Werner Van Steenbergen

Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial

BACKGROUND/AIMS Lipiodol chemoembolization is a widely used method of treatment in patients with unresectable hepatocellular carcinoma, but its efficacy is still debated. The aim of our study was to assess the efficacy of lipiodol chemoembolization in patients with unresectable hepatocellular carcinoma. METHODS Seventy-three patients with unresectable hepatocellular carcinoma, but without severe liver disease or portal vein occlusion, were randomly assigned to receive either repeated lipiodol chemoembolization (lipiodol, cisplatin (2 mg/kg), lecithin, and gelatin sponge injected into the hepatic artery) plus tamoxifen (40 mg) or tamoxifen alone. The main end-point was survival. RESULTS The 37 patients in the lipiodol chemoembolization group received 104 courses (median 3 per patient). By 1 September 1996, 58 patients had died: 30 in the lipiodol chemoembolization group and 28 in the tamoxifen group. There was no difference in survival between the two groups (p=0.77). The relative risk of death in the lipiodol chemoembolization plus tamoxifen group as compared to the tamoxifen group was 0.92 (95% confidence interval 0.55 to 1.56). At 1 year, survival was 51% and 55%, respectively. An objective tumoral response was more frequently observed in the lipiodol chemoembolization group than in the tamoxifen group (24 versus 5.5%, respectively, p=0.046). Lipiodol chemoembolization caused two deaths and induced signs of liver failure in 51% of the patients assigned to this treatment. CONCLUSION In our randomized study, lipiodol chemoembolization did not improve the survival of patients with unresectable hepatocellular carcinoma treated with tamoxifen.

Histological Diversity in Cholangiocellular Carcinoma Reflects the Different Cholangiocyte Phenotypes

Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin‐producing cholangiocytes are located in large bile ducts and the cuboidal non–mucin‐producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so‐called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC‐1, KMCH‐1, and KMCH‐2. Among 51 ICCs, 31 (60.8%) contained only mucin‐producing CC features (muc‐ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed‐ICCs). Clinicopathologically, muc‐ICCs and hilar CCs showed a predominantly (peri‐)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed‐ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc‐ICCs and hilar CCs and in mixed‐ICCs and CLCs. S100P and MUC1 were significantly up‐regulated in hilar CCs and muc‐ICCs compared with mixed‐ICCs and CLCs, whereas NCAM1 and ALB tended to be up‐regulated in mixed‐ICCs and CLCs compared with other tumors. KMC‐1 showed significantly higher invasiveness than KMCH‐1 and KMCH‐2. Conclusion: Muc‐ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin‐producing cholangiocytes), whereas mixed‐ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin. (HEPATOLOGY 2012;55:1876–1888)

Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery.

OBJECTIVES:Pregnancy in autoimmune hepatitis has been a rare event, but it has become more frequent with improved therapy. The present study aimed to analyze the consequences for mother and child in patients with autoimmune hepatitis.METHODS:Fourteen pregnancies have been followed in five patients with autoimmune chronic hepatitis (AIH) and in one with autoimmune sclerosing cholangitis (overlap AIH-PSC).RESULTS:Features of AIH improved markedly from the second trimester of pregnancy onward, allowing a decrease in immunosuppressive therapy. After delivery (or stillbirth in one patient), the activity of the autoimmune disease flared up rapidly in 12 of 14 events.CONCLUSIONS:Pregnancy induces a state of immune tolerance with improvement of the liver tests in AIH. This could result from a transition of TH1 to TH2 predominance during pregnancy. A flare-up often occurs after delivery. Preemptive increase of the immunosuppressive therapy is therefore advocated consecutive to delivery. Azathioprine use seems to be safe during pregnancy.

Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) can lead to the development of cholangiocarcinoma (CCA). The tumor may present as an intrahepatic focal cholangiocellular carcinoma but more often as a ductal infiltrating desmoplastic lesion. CCA is found synchronously with the diagnosis of PSC in 20–30% and within 1 year in 50%. During later follow-up, the yearly developmental rate of CCA is 0.5–1.5%. Most patients with PSC and CCA do not yet have cirrhosis but present with a severe stenosis at the hilum of the liver. This type of tumor is difficult to diagnose by imaging techniques.18F-FDG-PET scanning and CEA or CA 19-9 are not early diagnostic tools. Regular MRI, multislice CT, and repeated endoscopically obtained brush cytology of stenotic lesions are recommended. The recent use of more extensive surgical resection techniques in patients with CCA results in 5-year survival rates of ≥50%. If tumors are small or incidental findings, liver transplantation leads to a 3- to 5-year survival rate of 35%. Pretransplant radiotherapy with 5-FU chemosensitization followed by endoscopic brachytherapy with iridium-192 seems to greatly improve the outcome of transplantation. Treatment with ursodeoxycholic acid may prevent development of CCA.

Incomplete septal cirrhosis: histopathological aspects

We have reviewed 60 liver specimens from 47 patients with the diagnosis of incomplete septal cirrhosis observed between 1968 and 1987. In reaching this diagnosis evaluation of the following histological features appeared to be helpful: parenchymal nodularity, thin incomplete septa, hypoplastic portal tracts, increased number of venous channels, abnormal spacing between portal tracts and veins, crowding of reticulin fibres between adjacent zones of hyperplastic parenchyma, hyperplasia of hepatocytes and dilated sinusoids. These histological features were not specific for incomplete septal cirrhosis as they were also present–although less evident and less frequent–in a series of 87 non‐cirrhotic liver specimens. Reticulin stains were an essential adjunct to assess the architectural disturbance, which was often inconspicuous in needle biopsies. Histological features indicating a specific aetiology were lacking in the great majority of cases. On histological and clinical grounds, incomplete septal cirrhosis resembles idiopathic portal hypertension, nodular regenerative hyperplasia and partial nodular transformation; in these entities an obliterative portal venopathy with non‐uniformity of portal blood supply to the parenchyma has been suggested as a pathogenic mechanism. In the present study phlebosclerotic lesions of the portal vein were found in only two cases. This might be explained by sampling error or, alternatively, the hypoplastic portal tracts observed might be a functional equivalent of obliterative portal venopathy resulting in a deficient portal blood supply. Non‐uniformity of blood supply to the parenchyma may explain the similarities between incomplete septal cirrhosis and the diseases mentioned.

Congenital veno-venous malformations of the liver: widely variable clinical presentations.

Background and Aim:  Congenital portosystemic veno‐venous malformations are rare abnomalities that often remain undiagnosed. Typically they are classified by their anatomical characteristics according to Morgan (extrahepatic, Abernethy malformations type Ia,b and II) and Park (intrahepatic, types 1–4). However, their clinical presentation is less dependent on the anatomical type.

Reversal of hepatorenal syndrome in four patients by peroral misoprostol (prostaglandin E1 analogue) and albumin administration

Four consecutive patients with alcoholic cirrhosis and hepatorenal syndrome were treated with misoprostol, a synthetic methylester prostaglandin E1 analogue at twice the dosage advocated for anti-ulcer therapy (i.e., 0.4 mg four times per day orally) and albumin infusions. The mean urinary output obtained over the 3 days preceding misoprostol administration was 250, 315, 550 and 195 ml per 24 h, respectively, in the four patients, despite adequate volume expansion by plasma albumin to reach normal or high central venous pressure. Diuresis increased to 1450, 2440, 925 and 1300 ml, respectively, on days 2-4 after onset of therapy. Serum creatinine levels were 71, 51, 33 and 35 mg/l before and dropped to 26, 21, 13 and 17 mg/l during treatment. All patients had hyponatraemia (117-128 mequiv/l) which normalized, although they were continued on a low sodium intake of less than 10 mequiv per 24 h. Urinary sodium excretion increased from 0.4-3 mmol per 24 h, to 15-40 in the first two cases and only slightly to 3-5 in the last two patients. Three patients died after 10, 30 and 40 days due to oesophageal bleeding, encephalopathy or pulmonary infection, whereas one patient underwent an orthotopic liver transplantation when her serum creatinine attained a level of 13 mg/l. In the first patient, hepatorenal syndrome recurred 10 days after stopping the misoprostol treatment. High doses of misoprostol in the presence of adequate volume expansion thus seem to produce marked diuresis and creatininuria as well as mild natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver

