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• W2102801557 abstract "Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of unknown origin commonly associated with inflammatory bowel disease and characterized by fibrosing inflammatory destruction of intra- and/or extrahepatic biliary ducts. The course may be variable from one patient to another but PSC is often progressive, leading to biliary cirrhosis and its complications. Currently, there is no established effective medical treatment, and liver transplantation is the only life-extending therapeutic alternative for patients with end-stage PSC. Although hepatocellular carcinoma may occur in patients with cirrhotic-stage PSC, the hepatobiliary malignancies specific to PSC are cholangiocarcinoma and, in a lesser degree, gall-bladder carcinoma. In this regard, PSC should be considered as a premalignant disease of the biliary tract. The diagnosis of cholangiocarcinoma in the setting of PSC presents an extremely difficult challenge. Because of a very poor outcome in most series, presence of cholangiocarcinoma (except for incidental tumors) is usually regarded as a contraindication for liver transplantation unless in conjunction with a novel management strategy [[1]Devlin J O'Grady J Indications for referral and assessment in adult liver transplantation: a clinical guideline.Gut. 1999; 45: VI1-VI22Crossref PubMed Scopus (90) Google Scholar].In this issue of the Journal, Brandsaeter et al. report on hepatobiliary malignancy in a large series of 255 Nordic European PSC patients listed for liver transplantation during an 11-year period [[2]Brandsaeter B Isoniemi H Broomé U Olausson M Bäckman L Hansen B et al.Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy.J Hepatol. 2004; 40: 815-822Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar]. These patients had clearly an end-stage liver disease (mean serum bilirubin higher than 170 μmol/l). Only six (2%) had a known cancer at the time of acceptance but 83 (33%) had a ‘clinical suspicion’ of hepatobiliary malignancy. Eight patients died on the waiting list, 24 were permanently withdrawn and finally 233 were transplanted. Hepatobiliary malignancy was confirmed in 35% of patients (29/83) with a clinical suspicion whereas cancer was found in 10% of patients (17/166) without a clinical suspicion. Thus, the overall prevalence of malignancy (37 cholangiocarcinoma, 11 hepatocellular carcinoma and 4 gall-bladder carcinoma) was 20% (52/255) and 14% (31/223) of the patients who got transplant had cancer. The 1- and 5-year post-transplant survival of patients with cholangiocarcinoma was 65 and 35%, respectively.What do we learn from this paper ? At first glance, the picture seems as gloomy as usual and most of the data presented here only confirm previous reports. The high prevalence of cancer (the vast majority of which being biliary) is not unexpected since cancer incidence is usually higher in patients with icteric PSC referred for transplantation than in the average PSC population. Indeed, in the later the incidence rate of hepatobiliary carcinoma is 1.5% per year after the first year post-PSC diagnosis as shown by a very elegant study of a large cohort of Swedish patients [[3]Bergquist A Ekbom A Olsson R Kornfeldt D Lööf L Danielsson A et al.Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.J Hepatol. 2002; 36: 321-327Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar], whereas up to 36% of PSC patients undergoing liver transplantation are found to have cholangiocarcinoma despite an exhaustive pre-transplantation diagnostic approach [[4]Miros M Kerlin P Walker N Harper J Lynch S Strong R Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.Gut. 1991; 32: 1369-1373Crossref PubMed Scopus (98) Google Scholar]. In the same way, the poor predictive values (positive: 0.35, negative: 0.90) of the ill-defined ‘clinical suspicion’ of hepatobiliary malignancy are not surprising since cholangiocarcinoma is notoriously difficult to diagnosis in patients with PSC. A collaborative effort among multiple centers is clearly needed to develop standardized diagnostic criteria. Brandsaeter et al., as others, identified recent diagnosis of PSC as the factor with the most predictive value of cancer [3Bergquist A Ekbom A Olsson R Kornfeldt D Lööf L Danielsson A et al.Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.J Hepatol. 2002; 36: 321-327Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar, 5Abrendt S.A Pitt H.A Nakeeb A Klein A.S Lillemoe K.D Kalloo A.N et al.Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis.J Gastrointest Surg. 1999; 3: 357-368Crossref PubMed Google Scholar]. This suggests that many of these patients may well have had cholangiocarcinoma at the time of the initial diagnosis of PSC. Clinicians should be aware of this high incidence of cholangiocarcinoma already in the first year after the diagnosis of PSC has been made. Unfortunately no tool to detect these carcinomas early has been validated yet. Lastly, the authors found that, as usual, post-transplant survival of patients with cholangiocarcinoma was significantly lower than that of patients without hepatobiliary malignancy.So why Brandsaeter et al. have to be congratulated despite shortcomings with respect to the retrospective, at least in part, design of their multicentric study and the absence of a standard pre-transplantation diagnostic approach of hepatobiliary carcinoma ? There are several interesting aspects in this report.The first relates to the very poor survival of patients with previous colorectal cancer. Indeed, seven of their nine patients with history of colorectal cancer died either pre- or post-transplantation, the main cause of death being malignancy. These data are in keeping with previous papers suggesting that PSC patients with a concomitant ulcerative colitis and a diagnosis of colorectal carcinoma would run an even more increased risk of developing cholangiocarcinoma [[6]Broomé U Löfberg R Veress B Eriksson L.S Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential.Hepatology. 1995; 22: 1404-1408PubMed Google Scholar]. Whether or not an history of colorectal cancer should be considered as a contraindication to liver transplantation remains an open question but, clearly, clinicians should have an exhaustive pre-transplantation approach in this subset of patients.The second important finding is the absence of difference in survival between patients with a diagnosis of cancer made during transplantation procedure compared to patients whose cancer was identified only at the time of pathologic explant examination. These results challenge the current statement that liver transplantation should be proscribed in PSC patients with cholangiocarcinoma identified at the time of exploratory laparotomy and common bile duct frozen section biopsy [[7]Goss J.A Shackleton C.R Farmer D.G Arnaout W.S Seu P Markowitz J.S et al.Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience.Ann Surg. 1997; 5: 472-483Crossref Scopus (291) Google Scholar]. As a consequence, Brandsaeter et al. consider that if a cholangiocarcinoma is discovered intraoperatively, backing up from transplantation is not mandatory unless extrahepatic spread is demonstrated. These results have to be confirmed but there is no doubt that this opinion may make life easier to the transplant surgeon who has to take a tough decision in the operating room. In this regard, it may be argued that making a difference between pre- and peroperative diagnosis of cholangiocarcinoma is rather artificial and thus a known cholangiocarcinoma should not be considered as an absolute contraindication to transplantation in patients with PSC. Long term survival after neoadjuvant chemoirradiation followed by liver transplantation has been reported and some centers consider that PSC patients with small cholangiocarcinoma should be evaluated for liver transplantation [8De Vreede I Steers J.L Burch P.A Rosen C.B Gunderson L.L Haddock M.G et al.Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.Liver Transpl. 2000; 6: 309-316Crossref PubMed Scopus (302) Google Scholar, 9Sudan D DeRoover A Chinnakotla S Fox I Shaw Jr, B McCashland T et al.Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma.Am J Transplant. 2002; 2: 774-779Crossref PubMed Scopus (255) Google Scholar]. This issue remains very controversial and Brandsaeter et al. conclude in their present paper that they still consider an established cholangiocarcinoma as a contraindication to transplantation.The third interesting aspect relates to the effect of ursodeoxycholic acid (UDCA) and is probably the most promising. Indeed, the authors identified absence of UDCA therapy as a predictive factor of hepatobiliary malignancy by using multiple regression analysis. Although this effect was unexpectedly no longer significant when only biliary carcinomas were considered, presumably by loss of power, this finding raises very exciting issues. Results from studies using UDCA (with or without stenting of dominant strictures) for the treatment of PSC have already suggested that patients treated with this bile acid may develop fewer cholangiocarcinomas [10Lindor K.D for the Mayo Primary Sclerosing Cholangitis- Ursodeoxycholic acid Study Group Ursodiol for primary sclerosing cholangitis.N Engl J Med. 1997; 336: 691-695Crossref PubMed Scopus (544) Google Scholar, 11Stiehl A Rudolph G Sauer P Benz C Stremmel W Walkern S et al.Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis.J Hepatol. 1997; 26: 560-566Abstract Full Text PDF PubMed Scopus (174) Google Scholar]. Furthermore, there is also evidence that UDCA may decrease the frequency of colonic mucosal dysplasia in patients with ulcerative colitis and PSC [12Tung B.Y Emond M.J Haggitt R.C Bronner M.P Kimmey M.B Kowdley K.V et al.Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.Ann Intern Med. 2001; 134: 89-95Crossref PubMed Scopus (418) Google Scholar, 13Pardi D.S Loftus Jr, E.V Kremers W.K Keach J Lindor K.D Ursodeoxycholic acid as a chemoprotective agent in patients with ulcerative colitis and primary sclerosing cholangitis.Gastroenterology. 2003; 124: 889-893Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar] and the probability of colorectal adenoma recurrence following removal in patients with primary biliary cirrhosis [[14]Serfaty L De Leusse A Rosmorduc O Desaint B Flejou J.F Chazouillères O et al.Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study.Hepatology. 2003; 38: 203-209Crossref PubMed Scopus (84) Google Scholar]. Is there a rational and experimental basis supporting a chemoprotective effect of UDCA against development of neoplasia? The answer is unambiguously yes. Chronic inflammation of the biliary tree is the common feature of most of the risk conditions for cholangiocarcinoma. This inflammation is associated with generation of numerous cytokines by inflammatory cells and cholangiocytes that leads to alterations in critical growth factor pathways playing a significant role in the development and/or progression of biliary cancer [[15]Gores G.J Cholangiocarcinoma: current concepts and insights.Hepatology. 2003; 37: 961-969Crossref PubMed Scopus (248) Google Scholar]. Potential mechanisms of UDCA action include modulation of protein kinase C and phospholipase A2 expression, antioxidant effect and inhibition of cyclooxygenase-2 expression [16Brentnall T.A Ursodiol: good drug makes good.Gastroenterology. 2003; 124: 1139-1140Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 17Khare S Cerda S Wali R.K Von Linting F.C Tretiakova M Joseph L et al.Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer.Cancer Res. 2003; 63: 3517-3523PubMed Google Scholar]. Interestingly, UDCA could also act after initiation of tumorigenesis is completed since it has been shown that tauroursodeoxycholate inhibits the growth of a human cholangiocarcinoma cell line [[18]Alpini G Kanno N Phinizy J.L Glaser S Francis H Taffetani S et al.Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via CA2+-, PKC,- and MAPK-dependent pathways.Am J Physiol Gastrointest Liver Physiol. 2003; : 30Google Scholar]. These experimental data strongly support the hypothesis that UDCA has a chemoprotective effect on colon and biliary carcinogenesis and warrant large clinical studies in patients with PSC to determine whether ‘a good drug is even better than initially thought’ [[16]Brentnall T.A Ursodiol: good drug makes good.Gastroenterology. 2003; 124: 1139-1140Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. To assess the true impact of UDCA on outcome, these studies should have a long duration and include patients with non-decompensated PSC known for at least 1 year and treated with UDCA at daily doses of 20 mg/kg since preliminary results obtained with this high-dose look promising [[19]Mitchell S.A Bansi D.S Hunt N Von Bergmann K Fleming K.A Chapman R.W A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.Gastroenterology. 2001; 121: 900-907Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar].Biliary malignancy is still a nefarious complication in patients with PSC. However, thanks to new mechanistic and clinical insights such as those provided by this paper, we can hope that the next several years will bring significant advances in the prevention and management of this cancer. Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of unknown origin commonly associated with inflammatory bowel disease and characterized by fibrosing inflammatory destruction of intra- and/or extrahepatic biliary ducts. The course may be variable from one patient to another but PSC is often progressive, leading to biliary cirrhosis and its complications. Currently, there is no established effective medical treatment, and liver transplantation is the only life-extending therapeutic alternative for patients with end-stage PSC. Although hepatocellular carcinoma may occur in patients with cirrhotic-stage PSC, the hepatobiliary malignancies specific to PSC are cholangiocarcinoma and, in a lesser degree, gall-bladder carcinoma. In this regard, PSC should be considered as a premalignant disease of the biliary tract. The diagnosis of cholangiocarcinoma in the setting of PSC presents an extremely difficult challenge. Because of a very poor outcome in most series, presence of cholangiocarcinoma (except for incidental tumors) is usually regarded as a contraindication for liver transplantation unless in conjunction with a novel management strategy [[1]Devlin J O'Grady J Indications for referral and assessment in adult liver transplantation: a clinical guideline.Gut. 1999; 45: VI1-VI22Crossref PubMed Scopus (90) Google Scholar]. In this issue of the Journal, Brandsaeter et al. report on hepatobiliary malignancy in a large series of 255 Nordic European PSC patients listed for liver transplantation during an 11-year period [[2]Brandsaeter B Isoniemi H Broomé U Olausson M Bäckman L Hansen B et al.Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy.J Hepatol. 2004; 40: 815-822Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar]. These patients had clearly an end-stage liver disease (mean serum bilirubin higher than 170 μmol/l). Only six (2%) had a known cancer at the time of acceptance but 83 (33%) had a ‘clinical suspicion’ of hepatobiliary malignancy. Eight patients died on the waiting list, 24 were permanently withdrawn and finally 233 were transplanted. Hepatobiliary malignancy was confirmed in 35% of patients (29/83) with a clinical suspicion whereas cancer was found in 10% of patients (17/166) without a clinical suspicion. Thus, the overall prevalence of malignancy (37 cholangiocarcinoma, 11 hepatocellular carcinoma and 4 gall-bladder carcinoma) was 20% (52/255) and 14% (31/223) of the patients who got transplant had cancer. The 1- and 5-year post-transplant survival of patients with cholangiocarcinoma was 65 and 35%, respectively. What do we learn from this paper ? At first glance, the picture seems as gloomy as usual and most of the data presented here only confirm previous reports. The high prevalence of cancer (the vast majority of which being biliary) is not unexpected since cancer incidence is usually higher in patients with icteric PSC referred for transplantation than in the average PSC population. Indeed, in the later the incidence rate of hepatobiliary carcinoma is 1.5% per year after the first year post-PSC diagnosis as shown by a very elegant study of a large cohort of Swedish patients [[3]Bergquist A Ekbom A Olsson R Kornfeldt D Lööf L Danielsson A et al.Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.J Hepatol. 2002; 36: 321-327Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar], whereas up to 36% of PSC patients undergoing liver transplantation are found to have cholangiocarcinoma despite an exhaustive pre-transplantation diagnostic approach [[4]Miros M Kerlin P Walker N Harper J Lynch S Strong R Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.Gut. 1991; 32: 1369-1373Crossref PubMed Scopus (98) Google Scholar]. In the same way, the poor predictive values (positive: 0.35, negative: 0.90) of the ill-defined ‘clinical suspicion’ of hepatobiliary malignancy are not surprising since cholangiocarcinoma is notoriously difficult to diagnosis in patients with PSC. A collaborative effort among multiple centers is clearly needed to develop standardized diagnostic criteria. Brandsaeter et al., as others, identified recent diagnosis of PSC as the factor with the most predictive value of cancer [3Bergquist A Ekbom A Olsson R Kornfeldt D Lööf L Danielsson A et al.Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.J Hepatol. 2002; 36: 321-327Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar, 5Abrendt S.A Pitt H.A Nakeeb A Klein A.S Lillemoe K.D Kalloo A.N et al.Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis.J Gastrointest Surg. 1999; 3: 357-368Crossref PubMed Google Scholar]. This suggests that many of these patients may well have had cholangiocarcinoma at the time of the initial diagnosis of PSC. Clinicians should be aware of this high incidence of cholangiocarcinoma already in the first year after the diagnosis of PSC has been made. Unfortunately no tool to detect these carcinomas early has been validated yet. Lastly, the authors found that, as usual, post-transplant survival of patients with cholangiocarcinoma was significantly lower than that of patients without hepatobiliary malignancy. So why Brandsaeter et al. have to be congratulated despite shortcomings with respect to the retrospective, at least in part, design of their multicentric study and the absence of a standard pre-transplantation diagnostic approach of hepatobiliary carcinoma ? There are several interesting aspects in this report. The first relates to the very poor survival of patients with previous colorectal cancer. Indeed, seven of their nine patients with history of colorectal cancer died either pre- or post-transplantation, the main cause of death being malignancy. These data are in keeping with previous papers suggesting that PSC patients with a concomitant ulcerative colitis and a diagnosis of colorectal carcinoma would run an even more increased risk of developing cholangiocarcinoma [[6]Broomé U Löfberg R Veress B Eriksson L.S Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential.Hepatology. 1995; 22: 1404-1408PubMed Google Scholar]. Whether or not an history of colorectal cancer should be considered as a contraindication to liver transplantation remains an open question but, clearly, clinicians should have an exhaustive pre-transplantation approach in this subset of patients. The second important finding is the absence of difference in survival between patients with a diagnosis of cancer made during transplantation procedure compared to patients whose cancer was identified only at the time of pathologic explant examination. These results challenge the current statement that liver transplantation should be proscribed in PSC patients with cholangiocarcinoma identified at the time of exploratory laparotomy and common bile duct frozen section biopsy [[7]Goss J.A Shackleton C.R Farmer D.G Arnaout W.S Seu P Markowitz J.S et al.Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience.Ann Surg. 1997; 5: 472-483Crossref Scopus (291) Google Scholar]. As a consequence, Brandsaeter et al. consider that if a cholangiocarcinoma is discovered intraoperatively, backing up from transplantation is not mandatory unless extrahepatic spread is demonstrated. These results have to be confirmed but there is no doubt that this opinion may make life easier to the transplant surgeon who has to take a tough decision in the operating room. In this regard, it may be argued that making a difference between pre- and peroperative diagnosis of cholangiocarcinoma is rather artificial and thus a known cholangiocarcinoma should not be considered as an absolute contraindication to transplantation in patients with PSC. Long term survival after neoadjuvant chemoirradiation followed by liver transplantation has been reported and some centers consider that PSC patients with small cholangiocarcinoma should be evaluated for liver transplantation [8De Vreede I Steers J.L Burch P.A Rosen C.B Gunderson L.L Haddock M.G et al.Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.Liver Transpl. 2000; 6: 309-316Crossref PubMed Scopus (302) Google Scholar, 9Sudan D DeRoover A Chinnakotla S Fox I Shaw Jr, B McCashland T et al.Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma.Am J Transplant. 2002; 2: 774-779Crossref PubMed Scopus (255) Google Scholar]. This issue remains very controversial and Brandsaeter et al. conclude in their present paper that they still consider an established cholangiocarcinoma as a contraindication to transplantation. The third interesting aspect relates to the effect of ursodeoxycholic acid (UDCA) and is probably the most promising. Indeed, the authors identified absence of UDCA therapy as a predictive factor of hepatobiliary malignancy by using multiple regression analysis. Although this effect was unexpectedly no longer significant when only biliary carcinomas were considered, presumably by loss of power, this finding raises very exciting issues. Results from studies using UDCA (with or without stenting of dominant strictures) for the treatment of PSC have already suggested that patients treated with this bile acid may develop fewer cholangiocarcinomas [10Lindor K.D for the Mayo Primary Sclerosing Cholangitis- Ursodeoxycholic acid Study Group Ursodiol for primary sclerosing cholangitis.N Engl J Med. 1997; 336: 691-695Crossref PubMed Scopus (544) Google Scholar, 11Stiehl A Rudolph G Sauer P Benz C Stremmel W Walkern S et al.Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis.J Hepatol. 1997; 26: 560-566Abstract Full Text PDF PubMed Scopus (174) Google Scholar]. Furthermore, there is also evidence that UDCA may decrease the frequency of colonic mucosal dysplasia in patients with ulcerative colitis and PSC [12Tung B.Y Emond M.J Haggitt R.C Bronner M.P Kimmey M.B Kowdley K.V et al.Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.Ann Intern Med. 2001; 134: 89-95Crossref PubMed Scopus (418) Google Scholar, 13Pardi D.S Loftus Jr, E.V Kremers W.K Keach J Lindor K.D Ursodeoxycholic acid as a chemoprotective agent in patients with ulcerative colitis and primary sclerosing cholangitis.Gastroenterology. 2003; 124: 889-893Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar] and the probability of colorectal adenoma recurrence following removal in patients with primary biliary cirrhosis [[14]Serfaty L De Leusse A Rosmorduc O Desaint B Flejou J.F Chazouillères O et al.Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study.Hepatology. 2003; 38: 203-209Crossref PubMed Scopus (84) Google Scholar]. Is there a rational and experimental basis supporting a chemoprotective effect of UDCA against development of neoplasia? The answer is unambiguously yes. Chronic inflammation of the biliary tree is the common feature of most of the risk conditions for cholangiocarcinoma. This inflammation is associated with generation of numerous cytokines by inflammatory cells and cholangiocytes that leads to alterations in critical growth factor pathways playing a significant role in the development and/or progression of biliary cancer [[15]Gores G.J Cholangiocarcinoma: current concepts and insights.Hepatology. 2003; 37: 961-969Crossref PubMed Scopus (248) Google Scholar]. Potential mechanisms of UDCA action include modulation of protein kinase C and phospholipase A2 expression, antioxidant effect and inhibition of cyclooxygenase-2 expression [16Brentnall T.A Ursodiol: good drug makes good.Gastroenterology. 2003; 124: 1139-1140Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 17Khare S Cerda S Wali R.K Von Linting F.C Tretiakova M Joseph L et al.Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer.Cancer Res. 2003; 63: 3517-3523PubMed Google Scholar]. Interestingly, UDCA could also act after initiation of tumorigenesis is completed since it has been shown that tauroursodeoxycholate inhibits the growth of a human cholangiocarcinoma cell line [[18]Alpini G Kanno N Phinizy J.L Glaser S Francis H Taffetani S et al.Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via CA2+-, PKC,- and MAPK-dependent pathways.Am J Physiol Gastrointest Liver Physiol. 2003; : 30Google Scholar]. These experimental data strongly support the hypothesis that UDCA has a chemoprotective effect on colon and biliary carcinogenesis and warrant large clinical studies in patients with PSC to determine whether ‘a good drug is even better than initially thought’ [[16]Brentnall T.A Ursodiol: good drug makes good.Gastroenterology. 2003; 124: 1139-1140Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. To assess the true impact of UDCA on outcome, these studies should have a long duration and include patients with non-decompensated PSC known for at least 1 year and treated with UDCA at daily doses of 20 mg/kg since preliminary results obtained with this high-dose look promising [[19]Mitchell S.A Bansi D.S Hunt N Von Bergmann K Fleming K.A Chapman R.W A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.Gastroenterology. 2001; 121: 900-907Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. Biliary malignancy is still a nefarious complication in patients with PSC. However, thanks to new mechanistic and clinical insights such as those provided by this paper, we can hope that the next several years will bring significant advances in the prevention and management of this cancer." @default.
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• W2102801557 title "Primary sclerosing cholangitis and biliary malignancy: a glimmer of hope?" @default.
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