Role of transduodenal endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) for diagnosis of retroperitoneal fibrosis (Ormond's disease).

BACKGROUND: Retroperitoneal fibrosis (RPF), often referred to as Ormond's disease when it is of idiopathic origin, is a rare disease characterized by the presence of inflammatory infiltrates and periaortic masses in the retroperitoneum. For a definite diagnosis, a biopsy and subsequent pathological examination is required. Currently accepted methods for retroperitoneal biopsy include open, laparoscopic, or CT-guided approaches. However, transduodenal endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) for diagnosis of RPF has attracted only little attention in the literature. CASE REPORTS: We report two male patient cases who presented with leukocytosis, elevated C-reactive protein, and a suspicious retroperitoneal mass of unknown origin on computed tomography. One patient also reported left lower quadrant pain, whereas the other patient suffered from back pain and weight loss. In both patients, idiopathic RPF was successfully diagnosed by using transduodenal EUS-FNA/FNB with 22- and 20-gauge aspiration needles. Histopathology revealed dense lymphocytic infiltrates and fibrosis. The procedures lasted approximately 25 and 20 minutes, respectively, and in both patients no serious adverse events occurred. Treatment included steroid therapy and administration of Azathioprine. CONCLUSION: We demonstrate that using EUS-FNA/FNB to diagnose RPF is a feasible, fast, and safe method, which should always be considered as a first-line diagnostic modality. Hence, this case report emphasizes that gastrointestinal endoscopists are likely to play an important role in the setting of suspected RPF.

A Synthetic Glycopeptide Vaccine for the Induction of a Monoclonal Antibody that Differentiates between Normal and Tumor Mammary Cells and Enables the Diagnosis of Human Pancreatic Cancer.

In studies within the realm of cancer immunotherapy, the synthesis of exactly specified tumor-associated glycopeptide antigens is shown to be a key strategy for obtaining a highly selective biological reagent, that is, a monoclonal antibody that completely differentiates between tumor and normal epithelial cells and specifically marks the tumor cells in pancreas tumors. Mucin MUC1, which is overexpressed in many prevalent cancers, was identified as a promising target for this strategy. Tumor-associated MUC1 differs significantly from that expressed by normal cells, in particular by altered glycosylation. Structurally defined tumor-associated MUC1 cannot be isolated from tumor cells. We synthesized MUC1-glycopeptide vaccines and analyzed their structure-activity relationships in immunizations; a monoclonal antibody that specifically distinguishes between human normal and tumor epithelial cells was thus generated.

Multicenter randomized controlled trial comparing the performance of 22 gauge versus 25 gauge EUS-FNA needles in solid masses.

BACKGROUND AND AIMS: Few randomized studies have assessed the clinical performance of 25-gauge (25G) needles compared with 22-gauge (22G) needles during endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy of intra-abdominal lesions. We aimed to compare the diagnostic yield, as well as performance characteristics of 22G versus 25G EUS biopsy needles by determining their diagnostic capabilities, the number of needle passes as well as cellularity of aspirated tissue specimen. METHODS: The study is a prospective, randomized, multicenter study. Patients were referred between January 2009 and January 2010 for diagnostic EUS including EUS-guided FNA of different lesions adjacent to the upper GI tract. All patients were randomized to EUS-FNA performed with either a 22G or 25G aspiration needle. RESULTS: EUS-FNA was performed in 135 patients (62 patients with a 22G needle). Sensitivity and specificity of the 22G needle was 94.1% and 95.8%, respectively, and for the 25G needle 94.1% and 100%, respectively. Investigators reported better visualization and performance for the 22G needle compared to the 25G (p < 0.0001). The number of tissue slides obtained was higher for the 22G needle during the second and third needle passes (p < 0.05). We did not observe significant differences between the number and preservation status of obtained cells (p > 0.05). CONCLUSIONS: A significant difference was found between the two types of needles in terms of reduced visualization of the 25G needle and suboptimal performance rating. However, this did not impact on overall results since both needles were equally successful in terms of a high diagnostic yield and overall accuracy.

Liver resection using heat coagulative necrosis: indications and limits of a new method.

