Endoscopic Submucosal Dissection in Europe: Results of 1000 Neoplastic Lesions From the German Endoscopic Submucosal Dissection Registry.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) enables the curative resection of early malignant lesions and is associated with reduced recurrence risk. Due to the lack of comprehensive ESD data in the West, the German ESD registry was set up to evaluate relevant outcomes of ESD. METHODS: The German ESD registry is a prospective uncontrolled multicenter study. During a 35-month period, 20 centers included 1000 ESDs of neoplastic lesions. The results were evaluated in terms of en bloc, R0, curative resection rates, and recurrence rate after a 3-month and 12-month follow-up. Additionally, participating centers were grouped into low-volume (≤20 ESDs/y), middle-volume (20-50/y), and high-volume centers (>50/y). A multivariate analysis investigating risk factors for noncurative resection was performed. RESULTS: Overall, en bloc, R0, and curative resection rates of 92.4% (95% confidence interval [CI], 0.90-0.94), 78.8% (95% CI, 0.76-0.81), and 72.3% (95% CI, 0.69-0.75) were achieved, respectively. The overall complication rate was 8.3% (95% CI, 0.067-0.102), whereas the recurrence rate after 12 months was 2.1%. High-volume centers had significantly higher en bloc, R0, curative resection rates, and recurrence rates and lower complication rates than middle- or low-volume centers. The lesion size, hybrid ESD, age, stage T1b carcinoma, and treatment outside high-volume centers were identified as risk factors for noncurative ESD. CONCLUSION: In Germany, ESD achieves excellent en bloc resection rates but only modest curative resection rates. ESD requires a high level of expertise, and results vary significantly depending on the center's yearly case volume.

CD117 (c-kit) expression in human hepatocellular carcinoma.

AIMS: Although various methods of treatment have been tried, treatment options for advanced hepatocellular carcinoma (HCC) remain limited. Expression of the platelet-derived growth factor has been shown in HCC, which may derive from hepatic stem cells that express the c-kit proto-oncogene. Because of the promising results of imatinib and the key role played by c-kit in gastrointestinal stromal tumours and other solid tumours, the aim of this study was to determine the prevalence of c-kit (CD117) overexpression in patients with HCC. MATERIALS AND METHODS: A retrospective study of 258 archival specimens of subjects with histologically confirmed HCC was carried out. Expression of the c-kit proto-oncogene was evaluated by immunohistochemistry using rabbit anti-CD117 antibody A4502. RESULTS: The overall percentage of positive immunohistochemical staining of HCCs was 2.3% (6/258). CONCLUSIONS: Our results suggest that CD117 is not significantly overexpressed in HCC and there seems to be no role for the use of imatinib.

[Diet therapy in chronic inflammatory bowel disease: results from meta-analysis and randomized controlled trials]. / Diättherapie chronisch entzündlicher Darmerkrankungen: Resultate aus Meta-Analysen und randomisierten klinischen Studien.

BACKGROUND: Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases of unknown etiology. Unspecific immunosuppressive therapy represents current standard treatment and is often associated with severe side effects. Several treatment regimens have been evaluated to identify alternative therapeutic options. Among these different diet therapies were investigated. Objective of this paper is to review the results of diet therapy in chronic inflammatory bowel disease on the basis of randomised controlled trials and meta-analysis of randomised controlled trials. METHODS: Medline and Cochrane Library were searched for meta-analysis and randomised controlled trials investigating this question. Additionally reference lists of identified articles and text books were checked for further trials. RESULTS: Four meta-analyses investigated the treatment of acute Crohn's disease with elemental-, semi-elemental-, and polymeric diets in comparison to corticosteroids or to another form of enteral diet. All meta-analyses show a superiority of corticosteroids and no difference in the effect of the compared enteral diets. Randomised controlled trials investigating diet therapy in ulcerative colitis have not been summarised in a meta-analysis yet. Eleven randomised trials were identified which evaluated diets in ulcerative colitis patients: Dietary supplementation with n-3-fatty acids (6 trials), elemental diet [2], dietary supplementation with dietary fiber [1], elimination diet [1], and dietary supplementation with olestra [1]. Only for the elimination diet a significant positive effect on the course of disease was found in one trial which investigated only 18 patients. CONCLUSIONS: Enteral nutritional therapy of acute Crohn's disease is less effective than treatment with corticosteroids. In case of severe steroid induced side effects diet treatment can present a promising alternative. Superiority of one of the investigated different formulations was not found. Meta-analyses of randomised trials provide a clear and easy to understand presentation of the effect of this intervention. Eleven published trials investigating the effect of diets in ulcerative colitis show only for elimination diet a positive treatment effect. The trials do find a positive effect of one of the other interventions but the trials are very small and cannot exclude a treatment effect. Meta-analysis of these trials would be helpful for a better presentation and understanding of these results.

