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S Miehlke

Publications and source records attributed to S Miehlke.

At least 37 records · Page 2Linked to original sources
PubMed2001

Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely an hypothesis?

The results of recent investigations have suggested that the old hypothesis of an atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach needs to be qualified. The most common cause of intestinal metaplasia is Helicobacter pylori gastritis. The consequence of this intestinal metaplasia is focal atrophy. Helicobacter pylori infection may also trigger an autoimmune gastritis of the corpus mucosa, with atrophy and intestinal metaplasia. Most intestinal metaplasias are only 'paracancerous' but not 'precancerous' lesions. Diffuse gastric carcinomas, such as the signet ring cell carcinoma, arise independently of intestinal metaplasia. Histogenetically, numerous carcinomas of the stomach are primarily of the gastric type, and may secondarily change into the intestinal type.High-grade intra-epithelial neoplasias (dysplasias) detected during the biopsy-based diagnostic work-up appear to be a marker for carcinoma and must, therefore, be removed endoscopically. The detection of intestinal metaplasia in routinely obtained biopsy material is subject to sampling error and is, therefore, not a suitable marker for an increased risk of a gastric carcinoma developing. As an alternative, the concept of gastritis of the carcinoma phenotype, which is more frequently found in early gastric carcinomas and in the relatives of gastric carcinoma patients, has been developed. In this concept, the diffuse parameters of grade and activity of the gastritis in the antrum and corpus, which are independent of sampling error, are subjected to a comparative analysis. A risk gastritis of the carcinoma phenotype is diagnosed when the grade and activity of the gastritis in the corpus are at least equally as pronounced as in the antrum. Currently, this concept is being tested in a prospective ongoing study. Future studies must show whether, and if so which, immunohistochemical or molecular-genetically detectable changes can be applied as risk markers in the diagnostic work-up. Helicobacter pylori eradication probably does not lead to complete regression of the intestinal metaplasia and ensuing focal atrophy. However, eradication of H. pylori does lead to the normalization of changes that can lead to mutations of the stem cells of the gastric mucosa (free radicals, nitric oxide, cell proliferation and vitamin C secretion).

Gastric Mucosa↗
PubMed2001

Helicobacter pylori vacA, iceA, and cagA status and pattern of gastritis in patients with malignant and benign gastroduodenal disease.

OBJECTIVE: Both bacterial virulence factors and the pattern of Helicobacter pylori (H. pylori) gastritis may contribute to the development of clinically relevant gastroduodenal disease. The aim of our study was to investigate the frequency of H. pylori vacA alleles, iceA, and cagA, and the pattern of gastritis in patients with gastric cancer (GC), gastric lymphoma (MALT), duodenal ulcer (DU), and functional dyspepsia (FD). METHODS: H. pylori was cultured from 141 patients (34 GC, 26 MALT, 49 DU, 32 FD). Allelic variants of vacA and iceA, and cagA were identified by polymerase chain reaction. Antrum and corpus biopsies were obtained for assessment of gastritis according to the updated Sydney System. RESULTS: The vacA sl,ml genotype was more frequently detected in H. pylori from GC patients (70.6%) than from MALT, DU, and FD patients (p < 0.05). The frequency of iceA1 and cagA did not differ among the groups. The proportion of patients with severe gastritis in the corpus was significantly higher in patients with GC and MALT compared with patients with DU (p < 0.001). CONCLUSIONS: In a German patient population, only the vacA s1,m1 genotype of H. pylori is associated with GC, and therefore may be useful to identify infected patients being at an increased risk for GC.

Aged↗
PubMed2001

Helicobacter pylori and gastric cancer:current status of the Austrain Czech German gastric cancer prevention trial (PRISMA Study).

