Combined Vascular Resection for Locally Advanced Perihilar Cholangiocarcinoma.

OBJECTIVE: To evaluate the efficacy and safety of combined vascular resection (VR) in advanced perihilar cholangiocarcinoma (PHC). SUMMARY OF BACKGROUND DATA: Hepatectomy combined with portal vein resection (PVR) and/or hepatic artery resection (HAR) is technically demanding but an option only for tumor eradication against PHC involving the hilar hepatic inflow vessels; however, its efficacy and safety have not been well evaluated. METHODS: Patients diagnosed with PHC during 2001-2018 were included. Patients who underwent resection were divided according to combined VR. Patients undergoing VR were subdivided according to type of VR. Postoperative outcomes and OS were compared between patient groups. RESULTS: Among the 1055 consecutive patients, 787 (75%) underwent resection (without VR: n = 484, PVR: n = 157, HAR: n = 146). The incidences of postoperative complications and mortality were 49% (without VR vs with VR, 48% vs 50%; P= 0.715) and 2.1% (without VR vs with VR, 1.2% vs 3.6%; P= 0.040), respectively. The OS of patients who underwent resection with VR (median, 30 months) was shorter than that of those who underwent resection without VR (median, 61 months; P < 0.0001); however, it was longer than that of those who did not undergo resection (median, 10 months; P < 0.0001). OS was not significantly different between those who underwent PVR and those who underwent HAR (median, 29 months vs 34 months; P = 0.517). CONCLUSION: VR salvages a large number of patients from having locally advanced PHC that is otherwise unresectable and is recommended if the hilar hepatic inflow vessels are reconstructable, providing acceptable surgical outcomes and substantial survival benefits.

Prognostic impact of tumor microvessels in intrahepatic cholangiocarcinoma: association with tumor-infiltrating lymphocytes.

Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC. Immunohistochemical staining for cluster of differentiation 34 (CD34), cluster of differentiation 8 (CD8), forkhead box protein P3 (Foxp3), and programmed death-ligand 1 (PD-L1) was performed. The relationships between the MVD and clinicopathological characteristics and outcomes were analyzed. Additionally, the correlations between the MVD, CD8+ and Foxp3+ TIL counts, and PD-L1 expression were evaluated. One hundred ICC patients were classified into high (n = 50) and low (n = 50) MVD groups. The serum platelet and carbohydrate antigen 19-9 levels were higher in the low MVD group than in the high MVD group (P = 0.017 and P = 0.008, respectively). The low MVD group showed a significantly larger tumor size (P = 0.016), more frequent microvascular invasion (P = 0.001), and a higher rate of intrahepatic (P = 0.023) and lymph node (P < 0.001) metastasis than the high MVD group. Moreover, the MVD showed a high positive correlation with CD8+ TILs (r = 0.754, P < 0.001) and a negative correlation with Foxp3+ TILs (r = -0.302, P = 0.003). In contrast, no significant correlation was observed between the MVD and PD-L1 expression in cancer cells (P = 0.817). Patients with low MVDs had a significantly worse prognosis than those with high MVDs. Furthermore, multivariable analyses revealed that a low MVD influenced recurrence-free survival. A decreased intratumoral MVD might predict ICC patient outcomes. Tumor microvessels might be associated with ICC progression, possibly by altering TIL recruitment.

Dynamic 18F-FDG PET imaging of liver lesions: evaluation of a two-tissue compartment model with dual blood input function.