BACKGROUND: A new approach towards achieving bloodless liver resection is the use of heat coagulative necrosis. The latest stage of this technique is a four-probe device (Habib Sealer), which we used for a variety of resections to find the best indications for the method. METHODS: Between 2005 and 2006 we performed 28 liver resections in 20 consecutive patients. The most common indication was metastatic colorectal cancer (75%). We treated a heterogeneous patient collective in terms of tumour localization and extent of resection. Resection was performed after creating a necrotic zone. The device achieved an area of coagulation of 1-cm width in which even larger vessels and bile ducts were safely sealed. RESULTS: Operative spectrum covered atypical resections (8), one- or bisegmentectomies at different locations (15), hemihepatectomies (4) and one extended right hepatectomy. With one exception intra-operative blood loss was lower than 100 mL. Four patients (20%) developed operation-related complications comprising abscess formation at the resection site. Follow-up shows tumour-free survival for 13 of 18 patients 12 months after resection. CONCLUSION: Liver resection using the sealer device seems safe. In proximity of hilar structures or large vessels the method is not favourable for the fear of thermal damage. Extended resections are possible but not parenchyma saving. Good indications are atypical (deep) resections - especially in Segment IVb.

Losses of chromosome arms 4q, 8p, 13q and gain of 8q are correlated with increasing chromosomal instability in hepatocellular carcinoma.

OBJECTIVE: Chromosomal instability is a key feature in hepatocellular carcinoma (HCC). Array comparative genomic hybridization (aCGH) revealed recurring structural aberrations, whereas fluorescence in situ hybridization (FISH) indicated an increasing number of numerical aberrations in dedifferentiating HCC. Therefore, we examined whether there was a correlation between structural and numerical aberrations of chromosomal instability in HCC. METHODS AND RESULTS: 27 HCC (5 well, 10 moderately, 12 lower differentiated) already cytogenetically characterized by aCGH were analyzed. FISH analysis using probes for chromosomes 1, 3, 7, 8 and 17 revealed 1.46-4.24 signals/nucleus, which correlated with the histological grade (well vs. moderately,p < 0.0003; moderately vs. lower, p < 0.004). The number of chromosomes to each other was stable with exceptions only seen for chromosome 8. Loss of 4q and 13q, respectively, were correlated with the number of aberrations detected by aCGH (p < 0.001, p < 0.005; Mann-Whitney test). Loss of 4q and gain of 8q were correlated with an increasing number of numerical aberrations detected by FISH (p < 0.020, p < 0.031). Loss of 8p was correlated with the number of structural imbalances seen in aCGH (p < 0.048), but not with the number of numerical changes seen in FISH. CONCLUSION: We found that losses of 4q, 8p and 13q were closely correlated with an increasing number of aberrations detected by aCGH, whereas a loss of 4q and a gain of 8q were also observed in the context of polyploidization, the cytogenetic correlate of morphological dedifferentiation.

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma.

Dedifferentiation of hepatocellular carcinoma implies aggressive clinical behavior and is associated with an increasing number of genomic alterations, eg deletion of 13q. Genes directly or indirectly deregulated due to these genomic alterations are mainly unknown. Therefore this study compares array comparative genomic hybridization and whole genome gene expression data of 23 well, moderately, or poorly dedifferentiated hepatocellular carcinoma, using unsupervised hierarchical clustering. Dedifferentiated carcinoma clearly branched off from well and moderately differentiated carcinoma (P<0.001 chi(2)-test). Within the dedifferentiated group, 827 genes were upregulated and 33 genes were downregulated. Significance analysis of microarrays for hepatocellular carcinoma with and without deletion of 13q did not display deregulation of any gene located in the deleted region. However, 531 significantly upregulated genes were identified in these cases. A total of 6 genes (BIC, CPNE1, RBPMS, RFC4, RPSA, TOP2A) were among the 20 most significantly upregulated genes both in dedifferentiated carcinoma and in carcinoma with loss of 13q. These genes are involved in cell-cycle control and proliferation. Of 33 downregulated genes in the dedifferentiated subgroup, 4 metallothioneins had the lowest fold change, most probably mediated through inactivation of C/EBPalpha by the PI3K/AKT cascade. In conclusion dedifferentiation of hepatocellular carcinoma is associated with upregulation of genes involved in cell-cycle control and proliferation. Notably, a significant portion of these genes is also upregulated in carcinoma with deletion of 13q. As no downregulated genes were identified and microRNAs (mir-621, mir-16-1, mir-15a) are located within the deleted region of 13q and may be lost, we speculate that these miRNAs may induce the upregulation of critical cell-cycle control genes.

Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions.

Cytogenetics of hepatocellular carcinoma and adenoma have revealed gains of chromosome 1q as a significant differentiating factor. However, no studies are available comparing these amplification events with gene expression. Therefore, gene expression profiling was performed on tumours cytogenetically well characterized by array-based comparative genomic hybridisation. For this approach analysis was carried out on 24 hepatocellular carcinoma and 8 hepatocellular adenoma cytogenetically characterised by array-based comparative genomic hybridisation. Expression profiles of mRNA were determined using a genome-wide microarray containing 43,000 spots. Hierarchical clustering analysis branched all hepatocellular adenoma from hepatocellular carcinoma. Significance analysis of microarray demonstrated 722 dysregulated genes in hepatocellular carcinoma. Gene set enrichment analysis detected groups of upregulated genes located in chromosome bands 1q22-42 seen also as the most frequently gained regions by comparative genomic hybridisation. Comparison of significance analysis of microarray and gene set enrichment analysis narrowed down the number of dysregulated genes to 18, with 7 genes localised on 1q22 (SCAMP3, IQGAP3, PYGO2, GPATC4, ASH1L, APOA1BP, and CCT3). In hepatocellular adenoma 26 genes in bands 11p15, 11q12, and 12p13 were upregulated. However, the respective chromosome bands were not gained in hepatocellular adenoma. Expression analysis and comparative genomic hybridisation identified an upregulation of genes in amplified regions of 1q. These results may serve to further narrow down the number of candidate driver genes in hepatocarcinogenesis.

Epigenetic defects of hepatocellular carcinoma are already found in non-neoplastic liver cells from patients with hereditary haemochromatosis.

Gene silencing through aberrant CpG island methylation is a frequent epigenetic defect in hepatocellular carcinoma (HCC). However, nothing is known as yet whether aberrant hypermethylation occurs already in non-neoplastic liver cells from patients with hereditary haemochromatosis who have a clearly elevated risk for developing HCC. Therefore, quantitative real-time PCR-based methylation analysis of six genes frequently hypermethylated in HCC (RASSF1A, cyclinD2, p16(INK4a), GSTpi1, SOCS-1, APC) was performed for liver biopsies from patients with hereditary haemochromatosis. For genotyping of the HFE gene restriction enzyme analysis and Pyrosequencing were used. Transcriptional repression of hypermethylated genes was assessed using real-time RT-PCR. Eighty-four percent of all samples with severe hepatic iron overload and a mutated HFE gene (but without HCC) had at least one gene hypermethylated. All six genes tested were affected by aberrant hypermethylation, albeit to a different extent: RASSF1A 55%, cyclinD2 45%, p16(INK4a) 32%, GSTpi1 10%, SOCS-1 6%, APC 8%. Concomitant transcriptional down-regulation was shown for RASSF1A, cyclinD2, GSTpi1 and SOCS-1. Biopsies from haemochromatosis patients showed significantly more aberrant hypermethylation than normal liver tissue or benign liver tumours (P < 0.001) and also to a higher degree. This effect is independent of patient age, cirrhosis or hepatitis infection. This is the first report demonstrating that longstanding severe iron overload is frequently associated with epigenetic defects characteristic of HCC, which reflects the increased risk of these lesions to progress to HCC. Thus, changes in DNA methylation patterns are an early event preceding morphological alterations of malignant transformation and represent promising targets for early detection.

Assessment of differentiation and progression of hepatic tumors using array-based comparative genomic hybridization.