AIM: To test the hypothesis that Helicobacter pylori eradication alone can reduce the incidence of gastric cancer in a subgroup of individuals with an increased risk for this fatal disease. METHODS: It is a prospective, randomized, double blind, placebo controlled multinational multicenter trial. Men between 55 and 65 years of age with a gastric cancer phenotype of Helicobacter pylori gastritis are randomized to receive a 7 day course of omeprazole 2 X 20mg, clarithromycin 2 X 500mg, and amoxicillin 2 X 1g for 7 days, or omeprazole 2 X 20mg plus placebo. Follow-up endoscopy is scheduled 3 months after therapy, and thereafter in one-year intervals. Predefined study endpoints are gastric cancer, precancerous lesions (dysplasia, adenoma), other cancers, and death. RESULTS: Since March 1998, 1524 target patients have been screened, 279 patients (18.3%) had a corpus dominant type of H. pylori gastritis, and 167 of those were randomized (58.8%). In the active treatment group (r = 86), H. pylori infection infection was cured in 88.9% of patients. Currently, the cumulative follow-up time is 3046 months (253.38 patient years, median follow up 16 months). So far, none of the patients developed gastric cancer or any precancerous lesion. Three (1.8%) patients reached study endpoints other than gastric cancer. CONCLUSION: Among men between 55 and 65 years of age, the gastric cancer phenotype of H. pylori gastritis appears to be more common than expected. Further follow up and continuing recruitment are necessary to fulfil the main aim of the study.

Amoxicillin↗
PubMed2001

Development of early gastric cancer 4 and 5 years after complete remission of Helicobacter pylori associated gastric low grade marginal zone B cell lymphoma of MALT type.

AIM: To report 3 of 120 patients on the German MALT lymphoma trial with H. pylori associated gastric MALT lymphoma who developed early gastric cancer 4 and 5 years, after complete lymphoma remission following cure of H. pylori infection. PATIENTS AND RESULTS: Three patients (two men, 74 and 70 years; one women, 77 years) with H. pylori-associated low-grade MALT lymphoma achieved complete lymphoma remission after being cured. Surveillance endoscopies were performed twice a year in accordance to the protocol. Four years after complete lymphoma remission in two patients, and after 5 years in the other, early gastric adenocarcinoma of the mucosa-type, type IIa and type IIc, respectively, was detected, which were completely removed by endoscopic mucosa resection. In one patient, the gastric cancer was diagnosed at the same location as the previous MALT lymphoma, in the other patients it was detected at different sites of the stomach distant from location of the previous MALT lymphoma. The patients were H. pylori negative during the whole follow-up time. CONCLUSION: These findings strengthen the importance of regular Long-term follow-up endoscopies in patients with complete remission of gastric MALT lymphoma after cure of H. pylori infection. Furthermore, gastric adenocarcinoma may develop despite eradication of H. pylori.

Adenocarcinoma↗
PubMed2001

Treatment of Helicobacter pylori infection.

Helicobacter pylori is a serious, chronic, progressive, and transmissible infection associated with a significant morbidity and mortality, which alone emphasizes the priority of developing adequate prophylactic or therapeutic measures. What was previously termed "asymptomatic H. pylori infection" is now recognized as a latent infection, and it is now accepted that the presence of an H. pylori infection is an indication for eradication therapy. Successful cure of H. pylori infection requires 2 or more antibiotics. Antibiotic resistance is the major impediment of cure. The ideal duration of therapy is unknown, but in general, 1 week therapy is less effective than longer durations. Compliance is important for the success of treatment; therefore, the favored regimen should have the least side effects. At present, a proton pump inhibitor (or ranitidine bismuth citrate)-clarithromycin triple therapy with either amoxicillin or metronidazole, for at least 10 days is considered first-line therapy. The alternative is quadruple therapy containing a proton pump inhibitor, bismuth, tetracycline, and a higher dose of metronidazole. Quadruple therapy is the best choice after failure of proton pump inhibitor-clarithromycin triple therapy. Confirmation of successful therapy with a urea breath test or a stool antigen test is now the standard of practice.

Anti-Bacterial Agents↗
PubMed2000

The Helicobacter pylori vacA s1, m1 genotype and cagA is associated with gastric carcinoma in Germany.