BACKGROUND: Dynamic PET with kinetic modeling was reported to be potentially helpful in the assessment of hepatic malignancy. In this study, a kinetic modeling analysis was performed on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) from dynamic FDG positron emission tomography/computer tomography (PET/CT) scans. METHODS: A reversible two-tissue compartment model with dual blood input function, which takes into consideration the blood supply from both hepatic artery and portal vein, was used for accurate kinetic modeling of liver dynamic 18F-FDG PET imaging. The blood input functions were directly measured as the mean values over the VOIs on descending aorta and portal vein respectively. And the contribution of hepatic artery to the blood input function was optimization-derived in the process of model fitting. The kinetic model was evaluated using dynamic PET data acquired on 24 patients with identified hepatobiliary malignancy. 38 HCC or ICC identified lesions and 24 healthy liver regions were analyzed. RESULTS: Results showed significant differences in kinetic parameters [Formula: see text], blood supplying fraction [Formula: see text], and metabolic rate constant [Formula: see text] between malignant lesions and healthy liver tissue. And significant differences were also observed in [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] between HCC and ICC lesions. Further investigations of the effect of SUV measurements on the derived kinetic parameters were conducted. And results showed comparable effectiveness of the kinetic modeling using either SUVmean or SUVmax measurements. CONCLUSIONS: Dynamic 18F-FDG PET imaging with optimization-derived hepatic artery blood supply fraction dual-blood input function kinetic modeling can effectively distinguish malignant lesions from healthy liver tissue, as well as HCC and ICC lesions.

Silencing of LAMC2 Reverses Epithelial-Mesenchymal Transition and Inhibits Angiogenesis in Cholangiocarcinoma via Inactivation of the Epidermal Growth Factor Receptor Signaling Pathway.

Cholangiocarcinoma (CCA) is a malignant cancer that is associated with high mortality rates. The relationship between laminin γ 2 chain gene (LAMC2) and epidermal growth factor receptor (EGFR) has been previously documented in gastric cancer and oral squamous cell carcinoma. This study investigates the role of LAMC2 in epithelial-mesenchymal transition (EMT) and angiogenesis in CCA and explores the underlying mechanism(s). Differentially expressed genes related to CCA were initially screened using a microarray analysis, and the interaction between LAMC2 and the EGFR signaling pathway was identified. To determine the regulatory effects of LAMC2 on CCA progression, LAMC2 was silenced or overexpressed and the EGFR signaling pathway was activated or blocked. Subsequently, the regulation effects of LAMC2 were evaluated on the expression of EMT markers, invasion and migration of CCA cells, as well as microvessel density in nude mice. Microarray analysis demonstrated that highly expressed LAMC2 is linked to CCA development, which involves the EGFR signaling pathway. When LAMC2 expression was increased, the EGFR signaling pathway and EMT were activated in CCA tissues. Silencing of LAMC2 as well as EGFR signaling pathway inhibition led to suppression of EMT, cell invasion, and migration abilities in vitro, as well as angiogenesis in vivo. This study demonstrates that LAMC2 silencing suppresses the activity of the EGFR signaling pathway, thus functioning as a tumor suppressor in CCA.

Combined hepatocellular-cholangiocarcinoma: which preoperative clinical data and conventional MRI characteristics have value for the prediction of microvascular invasion and clinical significance?

OBJECTIVES: To explore which preoperative clinical data and conventional MRI findings may indicate microvascular invasion (MVI) of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and have clinical significance. METHODS: The study enrolled 113 patients with histopathologically confirmed cHCC-CCA (MVI-positive group [n = 56], MVI-negative group [n = 57]). Two radiologists retrospectively assessed the preoperative MRI features (qualitative analysis of morphology and dynamic enhancement features), and each lesion was assigned according to the LI-RADS. Preoperative clinical data were also evaluated. Logistic regression analyses were used to assess the relative value of these parameters as potential predictors of MVI. Recurrence-free survival (RFS) rates after hepatectomy in the two groups were estimated using Kaplan-Meier survival curves and compared using the log-rank test. RESULTS: The majority of cHCC-CCAs were categorized as LR-M. On multivariate analysis, a higher serum AFP level (OR, 0.523; 95% CI, 0.282-0.971; p = 0.040), intratumoral fat deposition (OR, 14.368; 95% CI, 2.749-75.098; p = 0.002), and irregular arterial peritumoral enhancement (OR, 0.322; 95% CI, 0.164-0.631; p = 0.001) were independent variables associated with the MVI of cHCC-CCA. After hepatectomy, patients with MVI of cHCC-CCA showed earlier recurrence than those without MVI (hazard ratio [HR], 0.402; 95% CI, 0.189-0.854, p = 0.013). CONCLUSION: A higher serum AFP level and irregular arterial peritumoral enhancement are potential predictive biomarkers for the MVI of cHCC-CCA, while intratumoral fat detected on MRI suggests a low risk of MVI. Furthermore, cHCC-CCAs with MVI may have worse surgical outcomes with regard to early recurrence than those without MVI. KEY POINTS: • Higher serum levels of AFP combined with irregular arterial peritumoral enhancement are independent risk factors for the MVI of cHCC-CCA, while fat deposition might be a protective factor. • cHCC-CCA with MVI may have a higher risk of early recurrence after surgery. • Most cHCC-CCAs were categorized as LR-M in this study, and no significant difference was found in MVI based on LI-RADS category.

