[Extrapulmonary sarcoidosis: gastrointestinal involvement -case report and review of literature]. / Extrapulmonale Sarkoidose: Befall des Gastrointestinaltraktes - Fallbericht und Literaturrecherche.

Sarcoidosis is a rare systemic disease characterized by noncaseating granulomas in affected organs. With > 90 % of all cases lung involvement is the most frequent site of manifestation of sarcoidosis, nevertheless multiple other organs can be affected. Extrapulmonary manifestations are lymph nodes, skin, nervous system, heart, eyes, bone marrow, spleen or gastrointestinal tract including liver and pancreas. Involvement of the gastrointestinal tract is rare, it can affect the whole intestine and is most frequently found in the stomach. Despite its infrequent manifestation, gastrointestinal sarcoidosis can have a significant clinical impact depending on the organ involved, so that early diagnosis is warranted. Medical treatment mainly consists of immunosuppressive therapy, most frequently with corticosteroids being the first treatment of choice. Dosage and duration of therapy is not well established yet. In the literature very limited data are available on this topic with randomized trials missing completely. The aim of this paper is to give a summary of the available data to this date.

[Colon Polypectomy - And Then?]. / Polypektomie am Kolon - und dann?

Colorectal cancer (CRC) is the most frequent gastrointestinal tumour. Most CRC appear to arise from adenomas of the colon in a period of 10 or 15 years. The ultimately progression of benign adenomas to malignant CRC is known as the adenoma-carcinoma sequence. In addition, the description of the "serrated pathway" has shifted the focus of interest also towards to sessile serrated adenomas and traditional serrated adenomas in the development of CRC. It has been proven that the screening colonoscopy might prevent CRC by early detection of adenomatous polyps as precursors for colorectal cancer and polypectomy. Thus, disease-associated mortality of CRC could be reduced. Colonoscopy, the gold standard in CRC diagnosis, is recommended to men and women from the age of 55. On the one hand, there are requirements to the endoscopists. On the other hand there are also essential requirements to pathologists' findings. After polypectomy a risk stratification for aftercare based on endoscopic and histological findings is necessary. Endoscopic follow-up of high-risk patients (≥ 3 tubular adenomas, ≥ 1 adenoma ≥ 1 cm, tubulovillous or villous adenoma, ≥ 1 adenoma with high-grade intraepithelial neoplasia, ≥ 10 adenoma no matter what size or histological findings) should be done sooner (< 3 years). In contrast, colonoscopy in low-risk patients (1 or 2 [tubular] adenomas, size < 1 cm) should be performed later rather than sooner (> 5 years). Colonoscopic surveys under 12 months should be done only in exceptional and very serious situations. Pharmaceutical chemoprevention of adenomas or CRC are still part of clinical trails. More data are necessary.

Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.

BACKGROUND: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. PATIENTS AND METHODS: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks+1-week rest followed by once 3-weeks+1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). RESULTS: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P=0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P=0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P=0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRß expression correlated with longer PFS. CONCLUSION: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.

[Epidemiology and risk factors of hepatocellular carcinoma]. / Epidemiologie und Risikofaktoren des hepatozellulären Karzinoms.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has increased over the past decades as a result of alcoholic liver disease, the metabolic syndrome and the increasing incidence of viral hepatitis B and C. OBJECTIVES: An evaluation of the epidemiology of HCC, presentation and discussion of the risk factors for the development of HCC. MATERIAL AND METHODS: This study was based on a literature review, analysis of the statistics of the World Health Organization (WHO), discussion of current basic research and expert recommendations. RESULTS: The results show that HCC already represents the fifth most common malignancy in men and the ninth most common malignancy in women, and the incidence is still rising. The pronounced regional differences in prevalence and underlying risk factors are mainly, but not exclusively, due to the prevalence of chronic viral hepatitis B. CONCLUSION: Hepatocellular carcinoma is a major medical problem. Primary prevention measures and suitable screening algorithms are gaining more and more importance.

Subclinical ascites defines an intermediate stage between compensated and decompensated cirrhosis.