BACKGROUND & AIMS: To gain more information about the molecular mechanisms leading to dedifferentiation of hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC), high-resolution array-based comparative genomic hybridization (array-CGH) was performed on 24 cases of HCC and 10 cases of HCA. METHODS: DNA chips containing 6251 individual bacterial artificial chromosome/plasmid artificial chromosome clones were used. They allowed for a genome-wide resolution of 1 Mb and an even higher resolution of up to 100 kb for chromosome regions recurrently involved in human tumors and for regions containing known tumor-suppressor genes and oncogenes. RESULTS: Copy number changes on the genomic scale were found by array-based comparative genomic hybridization in all cases. In HCC, gains of chromosomal regions 1q (91.6%), and 8q (58.3%), and losses of 8p (54%) were found most frequently. Hierarchic cluster analysis branched all HCA from HCC. However, in 2 adenomas with a known history of glycogenosis type I and adenomatosis hepatis gains of 1q were found, too. The critically gained region was narrowed down to bands 1q22-23. Although no significant differences in the mean number of chromosomal aberrations were seen between adenomas and well-differentiated carcinomas (2.7 vs 4.6), a significant increase accompanied the dedifferentiation of HCC (14.1 in HCC-G2 and 16.3 in HCC-G2/3; P < .02). Dedifferentiation of HCC also was correlated closely to losses of 4q and 13q (P <.001 and <.005, respectively). CONCLUSIONS: The increased chromosomal instability during dedifferentiation of HCC leads to an accumulation of structural chromosomal aberrations and losses and gains of defined chromosome regions.

Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.

The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.

Expression of the interferon-induced Mx proteins in biliary atresia.

Biliary atresia (BA) is a rare disease of the newborn for which the Kasai procedure is curative only for a few of the patients. The dilemma is that all therapeutic attempts to cure the disease are symptomatic because the etiology is still unclear. One theory suggests a progressive inflammatory process, possibly induced by a viral infection. The aim of the present study was to investigate the activity of type I interferons (IFNs) in the livers of patients with BA. Mx proteins, which mediate an early innate immune response, are a very sensitive marker for type I IFN activity (eg, to viral infection). Liver biopsies were taken during the Kasai procedure from 13 newborns with BA who were serologically negative for hepatotropic viruses. Age-matched controls originated from 7 patients with neonatal cholestasis (eg, inspissated bile syndrome), 3 aborted fetuses, and a 10-year-old child. The immunostaining procedure (alkaline phosphatase anti-alkaline phosphatase) was performed with Mx-specific monoclonal antibody. Immunostaining for Mx proteins was positive in the hepatocytes of all newborns with BA, whereas the intrahepatic bile ducts were positive in all but one. In the control group, 8 of 11 liver samples were Mx-negative. This is the first study dealing with the detection of type I IFN activity in the liver of patients with BA. This observation supports the etiologic consideration of type I IFN-mediated immune response. Although positive findings of viruses in patients with BA are still inconsistent, the present study retraces the progressive inflammatory process in BA one more step toward its beginning.

Liver resection for metastasis due to malignant mesenchymal tumours.

While liver resection for colorectal metastases has shown promising long-term survival, data for metastasectomy in sarcoma and leiomyosarcoma patients have not yielded the same optimism. Due to the rarity of the tumour entity it has always been difficult to provide significant data. Advances in tumour classification suggest that most of the metastases formerly classified to be of sarcomatoid and especially leiomyosarcomatoid origin are actually metastases of GISTs (gastro-intestinal stromal tumours). Neoadjuvant/adjuvant imatinib therapy might improve overall survival and enable surgeons to provide resections in previously unresectable patients. Only R0 resection has been proven to prolong survival so far, with a long disease-free interval as the only independent predictor of outcome.

Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma.