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.

Vascular Resection During Hepatectomy for Liver Malignancies. Results from a Tertiary Center using Autologous Peritoneal Patch for Venous Reconstruction.

BACKGROUND: To evaluate early outcomes of venous reconstruction with peritoneal patch (PP) during resection for hepatic malignancies. METHODS: Since May 2015, PP was considered as the first option for venous reconstruction in the case of lateral resection. Between May 2015 and June 2019, 579 consecutive hepatectomies for malignancies were performed at our institution. Among 27 patients requiring venous resection, PP was used in 22, who were included in the present study. Data from a prospectively collected database were analysed. RESULTS: Tumour types were ten colorectal metastases (CRLM), six intrahepatic cholangiocarcinomas, four hilar cholangiocarcinomas, one hepatocellular carcinoma and one gallbladder carcinoma. Hepatectomies were major in 50% of cases. Eleven patients had hepatic vein resections, eight portal vein and three inferior vena cava. Venous reconstruction enabled resection in 12 (54.5%) patients, otherwise non-resectable. Among CRLM, the venous reconstruction allowed avoidance of major resection in eight (80%) cases. Median operative time was 456 min (range 270-960). Blood loss was a median 300 cc (range 40-1500), and blood transfusions were required in three patients (13.6%). At pathological examination, venous infiltration was confirmed in 14 (63.6%) patients. No vascular complications related to the patch were recorded. Post-operative major (Dindo III/IV) complications were observed in two (9%) patients. One patient died because of liver failure without vascular thrombosis and one due to biliary fistula complicated by arterial bleeding. Overall, post-operative mortality was 9% (2/22). CONCLUSIONS: Venous reconstruction with peritoneal patch during hepatectomy for malignancies can feasibly allow resection in otherwise unresectable patients and decrease the rate of major resection in colorectal liver metastases.

TCF21 inhibits tumor-associated angiogenesis and suppresses the growth of cholangiocarcinoma by targeting PI3K/Akt and ERK signaling.

Tumor-associated angiogenesis plays a critical role in the pathogenesis of cholangiocarcinoma (CCA). In this study, we examined the biological effects and molecular mechanisms of transcription factor 21 (TCF21) on CCA-associated angiogenesis. TCF21 expression was compared between 15 pairs of peritumor normal tissues and CCA tissues and also between normal bile duct epithelial cells and two CCA cell lines (QBC-939 and TFK-1) using real-time PCR and Western blot. With the use of both CCA cell lines as the model system, we stably expressed TCF21 by lentiviral transduction (Lv-TCF21). In vivo, we monitored xenograft growth from different CCA cells, measured tumor-associated angiogenesis by histological analysis, and determined the expressions and circulatory levels of VEGFA and PDGF-BB by immunohistochemistry and ELISA, respectively. In vitro, we assessed the effects of conditioned medium collected from different CCA cells on the viability, migration, and tube formation of endothelial cells and explored the significance of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), as well as ERK1/2 signaling in this process. TCF21 was significantly downregulated in CCA tissues or cell lines. Ectopic expression of TCF21 in CCA cells inhibited xenograft growth or tumor-associated angiogenesis in vivo and targeted the expression and secretion of proangiogenic factors, VEGFA and PDGF-BB. In vitro, the conditioned medium collected from Lv-TCF21 CCA cells significantly reduced the viability, migration, and tube formation of endothelial cells. On the molecular level, the targeting of PI3K/Akt and ERK1/2 signaling mediated the anti-angiogenic activity of TCF21. TCF21 presents growth-inhibitory and anti-angiogenic activities, and thus the elevation of TCF21 expression may provide therapeutic benefits for CCA. NEW & NOTEWORTHY Transcription factor 21 (TCF21) is downregulated in cholangiocarcinoma (CCA) tissues or cells. TCF21 inhibits the growth of xenografts derived from CCA cells. TCF21 suppresses in vivo tumor-associated angiogenesis. TCF21 targets expression and production of proangiogenic factors from CCA cells. The targeting of phosphatidylinositol 3-kinase/protein kinase B and ERK1/2 signaling mediates the anti-angiogenesis of TCF21.

