High-throughput sequencing identifies aetiology-dependent differences in ductular reaction in human chronic liver disease.

Ductular reaction (DR) represents the activation of hepatic progenitor cells (HPCs) and has been associated with features of advanced chronic liver disease; yet it is not clear whether these cells contribute to disease progression and how the composition of their micro-environment differs depending on the aetiology. This study aimed to identify HPC-associated signalling pathways relevant in different chronic liver diseases using a high-throughput sequencing approach. DR/HPCs were isolated using laser microdissection from patient samples diagnosed with HCV or primary sclerosing cholangitis (PSC), as models for hepatocellular or biliary regeneration. Key signals were validated at the protein level for a cohort of 56 patients (20 early and 36 advanced stage). In total, 330 genes were significantly differentially expressed between the HPCs in HCV and PSC. Recruitment and homing of inflammatory cells were distinctly different depending on the aetiology. HPCs in PSC were characterised by a response to oxidative stress (e.g. JUN, VNN1) and neutrophil-attractant chemokines (CXCL5, CXCL6, IL-8), whereas HPCs in HCV were identified by T- and B-lymphocyte infiltration. Moreover, we found that communication between HPCs and macrophages was aetiology driven. In PSC, a high frequency of CCL28-positive macrophages was observed in the portal infiltrate, already in early disease in the absence of advanced fibrosis, while in HCV, HPCs showed a strong expression of the macrophage scavenger receptor MARCO. Interestingly, DR/HPCs in PSC showed more deposition of ECM (e.g. FN1, LAMC2, collagens) compared to HCV, where an increase of pro-invasive genes (e.g. PDGFRA, IGF2) was observed. Additionally, endothelial cells in the vicinity of DR/HPCs showed differential immunopositivity (e.g. IGF2 and INHBA expression). In conclusion, our data shine light on the role of DR/HPCs in immune signalling, fibrogenesis and angiogenesis in chronic liver disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

No Superiority of Stents vs Balloon Dilatation for Dominant Strictures in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917.

Effective treatment of benign biliary strictures with a removable, fully covered, self-expandable metal stent: A prospective, multicenter European study.

BACKGROUND: Temporary placement of removable, fully covered, self-expandable metal stents (fcSEMS) for treatment of benign biliary strictures (BBS) has been reported to be effective. However, the optimal extraction time point remains unclear and stent migration has been a major concern. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of this treatment modality using an fcSEMS with a special antimigration design and prolonged stent indwell time. METHODS: We performed a prospective, single-arm study at six tertiary care centers in Europe. Patients with BBS underwent endoscopic or percutaneous implantation of an fcSEMS (GORE® VIABIL® Biliary Endoprosthesis, W.L. Gore & Associates, Flagstaff, AZ, USA). The devices were scheduled to be removed nine months later, and patients were to return for follow-up for an additional 15 months. RESULTS: Forty-three patients were enrolled in the study. Stricture etiology was chronic pancreatitis in the majority of patients (57.5%). All fcSEMS were placed successfully, either endoscopically (76.7%) or percutaneously (23.3%). Stent migration was observed in two patients (5.2%). Primary patency of the SEMS prior to removal was 73.0%. All attempted stent removals were successful. At removal, stricture was resolved or significantly improved without need for further therapy in 78.9% of patients. Stricture recurrence during a follow-up of two years post-implant was observed in two patients. CONCLUSIONS: Temporary placement of the fcSEMS is a feasible, safe and effective treatment for BBS. The design of the device used in this study accounts for very low migration rates and facilitates easy stent retrieval, even after it has been in place for up to 11 months.

Long-term clinical and radiological outcome of endovascular embolization of pancreatitis-related pseudoaneurysms.