Chromosomal instability (CIN) leads to an increase in aneuploidy and chromosomal aberrations in human hepatocellular carcinoma (HCC). Telomere shortening appears as one mechanism fostering the development of CIN. Whether telomere shortening correlates to specific genetic changes that characterize a certain type of cancer has yet to be established. In our recent study, we combined on a cellular level the analysis of hepatocellular telomere fluorescent intensity (TFI) and copy number of chromosome 8-one of the hallmark chromosomal alterations in hepatocellular carcinoma (HCC). We investigated 15 cytological fine-needle biopsies of aneuploid HCC and 5 touch prints of cadaver livers without cancer. Hepatocyte-specific TFI and the measurement of centromere-specific probe for chromosome 8 were both performed by quantitative fluorescence in situ hybridization (qFISH) or FISH. Combined analysis of both methods (coFISH) allowed measurement of telomere length and chromosome 8 copy number on a single cell level. We observed that telomere shortening correlates significantly with increasing copy number of chromosome 8 in HCC on the cellular level. Above the level of 5 copies of chromosome 8 per nucleus, no further shortening of telomeres was found, indicating that telomeres had reached a critically short length at this stage of aneuploidy. In conclusion, our study gives direct evidence that telomere shortening is linked to a specific genetic alteration characteristic for human HCC.

Distinct methylation patterns of benign and malignant liver tumors revealed by quantitative methylation profiling.

PURPOSE: A comparative quantitative methylation profiling of hepatocellular carcinoma and the most frequent benign liver tumor, hepatocellular adenoma, was set up for the identification of tumor-specific methylation patterns. EXPERIMENTAL DESIGN: The quantitative methylation levels of nine genes (RASSF1A, cyclinD2, p16INK4a, DAP-K, APC, RIZ-1, HIN-1, GSTpi1, SOCS-1) were analyzed in hepatocellular carcinoma and adjacent normal tissue (n = 41), hepatocellular adenoma and adjacent normal tissue (n = 26), focal nodular hyperplasia (n = 10), and unrelated normal liver tissue (n = 28). Accumulated methylation data were analyzed using various statistical algorithms, including hierarchical clustering, to detect tumor-specific methylation patterns. RESULTS: Cluster analysis revealed that hepatocellular adenoma displays a methylation profile much more similar to that found in normal liver tissue and focal nodular hyperplasia than to that found in hepatocellular carcinoma. Many characteristic differences were not detected when using mere qualitative methylation assays. The cyclinD2 gene was identified as a new and frequent target for aberrant hypermethylation in hepatocellular carcinoma (68%). In the control group of 28 liver specimens from healthy donors, a clear correlation between age of patient and frequency and level of aberrant methylation was seen, which could not be detected in the group of hepatocellular carcinoma specimens. CONCLUSIONS: Methylation profiling can clearly contribute to the unequivocal classification of suspicious lesions, but only if done in a quantitative manner applying cell type and gene-specific thresholds. In hepatocellular carcinoma, the altered methylation patterns accompanying malignant transformation override the age-dependent increase in gene methylation.

The extent of liver steatosis in chronic hepatitis C virus infection is mirrored by caspase activity in serum.

Hepatic steatosis is a frequent histological alteration in chronic hepatitis C virus (HCV) infection that sensitizes the liver to cell injury, inflammation, and fibrosis via unclear mechanisms. Although apoptosis has been implicated in various liver diseases, its importance in HCV-associated steatosis is largely unknown. In this study, we investigated the role of caspases, the key regulators of apoptosis, and employed two novel caspase assays, an immunological and a luminometric enzyme test, to detect hepatic caspase activation in sera from HCV patients with different grades of steatosis. Our data show that increased caspase activation can be found not only in liver biopsies, but also in sera from HCV patients with liver steatosis. Patients with steatosis exhibited significantly higher serum levels of caspase activity compared with normal healthy individuals. Moreover, the extent of steatosis closely correlated with serum caspase activity, whereas in particular in cases of low or moderate steatosis, no correlation was found with aminotransferase levels. In conclusion, apoptotic caspase activation is considerably elevated in HCV-associated steatosis. More importantly, our data imply that measurement of caspase activation might be a sensitive serum biomarker to detect liver steatosis in patients with chronic HCV infection and other liver diseases.

LMNA mutations in cardiac transplant recipients.