[Nonsurgical therapy of hepatocellular carcinoma]. / Nicht-chirurgische Therapie des hepatozellulären Karzinoms.

Several non-surgical local ablation methods for the treatment of hepatocellular carcinoma (HCC) have been developed. Among them, percutaneous ethanol injection is worldwide an accepted alternative to surgery in patients with small HCCs. Other local minimal-invasive treatment options, like one time radio-frequency thermal ablation seem to result in more effective tumor control. Randomized controlled trials showed no survival benefit after transarterial chemoembolization and its variants for the treatment of local advanced HCCs. Combined therapeutic strategies may play an increasing role in future in these cases. Effective chemotherapy is not available for metastasized or advanced HCCs. The role of novel techniques for the treatment of HCC has to be carefully determined in large controlled clinical studies.

[Prevention of hepatocellular carcinoma]. / Prävention des hepatozellulären Karzinoms.

Prevention is an increasingly important area of modern medicine. One of the foremost goals in the field of hepatology is prevention of hepatocellular carcinoma since this tumor has a poor prognosis and current therapeutic options are limited. Most hepatocellular carcinomas arise from chronic liver disease and liver cirrhosis which is considered a major risk factor for tumor development. The most common etiologic factors causing liver cirrhosis include chronic viral hepatitis, alcohol consumption, toxins and a few metabolic disorders. This review discusses current therapeutic concepts for prevention and treatment of chronic liver disease and cirrhosis.

Ursodeoxycholic acid and/or antibiotics for prevention of biliary stent occlusion.

BACKGROUND: Malignant biliary obstruction, which requires endoscopic stenting as palliative therapy, is often complicated by clogging of the stent with subsequent jaundice and/or cholangitis. Stent clogging may be caused by microbiological adhesion and biliary stasis. Therefore, antibiotics and choleretic agents like ursodeoxycholic acid (UDCA) have been investigated to see whether they prolong stent patency. OBJECTIVES: To evaluate if UDCA and/or antibiotics may prolong stent patency and survival in patients with strictures of the biliary tract and endoscopically inserted stents. SEARCH STRATEGY: The Trials Register of The Cochrane Hepato-Biliary Group, The Cochrane Library, MEDLINE, Current Contents, EMBASE, and CancerLit were searched until June 2001. Reference lists of the identified articles were checked for further trials. SELECTION CRITERIA: All randomised or quasi-randomised clinical trials investigating UDCA and/or antibiotics in patients with biliary stents were considered for inclusion, regardless of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: Trial inclusion, quality assessment, and data extraction were performed independently by two reviewers. Principal investigators were contacted for further information. Survival data were combined by using hazard ratios (with 95% confidence interval (95% CI)). MAIN RESULTS: Five non-blinded randomised trials with 258 patients with malignant strictures treated with polyethylene stents were included. Three trials, including 152 patients, investigated a combination of UDCA and antibiotics versus no treatment. The meta-analysis of these three trials does not show a significant treatment effect on the duration of stent patency (hazard ratio (random effects model) 0.58, 95% CI 0.22 to 1.54) or mortality (hazard ratio (fixed effect model) 0.99, 95% CI 0.68 to 1.43). Two trials with 106 patients compared antibiotics with no treatment, one of these trials used a combination of antibiotics and rowachol (an 'alternative' drug of the 'mint' family). The pooled results of these two trials do not show significant effects of antibiotics on the duration of stent patency (hazard ratio (fixed effect model) 0.69 (95% CI 0.37 to 1.30)) or mortality (hazard ratio (fixed effect model) 1.23 (95% CI 0.72 to 2.08). Data concerning duration of hospital stay, frequency of cholangitis, and rate of infectious complications due to selection of antibiotic resistant bacteria strains were not available. REVIEWER'S CONCLUSIONS: Treatment with UDCA and/or antibiotics to prevent clogging of biliary stents in patients with malignant stricture of the biliary tract cannot be recommended routinely on the basis of the existing randomised clinical trials. Further trials are needed with rigorous methodology and sufficient statistical power.