Background Long-term outcome after embolization of pancreatitis-induced pseudoaneurysm is not yet determined. Purpose To assess the long-term efficacy and patients' overall survival after embolization of pancreatitis-induced pseudoaneurysm. Material and Methods Patients referred for endovascular treatment of a pancreatitis-induced pseudoaneurysm between January 1998 and January 2014 were analyzed. Embolization procedures were performed by transcatheter techniques using different types of embolic agents. Demographic, technical-radiological, and clinical data were collected. Results Thirty-four patients were identified with a pancreatitis-induced pseudoaneurysm; the underlying disease was acute (n = 13; 38%) or chronic (n = 21; 62%) pancreatitis; seven patients (20.6%) had active bleeding when embolized, while in the remaining 27 patients (79.4%) the pseudoaneurysm was not bleeding. In all 34 patients, successful endovascular exclusion of the pseudoaneurysm was obtained after the first attempt. Minor complications occurred in 11 patients (30%); no major complications were noted. A new pseudoaneurysm on a different vessel was identified during follow-up in three patients (9%). In another patient (3%), the excluded pseudoaneurysm reopened during follow-up. All four recurrences occurred within the first 5 months after embolization. Long-term follow-up (mean, 6.6 years; range, 4 months-16 years) revealed estimated survival rates of 94%, 89%, and 75% after 2, 5, and 10 years respectively, without pseudoaneurysm-related death. Conclusion Catheter-directed embolization of pancreatitis-induced pseudoaneurysms is relatively safe and effective. Recurrence or new pseudoaneurysm formation was low and occurred within the first 6 months after embolization. Overall survival is high, with no pseudoaneurysm-related deaths.

Usefulness of the single-operator cholangioscopy system SpyGlass in biliary disease: a single-center prospective cohort study and aggregated review.

BACKGROUND AND STUDY AIM: Indeterminate biliary strictures and difficult bile duct stones remain clinically arduous and challenging situations. We aimed to evaluate the utility of the single-operator cholangioscopy (SOC)-system SpyGlass in both conditions in a single-center biliopancreatic interventional unit and in perspective of available aggregated literature. METHODS: Usefulness of SOC was assessed for the above-mentioned indications by means of the combination of successful procedural completion, clinical success and incidence of procedure-related adverse events in our own prospective cohort from 3/2010 to 7/2014 and all available literature till 6/2015. RESULTS: Our single-center cohort constituted of 84 patients undergoing SpyGlass either for indeterminate strictures (n = 45) or difficult stones (n = 39). In addition, a comprehensive literature review yielded 851 patients (from 15 series) for either stenosis (n = 646, 75.9 %) and difficult stones (n = 205, 24.1 %). In our series, overall procedural success amounted to 85.7 % (with 88.9 % for stenosis or 82.1 % for stones) compared to 90.7, 91.5 and 88.3 % in overall literature, respectively. Sensitivity, specificity and accuracy for visual diagnosis in our cohort added up to 83.3, 82.9 and 82.9 % compared to 90.8, 90.9 and 90.8 % in the pooled analysis. Respective figures for SOC-directed biopsies totaled 85.7, 100 and 95.7 % in our cohort and 72.4, 100 and 84 % overall. Overall procedure-related complications varied between 9.4 and 21.4 %. CONCLUSIONS: The SOC-platform SpyGlass can be considered useful in the context of indeterminate biliary strictures and difficult-to-remove biliary stones. In both, SpyGlass-assisted intervention is associated with high procedural success and alters clinical outcome compared to conventional approaches with an acceptable safety profile.

Successful application of endoscopic ultrasound-guided fine needle biopsy to establish pancreatic patient-derived tumor xenografts: a pilot study.

Background and study aim: Typically, pancreatic patient-derived tumor xenografts (PDXs) are established by transplanting large tumor biopsies obtained through invasive surgery approaches into immunocompromised mice. We aimed to develop pancreatic PDXs by transplanting tumor tissue acquired by endoscopic ultrasound (EUS)-guided fine needle biopsies (FNB), assess take rates compared to surgery-derived PDXs, and demonstrate the histological and genetic resemblance to the original tumor. Patients and methods: Biopsies of untreated pancreatic carcinoma were collected at surgery and during EUS and processed to generate PDXs. Results: By centrifugation of FNB-derived tissue prior to engraftment, we achieved an engraftment rate of 60 % (6/10). Despite a decrease in stromal tissue, the general morphology of FNB-derived PDXs was conserved as assessed by histopathology. At the genetic level, somatic mutation and copy number profiles were largely similar to the primary tumor. Conclusion: We show that it is technically feasible to establish pancreatic PDXs using a minimally invasive sampling technique, such as EUS-FNB. Although only a limited amount of tumor tissue was acquired, we obtained results similar to those from surgery-derived PDXs.