BACKGROUND: The H. pylori vacuolating cytotoxin encoded by vacA and the cytotoxin-associated protein encoded by cagA are considered to be important virulence determinants that have been implicated in the development of peptic ulcers and gastric carcinoma. However, conflicting results regarding the association between these virulence factors and clinical disease have been reported from different geographic regions. AIMS: To determine the frequency of vacA genotypes, vacuolating cytotoxin activity, and cagA in H. pylori isolates obtained from patients with gastric cancer in Germany. METHODS: H. pylori isolates were obtained from 34 patients with gastric cancer and from 35 subjects with asymptomatic H. pylori gastritis. vacA genotypes and cagA were identified by PCR. Cytotoxic activity was determined by HeLa cell assays. Gastritis was assessed according to the updated Sydney System. RESULTS: The H. pylori vacA s1,m1 genotype was significantly more frequent in patients with gastric cancer (24/34, 70.6%) as compared with controls (12/35, 34. 3%) (p = 0.005). Cytotoxic activity was detected in 24 (70.6%) and 15 (42.9%) H. pylori isolates from gastric cancer patients and controls, respectively (p = 0.03). The cagA gene was identified in 30 (88.2%) and 21 (60%) H. pylori isolates in the respective groups (p = 0.01). CONCLUSIONS: Our study suggests a significant association between the H. pylori vacA s1,m1 genotype, cytotoxic activity, cagA, and gastric cancer. Detection of H. pylori possessing these virulence determinants may help to identify patients being at an increased risk to develop gastric cancer in our population.

Adenocarcinoma↗
PubMed2000

Frequency of TPR-MET rearrangement in patients with gastric carcinoma and in first-degree relatives.

BACKGROUND: The activation of the c-met protooncogene through a rearrangement has been detected previously in gastric carcinoma tissue and precancerous lesions. In the current study the authors analyzed the rearrangement of TPR-MET in gastric carcinoma patients and in first-degree relatives to evaluate the potential role and timepoint of this genetic alteration in the process of gastric carcinogenesis and its potential value in identifying those individuals with an increased risk of developing gastric carcinoma. METHODS: The presence of TPR-MET mRNA was determined in gastric tissue from 19 patients with gastric carcinoma and in the gastric mucosa of 18 first-degree relatives without gastric carcinoma and in the gastric mucosa of 18 first-degree relatives without gastric carcinoma using a nested reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis. A 205-base pair (bp) cDNA fragment and a 70-bp cDNA fragment spanning the breakpoint were amplified by nested PCR. Amplification products were hybridized with an oligonucleotide labeled at the 3'-end with DIG-11-dUTP spanning the breakpoint using Southern blot analysis. The MNNG-HOS cell line served as a positive control. RESULTS: TPR-MET mRNA was detected in nine gastric carcinoma patients (47%). Among these patients, TPR-MET mRNA was present in the both tumor and tumor free tissues in 5 patients (26%), in the tumor tissue only in 2 patients (11%), and in the tumor free gastric mucosa only in 2 patients (11%). It is interesting to note that TPR-MET rearrangement also was detected in the gastric corpus mucosa of 1 first-degree relative (6%), but in none of the control subjects. CONCLUSIONS: The data from the current study indicate that TPR-MET activation may be an early event in gastric carcinogenesis and may be useful for the identification of individuals with an increased risk of developing gastric carcinoma.

Adult↗
PubMed2000

Expression of metallothionein II in intestinal metaplasia, dysplasia, and gastric cancer.