[Clinical outcome of a cohort of 63 patients with hepatocellular carcinoma treated with octreotide].

Unresectable hepatocellular carcinoma (HCC) are associated with a poor prognosis. Recently, one controlled study reported a strikingly prolonged survival of patients with HCC who were treated with octreotide. Until other randomised controlled trials become available, this multicentric retrospective study therefore assesses the outcome of HCC-patients who received octreotide treatment. 63 patients (53 males, 10 females) who had been treated with octreotide at 13 participating German centres were included in the analysis. In 54 cases liver cirrhosis was present (25 Child-Pugh A, 20 Child-Pugh B, 7 Child-Pugh C, 2 unknown). The liver disease was associated with alcohol abuse in 19 patients, alcohol and viral hepatitis in four patients, while 12 patients had only markers of past or present hepatitis B infection, 11 patients suffered of chronic hepatitis C infection, and four patients were seropositive for both hepatitis B and hepatitis C markers. The Okuda stage was stage I in 23, stage II in 33, and stage III in 7 patients. The patients initially received octreotide as a long-acting release formula (20-30 mg/month) in 43 cases or through subcutaneous injection (dose 3 x 50-3 x 300 ug/day) in the remaining cases. 11 of the patients receiving subcutaneous treatment were later converted to the long-acting release form of the drug. At three months, a partial remission was achieved in two patients, while 22 tumours showed no change and 26 tumours progressed. At six months, 11 tumours showed no change, while 15 tumours progressed. The patients' median survival was 9 months (Okuda stage I 16 months, stage II 9 months, stage III 4 months). In conclusion, octreotide treatment did not result in markedly prolonged survival in this retrospective series of 63 patients.

Radiofrequency thermal ablation of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide. Due to advanced or decompensated liver cirrhosis, comorbidity and multicentricity of the tumor lesions, 70-80% of HCC patients are inoperable at the time of diagnosis. Radiofrequency thermal ablation (RFTA) is a new minimally invasive and sage technique for the nonsurgical treatment of HCCs. Similar to other ablation techniques, the treatment strategy depends on several factors, including the patient's clinical status, the stage of liver cirrhosis and of the HCC. RFTA can be performed percutaneously, laparoscopically or after laparotomy. Advanced RFTA equipment, refined techniques of modifying tumor tissue response to RFTA, and combined treatment strategies should lead to better response rates even in larger HCCs.

[Pancreatic and biliary tract tumors--diagnosis: ultrasonic diagnosis--endosonography]. / Pankreas- und Gallenwegstumoren--Diagnostik: Ultraschall--Endosonographie.

Pancreaticobiliary tumors are mostly adenocarcinomas with a poor 5-year survival of less than 2%. Early diagnosis of resectable tumors improves outcome. Conventional ultrasound (US) is non-invasive and is the first modality employed on suspicion of these tumors. With adequate skills and equipment, pancreatic tumors from 1.5 cm in diameter can be detected. By contrast, US is less sensitive in the detection of lymph node involvement and infiltration of blood vessels. Depending on the location tumors of the biliary tract appear as a mass lesion intrahepatically or within the gallbladder. Perihilar and extrahepatic bile duct carcinomas cause proximal duct dilatation which is readily detected by US. Again, sensitivity in the detection of lymph node metastases or portal vein invasion is limited. Endoscopic ultrasound (EUS) has emerged as the method of choice in detecting small pancreatic tumors (e.g. < 2 cm in diameter). An accuracy of over 90% in T-staging and blood vessel infiltration can be achieved whereas lymph node metastases are correctly diagnosed in only 67% of cases. EUS-guided biopsy is readily performed using a curved array scanner. This technique enables neurolysis of the coeliac plexus in patients with heavy pain. EUS adds valuable information in cases of distal extrahepatic bile duct cancer. The role of EUS is limited in perihilar and intrahepatic cholangiocarcinoma. Staging and palliative therapy of perihilar carcinoma is still a domain of endoscopic retrograde cholangiography. Intraductal EUS is restricted to specialized centers and plays no role for routine purposes.