The quality of hereditary haemochromatosis guidelines: a comparative analysis.

BACKGROUND AND OBJECTIVES: Hereditary haemochromatosis (HH) is the most prevalent genetic liver disease, with an incidence of 1/200 to 1/400 in the Caucasian population. HH patients are treated by family physicians as well as different specialists. When left untreated or insufficiently treated, the complications can become life threatening. To support and evaluate qualitative care for HH, we evaluated and compared the available structured guidelines on screening, diagnosis and management of HH patients. METHODS: Seven appraisers systematically reviewed the retrieved guidelines. The Appraisal of Guidelines Research and Evaluation II (AGREE II) was used to score and discuss the quality and reach consensus. The content of recommendations and the evidence behind them, were evaluated. RESULTS: Three guidelines, developed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and a DUTCH guideline were found. Fifty-seven percent of the recommendations were not shared between the guidelines, pointing to inconsistency of their content. Only two references supporting the recommendations were shared between all three guidelines. The AASLD guideline contains no information about management and follow-up. Moreover, the methodological quality of the AASLD guideline was rated insufficient, except for 'clarity and presentation' (77%). Applicability of the guidelines was scored very low in all three (AASLD: 31%, EASL: 23%, DUTCH: 35%). The DUTCH guideline was judged best. CONCLUSIONS: Very poor consistency between available guidelines for HH hampers qualitative care and its evaluation. An updated high-quality and evidence-based guideline that covers follow-up and management of patients with HH is needed.

Embolization of post-biliary sphincterotomy bleeding refractory to medical and endoscopic therapy: technical results, clinical efficacy and predictors of outcome.

PURPOSE: To retrospectively analyse the technical and clinical outcomes of embolotherapy for post-biliary sphincterotomy bleeding refractory to medical and endoscopic therapy, and in addition, to analyse factors potentially influencing 30-day mortality. MATERIALS AND METHODS: From November 1998 to November 2012, 34 patients underwent percutaneous embolotherapy for post-biliary sphincterotomy bleeding refractory to medical and endoscopic treatment. Demographic, laboratory, angiographic, and clinical follow-up data were collected. RESULTS: Indication for initial endoscopic sphincterotomy was benign (n = 28) or malignant (n = 6) disease. A precut sphincterotomy followed by sphincterotomy was performed in 13 patients (38 %), whereas the remaining 21 patients (62 %), underwent only sphincterotomy. Seven patients (20.6 %) were still on antithrombotic medication at the time of sphincterotomy. Angiographic evaluation revealed contrast extravasation (n = 31), pseudoaneurysm (n = 2), or a combination of both (n = 1). Embolization was successful in 33 of 34 patients (97 %). Recurrent bleeding occurred in three patients (9 %), and 30-day mortality was 20.6 % (n = 7). Factors significantly influencing 30-day mortality were INR (P = 0.008) and aPTT (P = 0.012). CONCLUSION: Angiographic embolization is very effective in stopping post-biliary sphincterotomy bleeding refractory to medical and endoscopic therapy. The rate of rebleeding is acceptably low, but 30-day mortality remains significant. Haemostatic disorders appear to significantly influence 30-day survival. KEY POINTS: • Transcatheter embolization is very effective in stopping major post-biliary sphincterotomy bleeding • The rate of rebleeding is acceptably low • Haemostatic disorders appear to significantly influence 30-day survival.

Belgian consensus on chronic pancreatitis in adults and children: statements on diagnosis and nutritional, medical, and surgical treatment.