Differential display is a valuable tool for the identification of differentially expressed genes in human carcinogenesis and development. The search for differentially expressed genes in gastric cancer and its premalignant lesions may help to define molecular alterations in the gastric mucosa that may precede the development of gastric cancer. Using the differential display technique, we identified a cDNA fragment, encoding metallothionein (MT) IIa mRNA. We performed immunohistochemical analysis using a monoclonal antibody directed against human MT and tissues obtained from 34 patients with gastric cancer and 20 healthy individuals to determine the expression and localization of MT in gastric cancer and its associated premalignant lesions and to correlate our findings with histomorphological features and Helicobacter pylori status. In addition, MT expression was assessed in gastric tissues obtained from patients with gastric cancer and first-degree relatives of patients with gastric cancers and healthy individuals using reverse transcription-PCR analysis. Northern blot analysis confirmed the overexpression of MT IIa in gastric cancer. In the normal gastric tissues, no MT immunoreactivity was observed at the superficial gastric epithelium toward the top of gastric glands. However, MT immunoreactivity was detected at the foveolar neck of the gastric glands. Immunohistochemical analysis revealed an intense MT immunoreactivity in gastric cancer cells, independent of tumor stage, grade of differentiation, or tumor type. Furthermore, areas of dysplasia and intestinal metaplasia also exhibited intense MT immunoreactivity. Reverse transcription-PCR analysis of gastric biopsies obtained from first-degree relatives of patients with gastric cancer revealed the frequent expression of MT Ia in this high-risk group as compared with healthy subjects (P < 0.01). The overexpression of MT in gastric cancer and the expression of MT in intestinal metaplasia and dysplasia, as well as the expression of MT in the gastric mucosa of first-degree relatives of patients with gastric cancer, point to a role for MT in the early process of malignant transformation of the gastric mucosa.

Adult↗
PubMed2000

Expression of transforming growth factor beta-1 in gastric cancer and in the gastric mucosa of first-degree relatives of patients with gastric cancer.

Transforming growth factors beta (TGF-beta) constitute a family of polypeptide growth factors that control cell growth, cell differentiation and migration, as well as the formation of the extracellular matrix. Recent analyses revealed the overexpression of TGF-beta1 in human gastric cancers and demonstrated increased cell proliferation in the stomach of patients with gastric cancer and their first-degree relatives. Using human gastric tissues obtained from patients with gastric cancer (n = 19), biopsies from healthy first-degree relatives of gastric cancer patients (n = 18) and healthy individuals (n = 19), we analysed the expression of TGF-beta1 using the reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Fifteen of 19 patients with gastric cancer expressed TGF-beta1 in the tumour. In 11 of these 15 cases TGF-beta1 mRNA was also detectable in the non-tumourous stomach. Interestingly, all but two individuals with a first-degree relative diagnosed with gastric cancer exhibited TGF-beta1 expression in either the antrum or corpus biopsy or both. In contrast, only one of 19 individuals without a family history of gastric cancer expressed TGF-beta1 in the stomach (P< 0.0001). TGF-beta1 expression is detectable in a large proportion of gastric cancers and in the stomach of healthy first-degree relatives of gastric cancer patients. Since individuals without gastric cancers in their family express TGF-beta1 only in one of 19 cases, the induction of TGF-beta1 expression in first-degree relatives of patients with gastric cancer points to the presence of specific molecular alterations in a subgroup of individuals with an increased risk of developing gastric cancer that may precede the development of gastric cancers.

Adult↗
PubMed2000

alpha-catenin expression is decreased in human gastric cancers and in the gastric mucosa of first degree relatives.

BACKGROUND AND AIMS: The role of altered cell adhesion is critical for the development of epithelial cancers. E-cadherin plays an important role in the maintenance of cell-cell adhesion and its function is thought to be regulated by its associated cytoplasmic proteins, such as alpha-catenin and beta-catenin. To determine the role of alpha-catenin expression in gastric carcinogenesis, we studied its expression in human gastric cancer and in the gastric mucosa of first degree relatives with no clinical disease. METHODS: alpha-Catenin expression was assessed by immunohistochemical analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) using gastric tissue specimens from patients with gastric cancer and from the gastric mucosa of first degree relatives of gastric cancer patients and healthy controls. RESULTS: mRNA levels of alpha-catenin were reduced or absent in 13 of 19 gastric cancer tissues, which differed significantly from levels found in the tumour free gastric mucosa of cancer patients (p<0.05). Of the cancer samples with altered alpha-catenin mRNA levels, alpha-catenin expression was negative in seven and decreased in six cases. Interestingly, decreased alpha-catenin mRNA expression also occurred in the mucosa of the corpus (11/18) and antrum (4/18) of first degree relatives. In the corpus biopsies alpha-catenin expression was more often decreased or lost compared with the antrum biopsies in first degree relatives and healthy controls (p<0.05). Immunohistochemical analysis revealed membranous expression of alpha-catenin in gastric cancer cells and the non-malignant gastric epithelium. However, some cancers also exhibited loss of membranous staining. Generally, loss or downregulation of alpha-catenin mRNA in the gastric mucosa was associated with Helicobacter pylori infection (p<0.05). CONCLUSION: Our findings suggest that loss or downregulation of alpha-catenin expression may be an early event in gastric carcinogenesis and may be associated with H pylori infection.