Hepatocellular adenoma and focal nodular hyperplasia (FNH) are benign liver tumours. The differential diagnosis of these lesions and of well‐ to moderately differentiated hepatocellular carcinomas is often difficult but is very important in view of their different treatment. Although neither type of lesion is connected to the biliary tree, FNHs are cholestatic, whereas this is rarely the case for hepatocellular adenomas. This suggests that hepatocellular uptake and secretion of bile constituents is different in FNHs compared to adenomas. We therefore evaluated the expression and localization of hepatic transporters in hepatocellular adenomas, different types of FNH and well‐ to moderately differentiated hepatocellular carcinomas in non‐cirrhotic liver and compared them with normal liver, using real‐time RT‐PCR and (semi‐)quantitative immunohistochemistry. The parenchymal expression of the uptake transporter OATP2/8 (OATP1B1/3) was minimal or absent in adenoma, while there was strong and diffuse expression in FNH. We observed diffuse parenchymal expression of the basolateral export pump MRP3 in adenomas, while only reactive bile ductules and adjacent cholestatic hepatocytes were MRP3‐positive in FNH. The MRP3/OATP2/8 expression pattern of atypical FNHs resembled that of adenomas, suggesting that both types of lesion are related. Most hepatocellular carcinomas showed decreased expression of one or more of the canalicular transporters (MDR1, MDR3, BSEP). The differences in transporter expression profile between FNHs and adenomas are most likely pathogenetically important and may explain why only FNHs are cholestatic. The finding that each type of focal lesion in non‐cirrhotic liver has a specific transporter expression pattern may be useful in the establishment of a correct diagnosis by imaging or on needle biopsy. Copyright

Systemic treatment of pancreatic cancer.

Patients with pancreatic cancer have a poor prognosis although systemic treatment has slightly improved the outcome for those with advanced pancreatic cancer, The approach to a patient with pancreatic cancer remains a great challenge. Patients often present with advanced disease and many are already in poor general condition at the time of diagnosis. Today, surgery remains the only curative therapeutic option. A small number of pancreatic adenocarcinomas, however, are resectable and relapses after surgery are very frequent. The reference treatment in patients with metastatic pancreatic cancer is gemcitabine. The median survival of patients with advanced pancreatic cancer who are treated with gemcitabine is approximately 6 months and only approximately 20% of patients will be alive at 1 year. Combinations of gemcitabine with new cytotoxic agents and with novel targeted agents hold the promise for improving the outcome. Randomized phase III studies are, however, still ongoing. Since most patients will relapse after complete surgical resection of pancreatic cancer, a search for a better adjuvant or neoadjuvant treatment is important. Although several randomized studies have suggested an improved outcome for a postoperative chemoradiotherapy or chemotherapy, the role of an adjuvant treatment remains today controversial. Randomized phase III studies are ongoing. A neoadjuvant strategy might therefore also play a role, but phase III studies are lacking. The systematic evaluation of new drugs in well designed clinical trials and the search for new molecular targets for treatment are crucial in our aim to improve the outcome for patients with pancreatic cancer.

Malignancies and mortality in 200 patients with primary sclerosering cholangitis: a long-term single-centre study

Background: The outcome of primary sclerosing cholangitis (PSC) has improved by liver transplantation (LT), but patients often develop malignancies. We analysed morbidity and mortality patterns to define strategies to prevent complications.