BACKGROUND: Clinical detection of ascites is a sign of decompensation and correlates with shorter survival in patients with cirrhosis. However, the prognostic relevance of sole detection of ascites by ultrasound (subclinical ascites) is not investigated so far. The aim of the study was to investigate the prognostic relevance of subclinical ascites detected by ultrasound in comparison to absent or clinically detectable ascites in patients with cirrhosis. METHODS: Between 11/1995 and 11/2004 a total of 729 patients with cirrhosis underwent sonographic and hemodynamic (including measurement of HVPG) evaluation. The mean follow up time was 47 months (range: 0.13 - 131). Kaplan-Meier survival curves and multivariate analysis were used to investigate differences. RESULTS: 443 patients were included in the final investigation - 153 patients without ascites, 38 with subclinical ascites and 252 patients with clinical ascites. Kaplan Meier survival curves were significantly different between the three groups (p < 0.001). Interestingly, patients with subclinical ascites had similar values compared to patients with clinical ascites regarding parameters of portal hypertension (HVPG) and liver dysfunction (INR), while parameters of systemic and renal dysfunction (heart beat, creatinin, serum sodium) were similar to patients without ascites. MELD, Child-Pugh score and ascites were independent predictors of mortality in the entire group, while Child-Pugh score and HVPG were independent factors in the subclinical ascites group. CONCLUSION: Detection of subclinical ascites by ultrasound allows the identification of a group of cirrhotic patients with intermediary survival compared to patients without or with clinical ascites. This group of patients is characterized by severe portal hypertension but absence of systemic and renal dysfunction.

KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy.

BACKGROUND: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. METHODS: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. RESULTS: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. CONCLUSIONS: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.

[Pregnancy under immunosuppression]. / Schwangerschaft unter Immunsuppression.

The desire to have children and pregnancy itself are important topics in the treatment of patients under immunosuppression. In this review the risks of frequently prescribed immunosuppressants are discussed regarding the safety of mother and child during and after pregnancy. Knowledge of the specific risks of immunosuppressants in pregnancy is important to balance the therapy between the patients' desire to be treated most effectively and to deliver a healthy child after an uncomplicated pregnancy. Generally, an interdisciplinary approach is advisable in treating and counseling immunosuppressed patients with a desire to have children and during pregnancy.

Comparison of balloon vs. straight catheter for the measurement of portal hypertension.

BACKGROUND: The hepatic venous pressure gradient (HVPG) is used as an estimation of portal pressure (PP) in the management of patients with cirrhosis. Two methods are available using either a straight or a balloon catheter, but have never been compared head-to-head. AIM: To compare the two methods of determining HVPG, straight and balloon catheter, regarding reproducibility and reliability. METHODS: In 47 patients with liver cirrhosis, HVPG was assessed using both catheters in sequence. In another 29 patients, the wedged hepatic venous pressure (WHVP) determined either with straight or balloon catheter was correlated with a direct measurement of PP. Variation coefficient and intraclass correlation coefficient were calculated. RESULTS: Variation coefficients for balloon catheter were 0.07 (HVPG), 0.02 (WHVP) and 0.06 [free hepatic venous pressure (FHVP)]. Variation coefficients for straight catheter were 0.17 (HVPG), 0.06 (WHVP) and 0.07 (FHVP), demonstrating a significantly wider variation of the HVPG and WHVP measurements (P < 0.001). Comparison of WHVP with PP revealed a correlation coefficient of 0.72 (P = 0.004) using balloon catheter and 0.58 (P = 0.011) using straight catheter. CONCLUSIONS: Measurements with the balloon catheter currently represent the most reliable and reproducible method to assess HVPG. The results are of particular clinical relevance if repeated measurements are required for therapeutic adjustments.

Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study.

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m(-2) at first infusion followed by weekly 250 mg m(-2) combined with gemcitabine 1000 mg m(-2) as a 100 min infusion on day 1 and oxaliplatin 100 mg m(-2) as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31-78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.

Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo.

