Estudo da lesão de isquemia e reperfusão hepática com e sem obstrução da via biliar e a modulação pela N-acetilcisteína e pelo precondicionamento isquêmico em ratos

O objetivo foi estudar os efeitos do precondicionamento isquêmico e da N-acetilcisteína no clampeamento da tríade portal comparado com o clampeamento vascular excluindo a via biliar. Foram utilizados oitenta ratos EPM-1 Wistar distribuídos aleatoriamente em 2 grupos de 40 animais. Estes se distinguiram pela inclusão (CVB=1) ou não (SVB=2) do ducto biliar no clampeamento e foram redistribuídos em subgrupos de 10. IR1: 20 minutos após a celiotomia, o pedículo contendo os elementos vasculares e o ducto biliar para os lobos mediano e lateral esquerdo do fígado foi clampeado por 40 minutos, seguido de 30 minutos de reperfusão; PCI1: 10 minutos de isquemia e 10 minutos de reperfusão. Após o PCI, seguiu-se o mesmo procedimento usado para IR1; NAC1: (150mg.Kg-1 ), administrada 15 minutos antes do período isquêmico e 5 minutos antes da reperfusão; S1: dissecção e clampeamento exclusivo do ducto biliar durante o período de isquemia. Nos subgrupos IR2, PCI2 e NAC2, o clampeamento excluiu a via biliar; S2: dissecção e observação por 90min. Foram colhidas amostras de sangue para a dosagem dos níveis enzimáticos e fragmento do fígado isquêmico para coloração HE. Na análise estatística dos resultados foram utilizados testes não paramétricos e o nível de rejeição da hipótese de nulidade foi fixado em 5%. A lesão de IR hepática foi menos grave nos animais do grupo de clampeamento seletivo incluindo o ducto biliar, com AST (766 vs 1380) e ALT (840 vs 1576); PCI protegeu o fígado da IR nos animais com clampeamento seletivo da tríade portal com relação à AST (421 vs 1131) e ALT (315 vs 1085). Na avaliação morfológica, o PCI inibiu a ocorrência de esteatose microvesicular e núcleos picnóticos (0% de lesão moderada ou intensa) e a NAC protegeu parcialmente 17% e 50% de lesão moderada ou intensa para CVB e SVB, respectivamente. O clampeamento seletivo da tríade portal resulta em lesão de IR do fígado menos grave, quando comparado à exclusão do ducto biliar. O PCI protege o fígado da lesão de IR. A NAC mostra um efeito de proteção parcial, reduzindo as alterações parenquimatosas, mas não os níveis de aminotransferases.

Dual-energy CT-cholangiography in potential donors for living-related liver transplantation: Improved biliary visualization by intravenous morphine co-medication

PURPOSE: To prospectively evaluate whether intravenous morphine co-medication improves bile duct visualization of dual-energy CT-cholangiography. MATERIALS AND METHODS: Forty potential donors for living-related liver transplantation underwent CT-cholangiography with infusion of a hepatobiliary contrast agent over 40min. Twenty minutes after the beginning of the contrast agent infusion, either normal saline (n=20 patients; control group [CG]) or morphine sulfate (n=20 patients; morphine group [MG]) was injected. Forty-five minutes after initiation of the contrast agent, a dual-energy CT acquisition of the liver was performed. Applying dual-energy post-processing, pure iodine images were generated. Primary study goals were determination of bile duct diameters and visualization scores (on a scale of 0 to 3: 0-not visualized; 3-excellent visualization). RESULTS: Bile duct visualization scores for second-order and third-order branch ducts were significantly higher in the MG compared to the CG (2.9±0.1 versus 2.6±0.2 [P<0.001] and 2.7±0.3 versus 2.1±0.6 [P<0.01], respectively). Bile duct diameters for the common duct and main ducts were significantly higher in the MG compared to the CG (5.9±1.3mm versus 4.9±1.3mm [P<0.05] and 3.7±1.3mm versus 2.6±0.5mm [P<0.01], respectively). CONCLUSION: Intravenous morphine co-medication significantly improved biliary visualization on dual-energy CT-cholangiography in potential donors for living-related liver transplantation.

Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis

BACKGROUND/AIMS: Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis. METHODS: Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR. RESULTS: Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats. CONCLUSIONS: Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.

