Angiogenesis in biliary tract cancer: targeting and therapeutic potential.

Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.

Inflammatory cells infiltrate and angiogenesis in locally advanced and metastatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is the second most common subtype of primary hepatobiliary cancer and one of the most aggressive characterized by an extremely poor prognosis with limited treatment options. Inflammatory cells in tumour microenvironment support tumour growth in term of progression, angiogenesis and metastatic capacity. A link between inflammation and biliary carcinogenesis has been previously observed but the mechanisms involved remain to be determined. METHODS: We investigated the microvascular density (MVD) and inflammatory cells in tissue samples from 40 patients with CCA with locally advanced CCA and metastatic CCA by means of immunohistochemical analysis of macrophages, mast cells, B and T lymphocytes and we correlated inflammatory infiltrate with MVD. RESULTS: We observed significant decrease in the levels of CD31 positive vessels, and CD8, CD4, CD68 and tryptase-positive cells in metastatic lesions as compared to the localized ones. A negative correlation between CD31 and CD8 and CD31 and CD4 in localized CCA samples was found as assessed by Spearman correlation analysis. CONCLUSIONS: In locally advanced CCA patients, there is a significant increase of immune cell infiltrate constituted by CD8+ and CD4+ lymphocytes, macrophages and mast cells as compared to the metastatic ones. This alteration in the tumour microenvironment infiltrate is related to a significant increased MVD in localized CCA lesions compared with the metastatic ones. Moreover, we observed a negative correlation between MVD and CD8+ , CD4+ cells in localized CCA patients.

Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models.

BACKGROUND: Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches. METHODS: We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28), two primary cell cultures derived from BTC patients, the EGI-1 and a new established BTC patient-derived xenografts, were used as preclinical models to investigate the anti-tumor activity of ET-743 in vitro and in vivo. Gene expression profiling was also analyzed upon ET-743 treatment in in vivo models. RESULTS: We found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in vitro. In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis. In vivo ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways. CONCLUSIONS: These results suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials in BTC patients resistant to standard chemotherapy.

[Results of preoperative embolization of portal vein in patients with biliary hepatic tumors].

The results of preoperative embolization of portal vein (EPV) in 90 patients, operated on for biliary hepatic tumors, were analyzed. In 47 patients Klatskin tumor was revealed, in 29--peripheral cholangiocarcinoma, in 14--tumor of a gallbladder. In all the patients a radical major hepatic resection was planned, a checking hepatic volume (CHHV) did not exceed 40% of a noninvolved parenchyma. The EPV volume have corresponded generally to the planned resection volume. After performance of EPV a pressure in a portal vein have risen by 75%, and later it have had lowered step by step during 24 h. The CHHV index have raised from (354 +/- 72) up to (462 +/- 118) cm3, or from (33 +/- 7) up to (45 +/- 11)%, permitting to perform radical hepatic resection in 79 (87.8%) patients. Thus, application of EPV in patients, suffering biliary hepatic tumors, have permitted to increase the CHHV index after radical resection, and to raise resectability of such tumors.

Development of new drug strategies in infrequent digestive tumors: esophageal, biliary tract, and anal cancers.

PURPOSE OF REVIEW: In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. RECENT FINDINGS: The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. SUMMARY: Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.

[The role of vascular reconstructions in the surgery of tumors of the hepatopancreatobiliary zone].

An analysis of results of 83 operations performed for tumors of the hepatopancreatobiliary zone included the period of 2006-2007. In 39 resections of the pancreas there were 16 (41.0%) cases when the operation was supplemented with a reconstruction of the major vessels. From 44 resections of the liver 10 (22.7%) interventions were made with resection of the major veins. No specific complications were noted associated with vascular reconstructions in the zones in question. Postoperative lethality after operations for malignant tumors of the hepatopancreatobiliary zone was 2.4%, after operations in the same zone supplemented with vascular reconstructions was 3.8%. The duration of postoperative hospital stay was practically the same of that of the patients operated for malignant tumors of the hepatopancreatobiliary zone without vascular reconstructions. One year survival of the patients operated for malignant tumors of the hepatopancreatobiliary zone without and with vascular reconstructions was commensurable. Reconstruction of the major vessels in operations for locally extensive tumors of the hepatopancreatobiliary zone allows more often using radical surgical interventions. Complete restoration of the patency of the major vessels in the zone of operations for tumor processes in the liver and pancreas alleviates the postoperative period, is not followed by more number of postoperative complications and lethality.