Chronic pancreatitis (CP) is an inflammatory disorder characterized by inflammation and fibrosis, resulting in a progressive and irreversible destruction of exocrine and endocrine pancreatic tissue. Clinicians should attempt to classify patients into one of the six etiologic groups according to the TIGARO classification system. MRI/MRCP, if possible with secretin enhancement, is considered the imaging modality of choice for the diagnosis of early-stage disease.In CP, pain is the most disabling symptom, with a significant impact on quality of life. Pain should be assessed using the Izbicki score and preferably treated using the "pain ladder" approach. In painful CP, endoscopic therapy (ET) can be considered as early as possible. This procedure can be combined with extracorporeal shock-wave lithotripsy (ESWL) in the presence of large (> 4 mm), obstructive stone(s) in the pancreatic head, and with ductal stenting in the presence of a single main pancreatic duct (MPD) stricture in the pancreatic head with a markedly dilated MPD. Pancreatic stenting should be pursued for at least 12 months in patients with persistent pain relief. On-demand stent exchange should be the preferred strategy. The simultaneous placement of multiple, side-by-side, pancreatic stents can be recommended in patients with MPD strictures persisting after 12 months of single plastic stenting. We recommend surgery in the following cases: a) technical failure of ET ; b) early (6 to 8 weeks) clinical failure ; c) definitive biliary drainage at a later time point; d) pancreatic ductal drainage when repetitive ET is considered unsuitable for young patients; e) resection of an inflammatory pancreatic head when pancreatic cancer cannot be ruled out; f) duodenal obstruction. Duodenopancreatectomy or oncological distal pancreatectomy should be considered for patients with suspected malignancy. Pediatricians should be aware of and systematically search for CP in the differential diagnosis of chronic abdominal pain. As malnutrition is highly prevalent in CP patients, patients at nutritional risk should be identified in order to allow for dietary counseling and nutritional intervention using oral supplements. Patients should follow a healthy balanced diet taken in small meals and snacks, with normal fat content. Enzyme replacement therapy is beneficial to symptomatic patients, but also in cases of subclinical insufficiency. Regular follow-up should be considered in CP patients, primarily to detect subclinical maldigestion and the development of pancreatogenic diabetes. Screening for pancreatic cancer is not recommended in CP patients, except in those with the hereditary form.

Transcatheter arterial chemoembolization with doxorubicin-eluting superabsorbent polymer microspheres in the treatment of hepatocellular carcinoma: midterm follow-up.

PURPOSE: To investigate prospectively the safety, tolerability, and efficacy of transarterial chemoembolization using superabsorbent polymer (SAP) microspheres loaded with doxorubicin for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: During the years 2006-2011, 64 patients underwent 144 transarterial chemoembolization with SAP microspheres procedures. Most of the patients were staged as Barcelona Clinic Liver Cancer class B (65%). The most frequent underlying liver diseases were hepatitis C (35%) and alcoholic liver disease (28%) resulting in Child-Pugh A (73.4%) or Child-Pugh B (17%) liver cirrhosis. Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors with magnetic resonance (MR) imaging performed 4-6 weeks after each procedure. RESULTS: Serious adverse events (n = 9) were ischemic or infectious in nature. Transarterial chemoembolization with SAP microspheres resulted in objective response rates of 67.5%, 44.5%, and 25% after first, second, and third sessions. There were 16 patients (25%) who underwent orthotopic liver transplantation after transarterial chemoembolization with SAP microspheres, of whom 2 experienced recurrent disease. During a median follow-up time of 14 months (range, 2-55 mo), 26 patients (40.5%) died. Median overall and transplant-free survivals were 20.5 months (95% confidence interval, 13.2-27.7) and 18 months (95% confidence interval, 14.2-21.8), respectively. CONCLUSIONS: Transarterial chemoembolization with SAP microspheres has an excellent safety profile in cirrhotic patients, even in the presence of advanced liver disease (Child-Pugh B) or advanced stages of HCC. This treatment produced meaningful tumor response rates as assessed by MR imaging.