Reliability and accuracy of a novel classification system using peroral cholangioscopy for the diagnosis of bile duct lesions.

BACKGROUND: The aim of this study was to propose a novel, comprehensive, macroscopic classification for bile duct lesions. METHODS: A two-stage protocol was designed. In Stage I, a retrospective study (September 2013 to September 2015) of patients with bile duct lesions detected by peroral cholangioscopy (POCS) was performed. A total of 315 images with at least 6 months of follow-up were recorded, analyzed, and correlated to histology, and were classified as non-neoplastic (one of three types, 1 - 3) or neoplastic (one of four types, 1 - 4) based on morphological and vascular patterns. In Stage II, a prospective, nonrandomized, double-blind study was performed from December 2015 to December 2016 to validate the proposed classification. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and positive and negative likelihood ratios (LR + and LR - , respectively) were calculated (gold standard: 6-month follow-up). Inter- and intraobserver agreement (kappa value, κ) among experts and non-experts were calculated. RESULTS: 171 patients were included (65 retrospective; 106 prospective). In Stage I, 28/65 cases were neoplastic and 37 /65 were non-neoplastic, according to the final diagnosis. In Stage II, 56/106 were neoplastic with a sensitivity, specificity, PPV, NPV, LR + , and LR - for neoplastic diagnosis of 96.3 %, 92.3 %, 92.9 %, 96 %, 12.52, and 0.04, respectively. The proposed classification presented high reproducibility among observers, for both neoplastic and subtypes categories. However, it was better for experts (κ > 80 %) than non-experts (κ 64.7 % - 81.9 %). CONCLUSION: The novel classification system could help physicians to distinguish non-neoplastic from neoplastic bile duct lesions.

Bile duct angulation and tumor vascularity are useful radiographic features for differentiating pancreatic head cancer and intrapancreatic bile duct cancer.

BACKGROUND AND PURPOSE: To perform radical resection without leaving residual cancer, surgeons must distinguish between pancreatic head cancer (PHC) and intrapancreatic bile duct cancer (IPBDC) preoperatively. The aim of this study was to establish the points of difference between these two cancers, especially on preoperative multi-detector computed tomography (MDCT) images. METHODS: The subjects of this study were 28 patients with PHC and proven bile duct invasion who underwent pancreatoduodenectomy (PHC group) and 22 patients with IPBDC and upstream bile duct dilation (IPBDC group). We compared the preoperative clinical and radiographic features, including the bile duct angle, calculated on coronal images of MDCT, and the vascularity of the tumor. RESULTS: The optimal cut-off values for the bile duct angle, the CT value ratio of the tumor (late arterial phase/non-enhanced), and the main pancreatic duct (MPD) ratio (diameter of MPD/diameter of parenchyma) were 110°, 3.0, and 0.2, respectively. Multivariate analysis revealed that a bile duct angle < 110°, a CT value ratio of the tumor < 3, and an MPD ratio ≥ 0.2 were independently associated with PHC. CONCLUSIONS: A bile duct angle and CT value reflecting the vascularity of the tumor might be useful radiographic features for differentiating PHC and IPBDC, in addition to MPD dilatation.

Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets.

BACKGROUND: Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. METHODS: Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. RESULTS: In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. CONCLUSIONS: CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy.

Direct peroral cholangioscopy for diagnosis of bile duct lesions using an I-SCAN ultraslim endoscope: a pilot study.