Hepatectomy and pancreatectomy with combined vascular resection in patients with hepato-biliary and pancreas diseases at a single cancer institute.

BACKGROUND/AIMS: In advanced cancers of hepatobiliary and pancreatic lesions, major vascular resection and reconstruction are necessary to accomplish curative resection, which may provide better patient outcomes. METHODOLOGY: Surgical records, morbidity and mortality, and prognosis were examined in patients with combined vascular resection. Thirty-six patients underwent 18 hepatectomies and 18 pancreatectomies. RESULTS: In 18 patients who underwent hepatic resection, the resected vessels were the portal vein (PV) in 10, vena cava or hepatic vein in 9 and right hepatic artery (RHA) in 3. An artificial graft was used in 2 to replace the vena cava. Vascular bypass was performed in 5 patients. Morbidity was due to biliary stricture in 1 patient and adult respiratory distress syndrome in another who died during hospital stay. Fourteen (82%) had cancer recurrence, of whom 12 died of cancer, one died of other disease, and 2 survived cancer-free. The 5-year survival was 28%. In 18 patients who underwent pancreatectomy, resected vessels were PV in 18 and RHA in 1. An artificial graft was used in 3 and vascular passive bypass was performed in 6. One patient died of sepsis after total pancreatectomy during hospital stay. Eleven (64%) had cancer recurrence, of whom 11 died of cancer, 2 died of other disease, and 4 survived cancer-free. The 3-year survival was 27%. CONCLUSIONS: Complete surgical resection (R0) combined with main vascular resection could be safely performed in many patients with disease of the hepatobiliary and pancreas, which achieved longer survival in some patients even in the advanced stage.

Unilateral hepatic artery reconstruction is unnecessary in biliary tract carcinomas involving lobar hepatic artery: implications of interlobar hepatic artery and its preservation.

BACKGROUND/AIMS: The interruption of hepatic arterial flow when performing a bilioenteric anastomosis has been reported to usually bring about serious postoperative complications, such as anastomotic leakage, hepatic abscess and infarction. We aimed to evaluate the surgical implications of the interlobar hepatic artery when patients with advanced biliary tract carcinomas undergo surgical resection with a bilioenteric anastomosis. METHODOLOGY: In 7 patients with advanced biliary tract carcinomas, the combined resection of the liver (greater than hemihepatectomy in 2 and less than hemihepatectomy in 5), extrahepatic bile duct, hepatic artery (right hepatic artery in 5, right and left hepatic artery in 1, left hepatic artery in 1), and the portal vein was performed in 4 patients. The portal vein was reconstructed in all 4 patients. The hepatic artery was reconstructed in only one patient, with combined resection of both right and left hepatic arteries, but was not reconstructed in 2 other patients, even though they underwent resection greater than hemihepatectomy. RESULTS: The interlobar hepatic artery running into the Glissonian sheath around the hepatic duct confluence could be preserved in 5 patients, as shown by angiography, but could not be preserved in 2 patients who underwent greater than hemihepatectomy. Moderate and transient ischemic liver damage occurred, but no serious postoperative complications were induced in any of the 5 patients in the unilateral hepatic artery preserved group. However, both cases without preservation of the hepatic artery encountered liver failure, liver abscess and leakage of bilioenteric anastomosis, and one patient died of multiple organ failure. CONCLUSIONS: One major lobar branch of the hepatic artery involved by cancer invasion could be safely resected without reconstruction in patients with advanced biliary tract carcinomas when the interlobar hepatic artery running into the Glissonian sheath around the hepatic duct confluence is preserved.

Intraportal endovascular ultrasonography for assessment of vascular invasion by biliary tract cancer.