Adult↗
PubMed2000

Ablation of Barrett's epithelium by endoscopic argon plasma coagulation in combination with high-dose omeprazole.

BACKGROUND: Barrett's esophagus is a premalignant condition induced by gastroesophageal reflux. The aim of this prospective study was to assess the efficacy of argon plasma coagulation in combination with high-dose omeprazole therapy to ablate nondysplastic Barrett's epithelium. METHODS: In 73 patients with histologically confirmed Barrett's epithelium, argon plasma coagulation was used in combination with maximal acid suppression (omeprazole 40 mg three times a day). Histologic and endoscopic changes were evaluated at 6- and 12-month intervals. RESULTS: In 69 of 70 patients (98.6%) complete squamous regeneration was achieved after a median of 2 argon plasma coagulation sessions (range 1 to 5). During a median follow-up of 12 months (range 2 to 51 months) there has been no relapse or evidence of the development of dysplasia under continuous acid suppression. Three patients (4.3%) developed a mild stricture of the distal esophagus that resolved after a single session of bougie dilation. CONCLUSIONS: In our experience, argon plasma coagulation in combination with high-dose omeprazole treatment is an effective and safe technique for complete ablation of nondysplastic Barrett's epithelium. Restoration of squamous mucosa after argon plasma coagulation appears to be long-lasting.

Adult↗
PubMed1999

Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin.

Infection with Helicobacter pylori is associated with different human gastric diseases. Biochemical studies, in vitro adherence assays, and in vivo animal models revealed that epithelial attachment of H. pylori can be mediated by the blood-group antigen-binding adhesin (BabA) targeting human Lewis(b) surface epitopes. Studies with transgenic mice expressing the Lewis(b) epitope have shown that such attachment can alter disease outcome. In the current study, the presence of the babA2 gene encoding the adhesin was investigated in clinical isolates from a German population by using PCR and reverse transcription-PCR. A positive genotype was correlated to allelic variations in the genes encoding VacA and CagA and also to the prevalence of duodenal ulcer, distal gastric adenocarcinoma, mucosa-associated lymphoid tissue lymphoma, and antral gastritis. The presence of babA2 was significantly associated with duodenal ulcer (P = 0.0002) and adenocarcinoma (P = 0.033). In contrast, type 1 strains (vacAs1- and cagA-positive) were associated with only duodenal ulcer (P = 0.004) but not adenocarcinoma (P = 0.235). Genotype presence of babA2, vacAs1, and cagA ("triple-positive" strains) showed a highly significant correlation to the prevalence of ulcer (P = 0.000002) and adenocarcinoma (P = 0.014) and discriminated significantly better between disease outcome than did the current type 1 classification. These results indicate that the babA2 gene is of high clinical relevance and would be a useful marker to identify patients who are at higher risk for specific H. pylori-related diseases.

Adhesins, Bacterial↗
PubMed1999

Leptin and its receptor in normal human gastric mucosa and in Helicobacter pylori-associated gastritis.

BACKGROUND: Leptin, a newly discovered weight-reducing hormone, is mainly produced in fat cells. Recently, this hormone has been reported to be produced in rat gastric mucosa cells. In the present study we analyzed the localization and expression of leptin and its receptors in normal human gastric mucosa and in patients with Helicobacter pylori-associated gastritis. METHODS: Plasma leptin levels and gastric mucosa leptin content were determined in 39 patients with dyspepsia. Cellular localization of leptin and of the signaling receptor (Ob-RL) were assessed by immunohistochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) for leptin receptor isoforms was performed on gastric epithelial cells isolated by laser-capture-microdissection. RESULTS: Leptin content of the corpus gastric mucosa in H. pylori-positive patients was significantly increased (4.6+/-1.2. n = 15) as compared with the H. pylori-negative group (27.5+/-0.5 pg/mg, n = 24, P = 0.006). The presence of leptin immunoreactivity was shown in the lower half of corpus epithelial glands. By RT-PCR no leptin mRNA was detectable in human gastric tissue. In contrast, expression of both Ob-R(L) and the leptin receptor isoforms could be detected in gastric epithelial cells. Leptin receptor protein was detected throughout the mucosa. CONCLUSIONS: Leptin itself is stored and secreted but not produced in human gastric mucosa. The functional receptor and all isoforms are present in human gastric mucosa. H. pylori-associated gastritis leads to significant increases in local leptin concentration in the gastric corpus.