A sphincterotome-based technique for selective transpapillary common bile duct cannulation.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) requires selective cannulation of the common bile duct and pancreatic duct. Selective common bile and pancreatic duct cannulation with standard techniques can be achieved in most but not all cases even in experienced centers. To facilitate selective cannulation, sphincterotomes can be used. METHODS: A prospective randomized study aimed at selective deep cannulation of the common bile and pancreatic ducts comparing different ERCP procedures was performed. One hundred patients were randomly assigned to undergo cannulation with a standard catheter or with a guidewire sphincterotome (GS) without guidewire. RESULTS: The primary success rate of selective common bile duct cannulation was significantly higher in the GS group (84%) as compared with the standard catheter group (62%) (p = 0.023). In patients with primary standard catheter failure, selective common bile duct cannulation was possible in 16 patients using a GS which increased the total success rate in the standard catheter group to 94% (p < 0.001). In GS failures selective common bile duct cannulation was possible in two patients using a standard catheter and increased the total success rate from 84% to 88%. The frequency of postinterventional pancreatitis did not differ significantly between the two groups. CONCLUSIONS: ERCP using a GS without guidewire has a significantly higher primary success rate for selective common bile duct cannulation then ERCP using a standard catheter. The use of a GS should be considered to optimize selective cannulation of the common bile duct before resorting to precut techniques.

Percutaneous radio-frequency thermal ablation of nonresectable hepatocellular carcinoma after occlusion of tumor blood supply.

PURPOSE: To evaluate the usefulness of percutaneous radio-frequency (RF) thermal ablation of nonresectable hepatocellular carcinoma (HCC) after occlusion of the tumor arterial supply. MATERIALS AND METHODS: Sixty-two patients with cirrhosis and biopsy-proved HCC underwent RF ablation after interruption of the tumor arterial supply by means of occlusion of either the hepatic artery with a balloon catheter (40 patients) or the feeding arteries with gelatin sponge particles (22 patients). RESULTS: After a single RF procedure in 56 patients and after two procedures in six patients, spiral computed tomography (CT) demonstrated a nonenhancing area corresponding in shape to the previously identified HCC, which was suggestive of complete necrosis. No major complications occurred. Two patients subsequently underwent surgical resection; the remaining 60 patients were followed up with spiral CT. During a mean follow-up of 12.1 months, 11 HCC nodules showed areas of local progression; 49 were identified as nonenhancing areas with a 40%-75% reduction in maximum diameter. The 1-year estimate of failure risk was 19% for local recurrence and 45% for overall intrahepatic recurrence. The estimated 1-year survival was 87%. Histopathologic analysis of one autopsy and two surgical specimens revealed more than 90% necrosis in one specimen and 100% necrosis in two. CONCLUSION: HCC nodules 3.5-8.5 cm in diameter can be ablated in one or two RF sessions after occlusion of the tumor arterial supply.

[Value of manometry]. / Stellenwert der Manometrie.

Manometry of the esophagus is essential in the diagnostic workup of patients with motility disorders of the esophagus. Before manometry organic diseases causing the symptoms should be excluded by a esophago-gastroscopy and/or a barium swallow meal. Indications for manometry are noncardiac chest pain, dysphagia of unknown origin, primary or secondary motility disorders of the esophagus and preoperative assessment before antireflux surgery.

[Hepatocellular carcinoma: percutaneous ethanol injection/transarterial chemoembolization/radiofrequency thermoablation]. / Hepatozelluläres Karzinom: perkutane Ethanoinjektion/transarterielle Chemoembolisation/Radiofrequenz-Thermoablation.

In the majority of patients hepatocellular carcinoma (HCC) is associated with liver cirrhosis. Advanced or decompensated liver cirrhosis, comorbidity and multicentricity make 70-80% of HCCs inoperable at the time of diagnosis. Therefore, percutaneous ethanol injection (PEI) and radiofrequency thermal ablation (RFTA) are non-surgical therapeutic options for patients with small HCCs. In patients with advanced tumor stage transarterial chemoembolization (TACE) and its variants showed no survival benefit on the basis of randomized trials. In several studies, however, combined treatment strategies like TACE and PEI or RFTA after occlusion of tumor blood supply in the treatment of advanced HCC seems to result in a survival benefit. All HCC patients should be included in randomized treatment studies.

Acute liver failure due to enalapril.