BACKGROUND: This study was performed to investigate the diagnostic accuracy of intraportal endovascular ultrasonography (IPEUS) in assessing vascular invasion by biliary tract cancer. METHODS: A prospective study of 31 consecutive patients with biliary tract cancer was performed. All patients underwent surgery. The sonographic criterion for right hepatic artery invasion was interruption of the hyperechoic layer or encasement by tumor. The sonographic criterion for portal vein invasion was obliteration of the echogenic band of the portal vein. IPEUS findings were confirmed by surgical exploration and pathologic examination of resected specimens. RESULTS: Right hepatic artery invasion was confirmed in resected specimens in seven patients and by operative findings in four patients. Portal vein invasion was confirmed in resected specimens in six patients and by operative findings in five patients. For diagnosis of right hepatic artery invasion, the sensitivity, specificity, and overall accuracy of IPEUS were all 100%; respective values were 63.6%, 84.2%, and 76.7% for angiography. For diagnosis of portal vein invasion, the sensitivity, specificity, and overall accuracy of IPEUS were 100%, 95%, and 96.8%, respectively. The corresponding values were 63.6%, 89.5%, and 80% for portography and 54.5%, 85%, and 74.2%, respectively, for CT. CONCLUSION: IPEUS will improve the assessment of vascular invasion at the hepatic hilum by biliary tract cancer.

[Evaluation of anastomosis between intrahepatic or extrahepatic vessels by intra-arterial digital subtraction angiography using carbon dioxide].

Carbon dioxide (CO2) intraarterial subtraction angiography (IADSA) was performed in 31 patients with various hepatobiliary diseases. The injection sites of CO2 were proper hepatic artery (10/31; group A), segmental hepatic artery (18/31; group B), and peripheral inferior phrenic artery (3/31; group C), respectively. In group A, only the third order branches of the portal venous system were visualized anterogradely in 8 of 10 patients. In group B, the microcatheter was placed coaxially through a 5 French guiding catheter at the main arterial supply of the tumor in 7 patients and at the peripheral segmental branch of the hepatic artery in 11 patients. The portal venous system was visualized retrogradely in all of the patients regardless of the injection site. The injected CO2 may flow back into the portal vein through the anastomosis known as the peribiliary or periportal plexus. In group C, not only the portal vein but also the pulmonary artery or pericardial vein were visualized by this method. CO2-IADSA was useful to image the minute communications between the various vessels, which have been not hitherto visualized by iodinated contrast medium.

Venous surgery in resection for abdominal malignancy.

Vascular surgical techniques were applied to the radical resection of carcinoma of the liver, biliary tract and pancreas. Distal and proximal portal vein reconstruction, respectively, was carried out in 16 patients with carcinoma of the pancreas and 16 with cancer of the liver and biliary tract. Hepatic vein trunks with tumour involvement were resected and reconstructed by various techniques in six patients. A suprarenal segment of the inferior vena cava was completely replaced by a prosthetic graft in three patients with retroperitoneal malignancy. Venous surgery increased the resectability of malignant tumours and preserved circulation in the organ remnant, although the long-term effect on survival is not yet clear. Vascular surgical techniques should be applied more widely in the field of general abdominal surgery.

[Combined digital subtraction angiography and cholangiography in assessing the spread of the tumor process in pancreatobiliary cancer]. / Sochetannaia digital'naia subtraktsionnaia angiografiia i kholangiografiia v otsenke rasprostranennosti opukholevogo protsessa pri pankreatobiliarnom rake.

The paper is concerned with comparative assessment of the efficacy of digital subtraction angiography and routine angiography in assessing tumor spreading in pancreatobiliary cancer. A combined method of digital subtraction angiography and cholangiography was developed and performed in 41 patients with pancreatobiliary cancer permitting maximum information on the topical location and spreading of a tumor process. The clinical importance of the obtained results permitted recommending simultaneous digital subtraction angiography and cholangiography in patients with hepatobiliary cancer.

Treatment of proximal biliary tract carcinoma: an overview of techniques and results.

Proximal biliary tract cancer carries a dismal prognosis. Few patients have a curative option. However, worthwhile palliation can be achieved in many patients by relieving obstructive jaundice. An overview is presented to place in perspective the treatment methods described and the results obtained.