ICC showed a higher density of arteries and microvessels (1.59 ± 0.58/mm(2) (mean ± SD) and 140 ± 43/mm(2) in ICC-cirrhosis and 1.74 ± 0.67/mm(2) and 131 ± 46/mm(2) in the cholangiocarcinoma component of HCC-ICC) than in ICC-reactive (1.26 ± 0.61/mm(2) and 103 ± 45/mm(2) ). Dynamic computed tomography (CT) and magnetic resonance imaging (MRI) showed that a majority of ICC-cirrhosis displayed strong hypervascular enhancement, whereas one-third of ICC-reactive each showed strong, weak and no or minimal enhancement respectively. The increased vascular density was positively correlated with enhanced arterial phase of dynamic CT and MRI. CONCLUSION: The density of arteries and microvessels of ICC-cirrhosis was higher than that in ICC-reactive and comparable to that in the cholangiocarcinoma component of HCC-ICC, and the higher density of arteries and microvessels in ICC may be responsible for the hypervascular enhancement of ICC-cirrhosis.

Intrahepatic biliary cystadenoma and cystadenocarcinoma: an experience of 30 cases.

BACKGROUND AND OBJECTIVES: Intrahepatic biliary cystadenoma and biliary cystadenocarcinoma are extremely rare neoplasms of the liver. They share similar radiological characteristics, and the clinicopathological features are poorly defined. We aim to provide an algorithm for preoperative differentiation of the two diseases. METHODS: Patients who underwent liver resection between May 2001 and May 2011 at Peking Union Medical College Hospital with biliary cystadenoma (20 cases) and biliary cystadenocarcinoma (10 cases) were reviewed. RESULTS: Significant differences were shown in age (P=0.030), gender (P=0.002) and symptom duration (P=0.012). Most biliary cystadenomas occurred in women ≤60 years old (85%), whilst most biliary cystadenocarcinomas occurred in older males (50%). Shorter symptom duration indicated a higher risk of biliary cystadenocarcinoma. Arterial blood flow and wall/nodule enhancement tended to be more common in biliary cystadenocarcinoma, but the difference was not significant (P=0.348). A score system was developed. The case-by-case validation and leave-one-out cross-validation showed an accuracy of 95.5% and 90.9%, respectively. The discriminative accuracy for cases from another hospital during the same period was 90.9%. CONCLUSIONS: Older age, male gender, and shorter symptom duration are associated with higher possibility of biliary cystadenocarcinoma. Location and blood supply by radiology might be instrumental but still need further verification.

Effects of partial portal vein arterialization on the hilar bile duct in a rat model.

BACKGROUND: Liver revascularization is frequently required during the enlarged radical operation for hilar cholangiocarcinoma involving the hepatic artery. Researchers have carried out a number of experiments applying partial portal vein arterialization (PVA) in clinical practice. In this study we aimed to establish a theoretical basis for clinical application of partial PVA and to investigate the effects of partial PVA on rat hilar bile duct and hepatic functions. METHODS: Thirty rats were randomly and equally assigned into 3 groups: control (group A), hepatic artery ligation+bile duct recanalization (group B), and partial PVA+bile duct recanalization (group C). Proliferation and apoptosis of rat hilar bile duct epithelial cells, arteriolar counts of the peribiliary plexus (PBP) of the bile duct wall, changes in serum biochemistry, and pathologic changes in the bile duct were assessed 1 month after operation. RESULTS: The proliferation of hilar bile duct epithelial cells in group B was greater than in groups A and C (P<0.01). No apoptotic hilar bile duct epithelial cells were detected in any of the groups. The PBP arteriolar counts of the hilar bile duct wall were similar in groups A and C (P>0.05), but the count was lower in group B than in group A (P<0.01). No statistically significant differences in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and albumin were found in the 3 groups. The gamma-glutamyltransferase value was higher in group B than in groups A and C (P<0.01). The hepatic tissues of groups A and C showed no significant abnormality. Chronic inflammatory changes in the hilar bile duct walls were observed only in group B. CONCLUSION: Partial PVA can restore the arterial blood supply of the hilar bile duct and significantly extenuate the injury to hilar bile duct epithelial cells resulting from hepatic artery ligation.