Analysis of Variance↗
PubMed1999

Hepatomegaly and cholestasis as primary clinical manifestations of an AL-kappa amyloidosis.

A 53-year-old man, who presented with weight loss over a period of 10 months, hepatomegaly, markedly raised cholestatic enzymes and Ca 19-9, was initially suspected of suffering from metastatic cholangio-carcinoma. Liver biopsy revealed depositions of AL-amyloid. Further investigations confirmed a generalized amyloidosis. Biopsies taken from the gastric, colonic, and bronchial mucosa all showed depositions of amyloid. A nephrotic syndrome was interpreted as being secondary to the renal involvement. Echocardiography identified changes which were consistent with cardiac involvement. A plasmacytoma or lymphoma was excluded. At the time of diagnosis the patient was in a good physical condition with normal renal function. Within a few weeks the renal function deteriorated and after 2 months the patient developed ascites and became jaundiced. Four months after initial presentation the patient died from cardiac failure.

Amyloid↗
PubMed1999

Molecular relationships of Helicobacter pylori strains in a family with gastroduodenal disease.

OBJECTIVE: Few studies have examined the genetic relationships of Helicobacter pylori strains affecting family members. Our aim was to do so. METHODS: We characterized H. pylori isolates obtained from members of a single family presenting with various gastroduodenal diseases to examine H. pylori bacterial genetic similarity. Endoscopic evaluation with gastric mapping was performed on each individual to establish clinical and histological disease. Genomic DNA extracted from each H. pylori isolate was used to generate DNA fingerprints for each strain by REP-PCR. vacA genotypes and cagA presence were established by PCR. RESULTS: Gastrointestinal diseases among the five members of this family included gastric adenocarcinoma in a 52-yr-old man (index patient), gastric MALT-lymphoma in the 73-yr-old mother; intestinal metaplasia (IV) and atrophic gastritis in the 48-yr-old brother; intestinal metaplasia (I-III) in the 47-yr-old brother, and a duodenal ulcer scar in the 42-yr-old sister. REP-PCR DNA fingerprints of H. pylori isolates from the index patient, his mother, and both of his brothers were identical or highly similar. By contrast, the H. pylori DNA fingerprint from the sister was markedly different from the H. pylori DNA fingerprints from the other family members. All isolates had the genotype cagA-positive and vacA slb/ml mosaic genotype. CONCLUSIONS: The DNA fingerprints of H. pylori strains obtained from members of this family with malignancy or premalignant histological disease were identical or highly similar and markedly different from the H. pylori DNA fingerprint from the sibling with duodenal ulcer disease. All H. pylori isolates within the family possessed genetic markers of enhanced virulence (presence of the cagA gene and vacA sl/ml mosaicism). In addition to host genetics and environmental factors, these findings suggest that infection with genetically similar H. pylori strains is a significant factor in determining the clinical outcome of an infection with H. pylori.

Adenocarcinoma↗
PubMed1999

DNA fingerprinting of single colonies of Helicobacter pylori from gastric cancer patients suggests infection with a single predominant strain.

In each of six gastric cancer patients, repetitive extragenic palindromic PCR DNA fingerprints of 18 single colonies of Helicobacter pylori from the gastric antrum, corpus, and cardia were identical and matched that of the parental isolate. In three additional gastric cancer patients, 17 of 18 single-colony DNA fingerprints were identical to each other and to the DNA fingerprint of the corresponding parental isolate.

Adenocarcinoma↗