This report presents a 46-year-old man who was treated for hypertension with the angiotensin-converting-enzyme (ACE) inhibitor enalapril. After 3 years of continuous treatment he presented with jaundice and progressive liver failure that continued despite withdrawal of the medication. The patient was taking no other medication. All known causes of acute liver failure could be excluded indicating a drug-induced liver damage after long-term treatment with enalapril. Analysis of liver biopsies revealed a pathomorphological pattern comparable to than observed in severe halothane hepatitis. Serological studies including T-cell stimulation with enalapril and a broad spectrum of tests for autoimmunity including autoantibodies against calreticulin, the major Ca2+ and Zn2+ binding protein of the endoplasmic reticulum and suggested to be involved in the pathogenesis of halothane hepatitis were negative. Thus, the mechanism of enalapril-induced liver injury remains obscure. Liver failure progressed and finally led to orthotopic liver transplantation. To our knowledge, this is the longest duration of chronic treatment with an ACE inhibitor before liver failure occurred. In addition, liver failure progressed despite withdrawal of the medication. It is concluded that even after long-term treatment with an ACE inhibitor liver failure may be induced. Therefore, regular monitoring of liver enzymes should be considered.

Ampullary hamartoma: A rare cause of biliary obstruction.

Tumors of the papilla of Vater are very rare. Despite advanced imaging techniques the distinction between benign and malignant tumors remains very difficult. Because most ampullary and periampullary tumors are malignant, primary management is surgical. Here we report the case of a 65-year-old man with biliary obstruction caused by an ampullary hamartoma simulating cancer. The correct diagnosis was not established until surgery.

Survival benefit of patients with inoperable hepatocellular carcinoma treated by a combination of transarterial chemoembolization and percutaneous ethanol injection--a single-center analysis including 132 patients.

Hepatocellular carcinoma (HCC) is one of the most severe sequelae of chronic liver disease. The only potentially curative therapeutic options are surgical resection and orthotopic liver transplantation. In most HCC patients, however, at clinical presentation the tumors are unresectable because of multicentricity or poor hepatic functional reserve due to pre-existing cirrhosis or not transplantable because of too advanced tumor stage or severe co-morbidity. In clinical practice, therefore, percutaneous ethanol injection (PEI) and transarterial chemoembolization (TACE) are widely used non-surgical therapeutic strategies. We prospectively analyzed the clinical factors determining the prognosis of 132 inoperable HCC patients and assessed the feasibility, therapeutic efficacy and safety of PEI, TACE and a combination thereof. Mean age of patients was 64 years; 95% of patients had liver cirrhosis and 39% were Okuda stage I, 48% stage II and 13% stage III. Fifteen patients were treated by PEI (group 1), 33 by TACE (group 2), 39 by TACE and PEI (group 3) and 45 received best supportive care (group 4). Survival correlated with the Child-Pugh class of liver cirrhosis and the Okuda stage of HCC. Favorable prognostic parameters were alpha-fetoprotein (AFP) levels <100 ng/ml and absence of portal vein thrombosis. Median survival time was 18 months in group 1 [interquartile range (IQR) 10-19], 8 months in group 2 (IQR 5-15), 25 months in group 3 (IQR 13-36) and 2 months in group 4 (IQR 1-9). Multivariate analysis revealed that patients treated with a combination of TACE and PEI have a significantly better survival than patients receiving either PEI or TACE only (p = 0.001). Patients with inoperable HCCs treated by the combination of TACE and PEI have a clear survival benefit. A favorable outcome can be expected in patients with compensated cirrhosis, a low Okuda stage, a baseline AFP level <100 ng/ml and absence of portal vein thrombosis.

[Hepatocellular carcinoma: npn-surgical treatment]. / Hepatozelluläres Karzinom: Nicht-chirurgische Therapieoptionen.

The therapeutic modalities in patients with hepatocellular carcinoma (HCC) depend on the number, size and location of the lesions as well as the stage of the underlying liver disease and the physical condition of the patients. In patients with small and solitary lesions resection, liver resection and in selected cases liver transplantation can be curative. In more advanced stages of the disease with larger or multiple lesions PEI and/or transarterial chemotherapy with or without embolisation (TACE or TAC) can slow the progression of the disease. In disseminated disease, a radio-therapeutic approach can be taken in selected cases. The therapeutic strategy in patients with HCCs has to be individualized, frequently using a combination of therapeutic modalities. Different from the earlier unfavourable prognosis, today for most HCC patients a therapeutic strategy can be offered that results in a prolongation of life and in some cases even cure.