Treatment of non-alcoholic fatty liver disease: can we already face the epidemic?

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder in the Western world. It comprises a disease spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis, cirrhosis and its complications like hepatocellular carcinoma and liver failure. In addition, evidence is accumulating that NAFLD is an independent risk factor for cardiovascular diseases. Progress has been made in unraveling the pathogenesis, which paved the way for several clinical trials for the treatment of NAFLD. Life style intervention consisting of increased physical activity and dietary modifications, remain the cornerstone of the treatment. Some pharmacological agents show promising results, although on the basis of recent clinical trials no firm conclusions can be drawn. Suggestions for treatment in some particular groups of patients can be made. Further research is required to face the burden of NAFLD, which is already present in epidemic proportions.

Heterozygous α1-antitrypsin Z allele mutation in presumed healthy donor livers used for transplantation.

OBJECTIVES: The Z allele (Glu342Lys) in α1-antitrypsin (AAT) deficiency is a combined deficiency and dysfunctional allele. Carrying one Z allele induces a risk of a more aggressive evolution in patients with a chronic liver disease. As most of the carriers of Z allele do not have overt liver disease, it is likely that Z allele-containing livers have been used previously for liver transplantation. We analyzed the incidence, epidemiology, and clinical features of AAT accumulation in the hepatocytes after liver transplantation. METHODS: Follow-up biopsies of liver transplant recipients were analyzed with periodic acid Schiff staining until 2006 (n=486); from 2006 on (n=303), all biopsies were stained with a specific monoclonal antibody against mutated AATZ protein. Genotyping of both recipient and donor was performed in the case of positive staining. RESULTS: Of 789 liver transplantation patients, six patients (0.8%) showed mutated AATZ accumulation in the transplanted liver. Mutation analysis confirmed the presence of the Z allele in all donor organs including one transplanted organ with the SZ phenotype. There was a clear concordance between the isoelectrical focusing of the recipient AAT after transplantation and the genotype of the donor. CONCLUSION: Presumed healthy donor organs containing the Z allele were used for transplantation in 0.8% of cases in our series. As the presence of a Z allele is an independent risk factor of aggravation of chronic liver disease, AATZ accumulation in biopsies after liver transplantation should be actively looked for.

Endoscopic resection of ampullary lesions: a single-center 8-year retrospective cohort study of 91 patients with long-term follow-up.

BACKGROUND: Endoscopic ampullectomy is established as a valuable treatment for adenomas of the Vaterian papilla. Few large series are available, however, let alone any with long-term follow-up. Moreover, multiple tangible issues remain. The aim of our study was to evaluate efficacy, safety, and outcome of endoscopic ampullectomy and compare it to existing literature METHODS: This is a single-center, retrospective study with a minimal follow-up of 3 years including 91 patients, including familial adenomatous polyposis (FAP) and non-FAP, who had an endoscopic ampullectomy between 2000 and 2008. Outcome parameters included ampulloma characteristics, biotical accuracy as well as safety, efficacy, recurrence rate, and survival after endoscopic ampullectomy. RESULTS: Endoscopic resection was successful in 71 patients (78%). Histological review of the resected specimens revealed nonspecific changes (13.8%), low or medium grade dysplasia (52.9%), high grade dysplasia (21.8%) and carcinoma (18.3%). Bioptic accuracy was 38.3%. Overall complications were observed in 23 patients (25.2%): pancreatitis (15.4%), hemorrhage (12.1%) and cholangitis (4.9%). Recurrence occurred in 18.3%. Fourteen patients underwent pancreaticoduodenectomy. Survival after complete endoscopic ampullectomy was excellent for patients with low to moderate grade dysplasia and high grade dysplasia. Incomplete endoscopic resection of high grade dysplasia or invasive carcinoma was associated with unfavorable outcome when treated merely endoscopically. CONCLUSIONS: Endoscopic ampullectomy is obligatory for assessment of the true histological nature of an ampulloma. Endoscopic resection is a safe and efficient procedure for adenomas with low to moderate dysplasia but also for high grade dysplastic lesions, provided that a complete endoscopic resection is achieved.