Background and study aims I-SCAN is a computed virtual chromoendoscopy (CVC) system designed to enhance surface and vascular patterns. In this study, we evaluated the usefulness of direct peroral cholangioscopy (POC) using I-SCAN compared with a conventional white-light image (WLI) to diagnose bile duct lesions. Patients and methods Patients with mucosal lesions in the bile duct detected during direct POC were enrolled prospectively. The quality of endoscopic visualization and the visual diagnosis were assessed using I-SCAN and WLI modes, respectively, during direct POC. Results A total of 20 patients (9 malignant and 11 benign lesions) underwent I-SCAN to evaluate lesions in the bile duct using direct POC. The quality of endoscopic visualization using direct POC with I-SCAN was significantly higher than that of WLI for surface structure (P = 0.04), surface microvascular architecture (P = 0.01), and margins (P = 0.02). Overall diagnostic accuracy of the visual diagnosis was not different between I-SCAN and WLI (90.0 % vs. 75.0 %; P = 0.20). Conclusion Direct POC using CVC by I-SCAN seems to be helpful for evaluating mucosal lesions of the bile duct, without the interference from bile. CLINICAL TRIAL REGISTRATION: UMIN000021009.

YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors.

UNLABELLED: The Yes-associated protein (YAP)/Hippo pathway has been implicated in tissue development, regeneration, and tumorigenesis. However, its role in cholangiocarcinoma (CC) is not established. We show that YAP activation is a common feature in CC patient biopsies and human CC cell lines. Using microarray expression profiling of CC cells with overexpressed or down-regulated YAP, we show that YAP regulates genes involved in proliferation, apoptosis, and angiogenesis. YAP activity promotes CC growth in vitro and in vivo by functionally interacting with TEAD transcription factors (TEADs). YAP activity together with TEADs prevents apoptosis induced by cytotoxic drugs, whereas YAP knockdown sensitizes CC cells to drug-induced apoptosis. We further show that the proangiogenic microfibrillar-associated protein 5 (MFAP5) is a direct transcriptional target of YAP/TEAD in CC cells and that secreted MFAP5 promotes tube formation of human microvascular endothelial cells. High YAP activity in human CC xenografts and clinical samples correlates with increased MFAP5 expression and CD31(+) vasculature. CONCLUSIONS: These findings establish YAP as a key regulator of proliferation and antiapoptotic mechanisms in CC and provide first evidence that YAP promotes angiogenesis by regulating the expression of secreted proangiogenic proteins.

[Strategies to Optimise R0 Resection for Hilar Cholangiocarcinoma]. / Strategien zur Optimierung der R0-Resektionsrate von zentralen Gallengangskarzinomen.

BACKGROUND: Retrospective analyses have shown a 20-40 % incidence of R1 resection in hilar cholangiocarcinoma, which therefore represents a significant issue to be addressed. METHODS: We have reviewed the literature on the impact of R1 resection in hilar cholangiocarcinomas and on possible surgical options to increase the rate of complete tumour resections. RESULTS: To minimise the rate of R1 resections a preoperative risk assessment concerning the predisposed anatomic locations is required. During planning of the surgical strategy, liver function plays a central role prior to right-sided hemihepatectomies. Due to the loss of a high amount of functional liver parenchyma, contralateral portal vein embolisation is often used prior to right trisectionectomies. For left-sided hepatectomies the management of the right hepatic artery is fundamental. The right hepatic artery has a very close contact to the tumour region, although arterial invasion is rarely seen. However, the risk of manifest or occult R1 resection is relatively high along the right artery. In selected cases an arterial resection might be considered, but this increases the risk of postoperative complications. Arterial resection might be performed either via direct anastomosis or by using an interposition graft. As reserve procedures preoperative embolisation of the hepatic artery without reconstruction or an arterialisation of the portal vein are available. However, the latter two procedures come along with an increased rate of biliary complications. In selected lymph-node negative patients with irresectable hilar cholangiocarcinoma liver transplantation might be considered. CONCLUSION: Despite significant advances in surgical technique, R1 resection remains a problem, which is aggravated by the lack of evidence-based adjuvant measures.

CEUS in hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma in 320 patients - early or late washout matters: a subanalysis of the DEGUM multicenter trial.