OBJECTIVE: The hepatic integration of human adipose tissue derived mesenchymal stem cells (hAT-MSCs) in vivo with or without prior differentiation to hepatocyte-like cells in vitro was investigated. METHODS AND RESULTS: Cells, isolated either from peritoneal or subcutaneous adipose tissue, expressed mesenchymal stem cell surface markers and featured multiple lineage differentiation. Under conditions favouring hepatocyte differentiation, hAT-MSCs gained hepatocytic functions in vitro including urea formation, glycogen synthesis, cytochrome P450 enzyme activity, and expression of hepatocyte-specific transcripts of carbamoylphosphate synthetase, albumin and cytochrome P450 type 3A4 (CYP3A4). Transgenic expression of green fluorescent protein emerged upon hepatocyte differentiation when driven by the hepatocyte-specific promoter of the cytosolic phosphoenolpyruvate carboxykinase gene but was constitutive from the ubiquitin gene promoter. Human AT-MSCs were transplanted into livers of immunodeficient Pfp/Rag2-/- mice with or without prior hepatocyte differentiation in vitro. Donor-derived human cells engrafted in the mouse host liver predominantly in the periportal region of the liver lobule. They expressed HepPar1 and albumin, typical features of differentiated human hepatocytes, in the otherwise negative mouse liver background. Engraftment was significantly more efficient using hAT-MSCs pre-differentiated to hepatocyte-like cells in vitro as compared with undifferentiated cells. CONCLUSIONS: Pre-differentiation of human MSCs from adipose tissue into hepatocyte-like cells in vitro facilitates long term functional hepatic integration in vivo.

Course of Crohn's disease prior to establishment of the diagnosis.

BACKGROUND: The course of Crohn's disease prior to the establishment of the diagnosis is widely unknown. Therefore, we instigated a survey amongst newly diagnosed patients. PATIENTS AND METHODS: Patients diagnosed with CD less than 12 months before enrollment were included. Data on demography, social status, time interval to diagnosis, symptoms, and health care service use were collected in a retrospective, web-based, census. Patients were contacted in cooperation with two organizations: a German patients' organization (Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung e.V. [DCCV]) and a professional organization of German gastroenterologists (Berufsverband der Niedergelassenen Gastroenterologen Deutschlands e.V. [bng]). Study participation was anonymous by use of a transaction number. RESULTS: The median interval period between onset of first symptoms and diagnosis was 13 months. During this time, participants reported having five doctor consultations on average, with 44% of them having a mean of 1.5 hospitalizations. 65% were unfit for work with a 14 day median (2 to 480 days) due to their symptoms. A mean (+/-SD) of 8.6 (+/-7.1) diagnostic tests were performed before the diagnosis was established. Overall health state was judged as temporarily bad or very bad by 84% of the participants. Age at diagnosis, characteristic symptoms, and localization of the disease for the participants did not differ from previously reported international data. DISCUSSION: This web-based survey shows a substantial time interval of over one year until diagnosis of Crohn's disease amongst the study participants. This period is characterized by both psychological stress and impaired ability to work.

[German guidelines on diagnosis and therapy of hepatitis B]. / Kurzfassung der aktualisierten S3-Leitlinie Diagnostik und Therapie der Hepatitis B.

Therapeutic option for hepatitis B virus infection have significantly improved in recent years. Moreover, new insights in the natural history of hepatitis B required an update of current national guidelines. Therefore, the German network of competence on viral hepatitis (Hep-Net) has revised guidelines on diagnosis and treatment og HBV incetion in cooperation with the national societies for Gastroenterology, Pathology, Virology, and Pediatric Gastroenterology. Important alterations concern the indication for antiviral therapy considering an HBV viremia of 104 copies/ml (2000 IU/ml) as a critical level. Moreover, specific recommendations how to prevent and to treat antiviral drug resistance are given. Finally, the importance of HBV in the context of organ and bone marrow transplantation, treatment of coinfections and children and prophylaxis of HBV is covered.

[Pulmonary complication of liver disease]. / Pulmonale Komplikationen von Lebererkrankungen.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two distinct pulmonary complications of liver disease, which seem pathogenetically linked to the presence of portal hypertension. The most common presenting symptom of both syndromes is dyspnoea, but HPS is more prevalent in 5-30% of patients. The diagnosis of HPS requires the documentation of arterial hypoxemia and intrapulmonary vascular dilatation with anatomical shunting. In contrast, POPH has a prevalence of 2-16% and is only considered proven, if other causes of the pulmonary hypertension than the high portal pressure are excluded. Moderate to severe HPS or POPH carry a poor prognosis and liver transplantation remains the only curative treatment, although POPH in particular is associated with high perioperative mortality.