HNF1B deficiency causes ciliary defects in human cholangiocytes.

Heterozygous deletion or mutation in hepatocyte nuclear factor 1 homeobox B/transcription factor 2 (HNF1B/TCF2) causes renal cyst and diabetes syndrome (OMIM #137920). Mice with homozygous liver-specific deletion of Hnf1ß revealed that a complete lack of this factor leads to ductopenia and bile duct dysplasia, in addition to mild hepatocyte defects. However, little is known about the hepatic consequences of deficient HNF1B function in humans. Three patients with heterozygous HNF1B deficiency were found to have normal bile duct formation on radiology and routine liver pathology. Electron microscopy revealed a paucity or absence of normal primary cilia. Therefore, heterozygous HNF1B deficiency is associated with ciliary anomalies in cholangiocytes, and this may cause cholestasis.

Transcatheter arterial embolization for iatrogenic hemobilia is a safe and effective procedure: case series and review of the literature.

OBJECTIVE: Hemobilia is an uncommon cause of gastrointestinal bleeding. The etiology is diverse, but most often, it is iatrogenic. The present study aims to reassess the clinical picture and the treatment of choice. METHODS: We describe a case series from a single center of patients who presented with nontraumatic iatrogenic hemobilia. RESULTS: Over a period of 8 years, hemobilia occurred in 12 patients: following liver biopsy in six patients and after endoscopic biliary interventions in four patients, with a respective prevalence of 0.1 and 0.04%. The clinical presentation was characterized by an upper gastrointestinal bleeding (n=11) and/or biochemical signs of sudden biliary obstruction (n=9). The onset of the symptoms occurred after a median of 6 days (range: 1-23). Ultrasound and computed tomography scan missed the diagnosis in, respectively, 4/5 and 2/5 of patients. On arteriography, pseudoaneurysm (6/12) was the most common finding. Transcatheter arterial embolization controlled the bleeding in all cases (12/12) without major complications. CONCLUSION: The delay between the intervention and the clinical presentation and the fact that imaging studies may fail to diagnose hemobilia may mislead the physician. Transcatheter arterial embolization is the treatment of choice for hemobilia. It has proven to be effective and safe and it offers a long-term definitive cure.

Histology obtained by needle biopsy gives additional information on the prognosis of hepatocellular carcinoma.

AIM: Hepatocellular carcinomas (HCC) have a strong biological heterogeneity. Current prognostic scores do not include histology. Information on the behavior of HCC based on histology has been characterized on retrospective data and large tissue specimens. We aimed to assess the additional value of needle biopsy and keratin 19 (K19) assessment in a prospective manner. METHODS: Between 2003 and 2008, all patients with a confirmed diagnosis of HCC by a percutaneous or laparoscopic needle biopsy at the time of diagnosis, and of Barcelona Clinic Liver Cancer (BCLC) stage A, B or C, were included. The exclusion criterion was a palliative setting. Biopsies were scored for microvascular invasion, differentiation, K19, epithelial cell adhesion molecule and α-fetoprotein staining. Clinical and radiological features were registered at time of biopsy. The added value of K19 was assessed using Cox proportional hazards regression. RESULTS: Of 74 patients screened, we included 58 patients. Based on the BCLC, 41% presented with early disease (BCLC A), 16% with intermediate disease (BCLC B) and 43% with advanced disease (BCLC C). In nine patients (16%), K19 staining was positive. Median follow up was 54 months (range 1-74) and 43 patients (72%) died. BCLC classification predicted the prognosis accurately, but histology offered additional prognostic information. In multivariate analysis, K19 was a strong predictor of overall survival (hazard ratio 4.57, 95% confidence interval 1.86-10.6), which improved predictive performance. No needle tract dissemination was observed. CONCLUSION: Despite the possible problem of sampling error, needle biopsy offered additional prognostic information. This is especially the case for K19 staining.

Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.

UNLABELLED: 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.