PURPOSE: The aim of the study was the comparison of tumor vascularization and contrast enhancement in contrast-enhanced ultrasound (CEUS) for the characterization of hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (ICC). We present data of the subpopulations HCC and ICC examined in the DEGUM multicenter trial for the characterization of focal liver lesions in clinical practice. MATERIALS AND METHODS: Based on the data of the DEGUM multicenter trial (1349 patients), all patients with histologically proven HCC (n = 278) and ICC (n = 42) were analyzed. The vascularity pattern and contrast enhancement pattern during the arterial, portal-venous and late phase were compared. RESULTS: An underlying liver cirrhosis was found in 214/278 patients with HCC (76.9 %) and 7/42 patients with ICC (16.7 %). In CEUS, HCC showed a global arterial hyperenhancement compared to ICC (HCC: tumor center: 60.3 %; tumor periphery: 75 %; ICC: tumor center: 16.7 %; tumor periphery: 40.5 %). ICC showed an initial contrast enhancement primarily at the tumor periphery (ICC: 85.7 % vs. HCC: 61 %) followed by an early portal-venous contrast washout in the tumor center (ICC: 85.8 % vs. HCC: 49.8 %) and tumor periphery (ICC: 66.7 % vs. HCC: 32.6 %). HCC showed a delayed contrast washout (late phase hypoenhancement: HCC: 75 % vs. ICC: 92.9 %). CONCLUSION: ICCs are rare in cirrhotic livers. CEUS can demonstrate differences in the vascularization patterns between HCC and ICC. HCC showed an arterial global hyperenhancement and delayed contrast washout in the late phase. ICCs are characterized by an arterial contrast enhancement at the tumor periphery with early contrast washout of the vascularized parts of the lesions in the portal-venous and late phase.

Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma.

OBJECTIVE: Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA(®)), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. METHODS: We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. RESULTS: Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P<0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P<0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. CONCLUSIONS: Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.

Surgical resection techniques for locally advanced hilar cholangiocarcinoma.

BACKGROUND: Resection of perihilar cholangiocarcinoma involves major hepatectomy including caudate lobectomy. It is technically challenging because of the complex, intimate and variable relationship between biliary and vascular structures in the liver hilum. Resectability rates vary from 30 to 80 % and about one third of patients have microscopically involved margins. However, adequately performed resections provide 5-year survival of 30-40 % and are worth pursuing. PURPOSE: Better understanding of anatomy, better imaging, improved surgical techniques and progress in perioperative care of these patients have pushed the limits of resection of these tumours. Many of the traditional indicators of inoperability such as bilateral involvement of second-order hepatic ducts, contralateral biliary and vascular involvement, and need for arterial resection have been overcome or are being challenged. This review discusses techniques that may increase margin-free resectability of Bismuth-Corlette type III and IV perihilar cholangiocarcinoma. CONCLUSION: Advanced perihilar cholangiocarcinoma requires extended liver resection and often vascular resection, despite which the margin may be compromised in about one third of patients. Right sided tumours are likely to need right trisectionectomy and portal vein resection, best served by an en bloc hilar resection or Rex-recess approach. Left-sided tumours often involve contralateral blood vessels and require left trisegmentectomy with possible right portal vein or right hepatic artery reconstruction. These tumours are best tackled by hepatobiliary surgeons with experience in microvascular techniques. Salvage procedures when arterial reconstruction is not feasible are still under evaluation.

Hepatopancreatoduodenectomy with arterial reconstruction for extrahepatic cholangiocarcinoma with celiac axis obstruction: report of a case.

We report a case of successful right hepatectomy plus pancreatoduodenectomy (Rt-HPD) with arterial reconstruction for extrahepatic bile duct carcinoma with obstruction of the celiac axis in a 76-year-old man. Obstruction of the celiac axis resulted in arterial blood supply to the upper abdominal organs coming from the pancreatic head arcade. The patient underwent arterial reconstruction before the Rt-HPD to maintain the blood supply from the pancreatic head arcade for as long as possible. His postoperative course was uneventful and he was well with no sign of recurrence when last seen, 64 months after surgery. To our knowledge, this is the first description of this modified HPD with arterial reconstruction. Thus, rational surgical planning based on careful preoperative assessment would expand the indications for HPD, even for patients with celiac axis obstruction requiring arterial reconstruction.

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.

[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.