Intraoperative three-dimensional fluoroscopic cholangiography

Precise intraoperative assessment of the architecture of the biliary tree could reduce lesions to intra- or extrahepatic bile ducts. The aim of this study was to test feasibility of intraoperative three-dimensional imaging during liver resections. Isocentric C-arm fluoroscopy acquires three-dimensional images during a 190 degrees orbital rotation. The bile ducts were displayed three-dimensionally by realtime rotational projections or multiplanar reconstructions. The technique was established ex vivo in a preserved cadaveric human liver. Intraoperative three-dimensional cholangiography was performed in five patients with centrally located liver malignancies. Complete data acquisition in 3 patients depicted precise anatomical details of the architecture of the biliary tree up to third order divisions. Biliary imaging can be improved by the application of real-time intraoperative three-dimensional cholangiography. For the development of computer-aided navigation in hepatobiliary procedures, this technique could be an important prerequisite for defining landmarks of the liver in a three-dimensional space.

Diethylhexylphthalate extracted by typical newborn lipid emulsions from polyvinylchloride infusion systems causes significant changes in histology of rabbit

Background: Looking for a candidate substance inducing hepatobiliary dysfunction under parenteral nutrition (PN) in newborns, we recently discovered that newborn infusions extract large amounts of the plasticizer diethylhexylphthalate (DEHP) from commonly used polyvinylchloride (PVC) infusion lines. This plasticizer is well known to be genotoxic and teratogenic in animals and to cause changes in various organs and enzyme systems even in humans. The aim of this study was to examine the effect of DEHP, extracted in the same way and in the same amount as in newborns, on livers of young rabbits. Methods: Prepubertal rabbits received lipid emulsion through central IV lines continuously for 3 weeks either via PVC or polyethylene (PE) infusion systems. Livers were examined after 1 and 3 weeks by light and electron microscopy. Results: By light microscopy, hydropic degeneration, single-cell necrosis, fibrosis, and bile duct proliferation were observed more in the PVC group. Electron microscopy revealed multiple nuclear changes, clusters and atypical forms of peroxisomes, proliferation of smooth endoplasmic reticulum, increased deposition of lipofuscin, and a mild perisinusoidal fibrosis only in the PVC group. These changes, which are generally regarded as reaction upon a toxic stimulus, could be exclusively attributed to DEHP. Conclusions: This investigation proved that DEHP produces toxin-like changes in livers of young rabbits in the same dose, duration, and method of administration as in newborn infants. For this reason, it is likely that DEHP is the substance that causes hepatobiliary dysfunction in newborns under PN. Possible modes of action of DEHP are proposed.

A novel secretin receptor splice variant potentially useful for early diagnosis of pancreatic carcinoma

BACKGROUND ; AIMS: Pancreatic and bile duct carcinomas represent highly aggressive malignancies that evolve from secretin receptor-rich ductular cells. With premessenger RNA splicing abnormalities common in cancer, we evaluated whether an abnormal secretin receptor spliceoform were present, characterized it, and developed a serum assay for it. METHODS: Cancer cell lines and healthy and neoplastic tissue were studied by nested reverse-transcription polymerase chain reaction and sequencing. A promising spliceoform was isolated and characterized, and monoclonal antibodies were raised to 2 distinct regions. A dual antibody enzyme-linked immunosorbent assay was developed and applied to blinded serum samples from 26 patients with pancreatic carcinoma, 10 patients with chronic pancreatitis, and 14 controls. RESULTS: Each of 9 pancreatic cancer specimens and no normal tissue expressed a secretin receptor variant with exons 3 and 4 deleted. This encoded a 111-residue peptide with its first 43 residues identical to wild-type receptor, but, subsequent to a shift in coding frame and early truncation, the next 68 residues were unique in the transcriptome/proteome. This nonfunctional soluble protein did not bind or signal in response to secretin and was secreted from transfected MiaPaCa-2 cells. Elevated serum levels of this variant were present in 69% of pancreatic cancer patients, 60% of chronic pancreatitis patients, and 1 of 14 controls. CONCLUSIONS: We identified a novel abnormal spliceoform of the secretin receptor in pancreatic and bile duct cancers and developed a dual antibody sandwich enzyme-linked immunosorbent assay to measure it in the circulation. Initial application of this assay in patients with pancreatic cancer and chronic pancreatitis was promising, but additional validation will be required to evaluate its clinical utility.

Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports

BACKGROUND AND OBJECTIVES: The thrombotic thrombocytopenic purpura-hemolytic uremic syndromes (TTP-HUS) have diverse etiologies, clinical manifestations, and risk factors, but the events that may trigger acute episodes are often unclear. We describe the occurrence of TTP-HUS following pancreatitis and consider whether pancreatitis may be a triggering event for acute episodes of TTP-HUS. DESIGN AND METHODS: We report on three patients from the Oklahoma Registry and two patients from Northwestern University who had an acute episode of TTP-HUS following pancreatitis. A systematic review of published case reports was performed to identify additional patients who had TTP-HUS following pancreatitis. RESULTS. In each of our five patients there was an apparent etiology of alcoholism or common bile duct obstruction for the pancreatitis and no evidence of TTP-HUS when the pancreatitis was diagnosed. Two patients had severe ADAMTS13 deficiency with an inhibitor; in one of these patients TTP-HUS recurred following a subsequent recurrent episode of pancreatitis. The systematic review identified 16 additional patients who had TTP-HUS following pancreatitis; recurrent TTP-HUS occurred in three of these patients following a subsequent episode of recurrent pancreatitis. In all 21 patients, the interval between the diagnosis of pancreatitis and TTP-HUS was short (1-13 days; median, 3 days). The three Oklahoma patients represent approximately 1% of the 356 patients in the Registry. INTERPRETATION AND CONCLUSIONS: These observations suggest that in some patients pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP-HUS.

Sodium retention and ascites formation in a cholestatic mice model: role of aldosterone and mineralocorticoid receptor?

Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenal-intact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodium- and potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium- and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum- and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium- and potassium-dependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. CONCLUSION: Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium- and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium- and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids.

Magnetic resonance (MR) cholangiography: quantitative and qualitative comparison of 3.0 Tesla with 1.5 Tesla

OBJECTIVES: To determine quantitative and qualitative image quality in patients undergoing magnetic resonance (MR) cholangiography at 3.0 Tesla (T) compared with 1.5 T. MATERIALS AND METHODS: Fifty patients (30 women; mean age, 51 years) underwent MR cholangiography at 1.5 T; another 50 patients (25 women; mean age 51 years) were scanned at 3.0 T. MR sequence protocol consisted of breath-hold single-slice rapid acquisition with relaxation enhancement (RARE) and a respiratory-triggered 3D turbo spin echo (3D TSE) sequence. Maximum intensity projections were generated from the 3D TSE datasets. Contrast-to-noise ratio (CNR) measurements between the common bile duct (CBD), left and right intrahepatic duct (LHD, RHD), and periductal tissue were performed. Three radiologists assessed qualitatively the visibility of the CBD, LHD, and RHD and the overall diagnostic quality. RESULTS: Mean gain in CNR at 3.0 T versus 1.5 T in all 3 locations ranged for the RARE sequence from 7.7% to 38.1% and for the 3D TSE from 0.5% to 26.1% (P > 0.05 for all differences). Qualitative analysis did not reveal any significant difference between the 2 field strengths (P > 0.05). CONCLUSIONS: MR cholangiography at 3.0 T shows a trend toward higher CNR without improving image quality significantly.

Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research

PURPOSE: To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. PATIENTS AND METHODS: Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. RESULTS: Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. CONCLUSION: Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.

Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease

Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosis-inducing ligand (TRAIL) receptor 2/death receptor 5 (DR5) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis.

Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression

BACKGROUND ; AIMS: Integrin alphavbeta6 is highly expressed on certain activated epithelia, where it mediates attachment to fibronectin and serves as coreceptor for the activation of latent transforming growth factor (TGF)-beta1. Because its role in liver fibrosis is unknown, we studied alphavbeta6 function in vitro and explored the antifibrotic potential of the specific alphavbeta6 antagonist EMD527040. METHODS: Experimental liver fibrosis was studied in rats after bile duct ligation (BDL) and in Mdr2(abcb4)(-/-) mice. Different doses of EMD527040 were given to rats from week 2 to 6 after BDL and to Mdr2(-/-) mice from week 4 to 8. Liver collagen was quantified, and expression of alphavbeta6 and fibrosis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. alphavbeta6-expressing cells, bile duct proliferation, and apoptosis were assessed histologically. The effect of EMD527040 on cholangiocyte adhesion, proliferation, apoptosis, and TGF-beta1 activation was studied in vitro. RESULTS: alphavbeta6 was highly expressed on proliferating bile duct epithelia in fibrosis, with 100-fold increased transcript levels in advanced fibrosis. EMD527040 attenuated bile ductular proliferation and peribiliary collagen deposition by 40%-50%, induced down-regulation of fibrogenic and up-regulation of fibrolytic genes, and improved liver architecture and function. In vitro alphavbeta6 inhibition reduced activated cholangiocyte proliferation, their adhesion to fibronectin, and endogenous activation of TGF-beta1 by 50% but did not affect bile duct apoptosis. CONCLUSIONS: Integrin alphavbeta6 is strongly up-regulated in proliferating bile duct epithelia and drives fibrogenesis via adhesion to fibronectin and auto/paracrine TGF-beta1 activation. Pharmacologic inhibition of alphavbeta6 potently inhibits the progression of primary and secondary biliary fibrosis.

Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies

BACKGROUND/AIMS: The integrin alphavbeta6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGFbeta1. We studied alphavbeta6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis. METHODS: alphavbeta6 expression was studied by quantitative PCR and immunohistochemistry in rats with cirrhosis due to bile duct ligation (BDL), administration of thioacetamide (TAA), in Mdr2(Abcb4)(-/-) mice with spontaneous biliary fibrosis, and in livers of patients with chronic hepatitis C (n=79) and end-stage liver disease due to various etiologies (n=18). The effect of a selective alphavbeta6 inhibitor was evaluated in Mdr2(Abcb4)(-/-) mice with ongoing fibrogenesis. RESULTS: Integrin beta6 mRNA increased with fibrosis stage in hepatitis C and was upregulated between 25- and 100-fold in TAA- and BDL-induced cirrhosis, in Mdr2(Abcb4)(-/-) mice and in human end-stage liver disease. alphavbeta6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the alphavbeta6 inhibitor injected into Mdr2(Abcb4)(-/-) mice significantly induced profibrolytic matrix metalloproteinases (MMP)-8 and -9 after 3 h, with a corresponding increase in extracellular matrix-degrading activities. In parallel profibrogenic transcripts (procollagen alpha1(I), TGFbeta2, and MMP-2) showed a trend of downregulation. CONCLUSIONS: (1) Integrin alphavbeta6 is induced de novo in rodent and human liver fibrosis, where it is expressed on activated bile duct epithelia and (transitional) hepatocytes during fibrosis progression. (2) In vivo a single dose of a small molecule alphavbeta6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting alphavbeta6 is a unique target for treatment of liver fibrosis.

Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis

The vitronectin receptor integrin alphavbeta3 promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSCs) in vitro. Expecting antifibrotic synergism, we studied the effect of alphavbeta3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by way of bile duct ligation (BDL) for 6 weeks or thioacetamide (TAA) injections for 12 weeks. A specific alphavbeta3 (alphavbeta5) inhibitor (Cilengitide) was given intraperitoneally twice daily at 15 mg/kg during BDL or after TAA administration. Liver collagen was determined as hydroxyproline, and gene expression was quantified by way of quantitative polymerase chain reaction. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, CD68 and hypoxia-inducible factor-1alpha immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and up-regulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased gamma glutamyl transpeptidase in both models, while other serum markers remained unchanged. alphavbeta3 inhibition resulted in mild liver hypoxia, as evidenced by up-regulation of hypoxia-inducible genes. Liver infiltration by macrophages/Kupffer cells was not affected, although increases in tumor necrosis factor alpha, interleukin-18, and cyclooxygenase-2 messenger RNA indicated modest macrophage activation. CONCLUSION: Specific inhibition of integrin alphavbeta3 (alphavbeta5) in vivo decreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSCs in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis.

Photodynamic therapy for cholangiocarcinoma: overview and new developments

PURPOSE OF REVIEW: Photodynamic therapy (PDT) with hematoporphyrins has emerged as promising treatment for nonresectable cholangiocarcinoma in several prospective observational studies and two randomized studies. This review describes the mechanism of action of PDT, gives an overview of clinical experience in cholangiocarcinoma and summarizes the results published in 2007 and 2008. RECENT FINDINGS: The mechanism of action of PDT has been further elucidated. PDT induces an apoptotic, antiangiogenic as well as an immunomodulatory response. Interleukin-6, a bile duct epithelium growth factor correlating with tumor burden, decreases after PDT. The efficacy of PDT was confirmed in a comparative study in the United States. Patients with no visible mass on imaging studies, high serum albumin levels and treatment immediately after diagnosis seem to benefit most from PDT. Although it is recommended to perform PDT in bile ducts without stents in place, illumination through metal stents is possible if the light dose is adjusted. Meso-tetrahydroxyphenyl chlorine is a new potent photosensitizer for PDT of cholangiocarcinoma. SUMMARY: In advanced nonresectable cholangiocarcinoma, PDT is the only evidence-based treatment that improves survival when compared with stenting. Therefore, PDT should be offered to those who are unsuitable for surgery.