Lamin A and C are components of the nuclear envelope, located at the nucleoplasmatic surface of the inner nuclear membrane within cells. Recently, mutations within LMNA encoding lamin A/C have been associated with various disease entities including cardiomyopathy. We screened heart transplant recipients suffering from dilated cardiomyopathy (DCM) with a positive family history of LMNA mutations. Four index patients and one relative belonging to four unrelated families carrying LMNA mutations were identified. The mutations p.Q355X and p.S22L have not been reported before, whereas p.R190W has already been reported in other studied DCM cohorts. In the patients of the present study, the mean age at manifestation of heart disease was 37.6 years (range 30-45 years), with progression to end-stage heart failure requiring transplantation at a mean age of 45.8 years (range 35-54 years). Three patients presented initially with atrial fibrillation. These data confirm the involvement of LMNA mutations in patients with DCM and extend the mutational spectrum of LMNA. The p.R190W mutation has been reported in different populations and may therefore be useful for analyzing the impact of a specific LMNA mutation on the phenotype of muscle disease.

Regional and transient ischemia/reperfusion injury in the liver improves therapeutic efficacy of allogeneic intraportal hepatocyte transplantation in low-density lipoprotein receptor deficient Watanabe rabbits.

BACKGROUND/AIMS: Hepatocyte transplantation has the potential to become an alternative to organ transplantation for the treatment of hereditary liver disease. Currently used hepatocyte transplantation techniques are often not sufficient for phenotypic correction. In a pre-clinical model we investigated the effect of regional transient ischemia reperfusion injury and repeated infusions of allogeneic hepatocytes on LDL cholesterol levels in LDL receptor deficient hyperlipidemic Watanabe rabbits. METHODS: A catheter was surgically inserted into the inferior mesenteric vein. Blood supply to the right liver lobe was transiently interrupted. Nine infusions of 2.5x10(7) adult allogeneic hepatocytes from white New Zealand rabbits were applied over a period of 2 months. RESULTS: Compared to pretreatment levels LDL cholesterol decreased significantly in Watanabe rabbits with transient ischemia reperfusion injury and repeated hepatocyte transplantation (-42+/-3%). Repeated hepatocyte transplantation without transient ischemia reperfusion injury decreased LDL cholesterol levels only moderately (-11+/-4%). LDL receptor messenger RNA and proteins were detected in hepatocyte transplanted liver but not in the liver of sham treated animals. CONCLUSIONS: Our data indicate that transient ischemia reperfusion injury of the recipient liver is safe and significantly improves the therapeutic efficacy of allogeneic hepatocyte transplantation in hyperlipidemic rabbits with congenital LDL receptor deficiency.

Effect of H. pylori on the expression of TRAIL, FasL and their receptor subtypes in human gastric epithelial cells and their role in apoptosis.

BACKGROUND AND AIMS: In the human stomach expression of TNF-related apoptosis inducing ligand (TRAIL) and its receptors and the modulatory role of Helicobacter pylori are not well described. Therefore, we investigated the effect of H. pylori on the expression of TRAIL, FasL and their receptors (TRAIL-R1-R4, Fas) in gastric epithelial cells and examined their role in apoptosis. MATERIALS AND METHODS: mRNA and protein expression of TRAIL, FasL and their receptors were analyzed in human gastric epithelial cells using RT-PCR, Western blot, and immunohistochemistry. Gastric epithelial cells were incubated with FasL, TRAIL and/or H. pylori, and effects on expression, cell viability and epithelial apoptosis were monitored. Apoptosis was analyzed by histone ELISA, DAPI staining and immunohistochemistry. RESULTS: TRAIL, FasL and their receptor subtypes were expressed in human gastric mucosa, gastric epithelial cell primary cultures and gastric cancer cells. TRAIL, FasL and H. pylori caused a time- and concentration-dependent induction of DNA fragmentation in gastric cancer cells with synergistic effects. In addition, H. pylori caused a selective up-regulation of TRAIL, TRAIL-R1 and Fas mRNA and protein expression in gastric cancer cells. CONCLUSIONS: Next to FasL and Fas, TRAIL and all of its receptor subtypes are expressed in the human stomach and differentially modulated by H. pylori. TRAIL, FasL and H. pylori show complex interaction mediating apoptosis in human gastric epithelial cells. These findings might be important for the understanding of gastric epithelial cell kinetics in patients with H. pylori infection.