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. METHODS: Two hundred consecutive patients diagnosed before October 2005 were studied. RESULTS: Malignancies developed in 40 (20%) and led to death in 28 patients (45.9% of the 61 mortalities). Cholangiocarcinoma (CCa) developed in 13 patients, and was detected shortly after the diagnosis of PSC in 31%. Colorectal carcinomas were documented in 10 and dysplastic adenomas in four patients; eight had ulcerative colitis, two Crohn's colitis, one unclassified inflammatory bowel disease (IBDu), three had no IBD. Five died of colorectal cancer. Three carcinomas and two adenomas were localized in the caecum or ascending colon, but most (n=10) in the recto-sigmoidal region. Hepatocellular carcinoma developed in three patients with advanced fibrosis/cirrhosis, and pancreatic cancer in five. LT has been carried out in 42 patients, 6.1 years (median, 0.5-25) after the diagnosis of PSC. Mortality was due to hepatic complications in 13 patients. Within 5 years of the diagnosis, deaths were because of malignancy in 12 patients and to hepatobiliary decompensation in only three, whereas 18 had been transplanted. CONCLUSIONS: Since the use of transplantation, malignancies are the major cause of death. CCa has to be searched for in any new symptomatic patient. Colorectal malignancy occurs frequently. Colonoscopy at the diagnosis of PSC is obligatory and should be repeated at 1-2 years interval in the patients with IBD and every 5 years in those without IBD.

Measurement of itching: validation of the Leuven Itch Scale.

OBJECTIVE: To develop the Leuven Itch Scale (LIS), which measures itching through evaluation of the dimensions of the itch experience; and to provide evidence of the validity, reliability, and responsiveness of the LIS. MATERIALS AND METHODS: A clinimetric study using a longitudinal design. Patients with burns (n=46), atopic dermatitis (n=63), or chronic urticaria (n=41) were included. Evidence for validity (based on test content, relations with other variables and internal structure), reliability and responsiveness of the LIS was evaluated. RESULTS: Validity evidence based on test content was demonstrated by very low percentages of invalid scores for most items. Validity evidence based on relations with other variables was found, because all hypotheses that were put forward could be accepted. With respect to validity evidence on internal structure, a significant moderate positive correlation was found between itch frequency and itch distress, and between itch frequency and severity. As hypothesized, itch severity and distress were strongly correlated. Test-retest reliability showed a moderate to almost perfect agreement for about half of the items. However, the remaining items could be subject to changes in the itch, rather than reflecting instability of the Leuven Itch Scale. In terms of responsiveness, the Leuven Itch Scale did not suffer from floor or ceiling effects and could detect changes in itch frequency in patients with burns. CONCLUSION: The Leuven Itch Scale is a useful and clinimetrically sound instrument to measure pruritus in different patient populations affected by itching.

Caroli disease: review of eight cases with emphasis on magnetic resonance imaging features.

BACKGROUND: Caroli disease is a rare congenital disorder characterized by segmental, nonobstructive dilatation of intrahepatic bile ducts. The term Caroli syndrome is used for the association of Caroli disease with congenital hepatic fibrosis. STUDY AIMS: To provide an overview of the clinical presentation and imaging features of Caroli disease and syndrome, with an emphasis on magnetic resonance imaging. PATIENTS AND METHODS: Retrospective analysis of medical records on eight patients in whom a histologic diagnosis of Caroli disease or syndrome had been made. RESULTS: Presenting signs and symptoms were (hepato)splenomegaly, hematemesis and/or melena, cholangitis, jaundice, and recurrent fever. The central dot sign, defined in the literature as a dot or bundle of strong contrast enhancement within dilated intrahepatic ducts, was found in seven cases on various imaging modalities. A 'dot-like structure' was found in one case in which only unenhanced studies were available. There was a tendency toward a right hepatic-lobe predominance. CONCLUSION: There is an overlap between the imaging features of Caroli disease and Caroli syndrome. Our findings support earlier reports that the central dot sign is highly specific for the disease, and that it can be reliably detected by current imaging techniques.