Increased p53 expression in the malignant transformation of Barrett's esophagus is accompanied by an upward shift of the proliferative compartment.

Neoplastic progression in Barrett's esophagus (BE) occurs by a multistep process associated with early molecular and morphological changes. This study evaluated cell proliferation and p53 expression and their correlation in the development and progression of esophageal adenocarcinoma. PCNA and p53 expressions were analyzed in biopsy samples by immunohistochemistry including patients with reflux esophagitis, BE, BE with concomitant esophagitis, Barrett's dysplasia, esophageal adenocarcinoma and a control group without any histological changes. Progressive increase in cell proliferation and p53 expression was found in the sequence of malignant transformation of the esophageal mucosa. While cell proliferation was significantly lower in the control group compared with all other groups, there was no increase in p53 expression of esophageal tissues that were negative for dysplasia. Dysplastic BE tissues revealed significantly higher cell proliferation and p53 expression levels compared to BE, reflux esophagitis or BE with concomitant esophagitis. Both, cell proliferation and p53 expression were significantly higher in adenocarcinoma compared to BE or Barrett's dysplasia. Interestingly, while just BE with concomitant esophagitis showed significantly higher p53 expression levels than BE, both, BE with concomitant esophagitis and reflux esophagitis revealed significantly higher cell proliferation levels compared to BE. Alterations of cell proliferation and p53 expression showed a strong correlation. Simultaneous activation of cell proliferation and p53 expression strongly suggest their association with esophageal epithelial tumor genesis and particularly, their specific role in the biology of esophageal adenocarcinoma. Quantification of these parameters in BE is thought to be useful to identify patients at higher risk for progression to adenocarcinoma.

Relationship between eradication of Helicobacter pylori and gastric mucosal superoxide dismutase activity.

BACKGROUND: Helicobacter pylori (HP) is the main pathogenic factor in the development of gastritis and gastric cancer. Superoxide-dismutase (SOD) is a key enzyme of mucosal antioxidant protection. In the presence of HP there is a significant increase of SOD activity in the antrum. Changes in gastric mucosal SOD activity were detected in response to eradication treatment of HP infection. PATIENTS AND METHODS: Biopsies were taken from 13 patients upon gastroscopy performed prior to and 88.3 +/- 12.6 days after treatment. The activity of SOD was determined by spectrophotometry. RESULTS: The activity of SOD in the gastric mucosa decreased significantly following the successful eradication, whereas in the corpus activity did not change significantly. CONCLUSION: In the presence of HP there is an oxidative stress in the gastric mucosa triggered by the bacterium. It may represent the final common path of HP carcinogenesis. Successful eradication treatment prevents the production of reactive oxygen metabolites.

Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and epithelial growth factor receptor expression and has no effect on apoptosis and p53 expression.

AIM: To study the effect of proton pump inhibitor (PPI) treatment on patients with reflux esophagitis and its in vivo effect on apoptosis, p53- and epidermal growth factor receptor (EGFR) expression. METHODS: After informed consent was obtained, gastric biopsies of the antrum were taken from patients with reflux oesophagitis prior to and after 6 mo of 20 mg omeprazole (n = 14) or 40 mg esomeprazole (n = 12) therapy. Patients did not take any other medications known to affect the gastric mucosa. All patients were Helicobacter pylori negative as confirmed by rapid urease test and histology, respectively. Cell proliferation, apoptosis, EGFR, and p53 expression were measured by immunohistochemical techniques. At least 600 glandular epithelial cells were encountered and results were expressed as percentage of total cells counted. Was considered statistically significant. RESULTS: Although there was a trend towards increase of cell proliferation and EGFR expression both in omeprazole and esomeprazole treated group, the difference was not statistically significant. Neither apoptosis nor p53 expression was affected. CONCLUSION: Long-term PPI treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression.

[Redox homeostasis in inflammatory bowel diseases]. / Redox-homeosztázis gyulladásos bélbetegségekben.

Janus faced oxygen radicals are secondary messengers of intracellular signal transduction pathways but also cytotoxic agents of cells. Activation of signal transduction proteins on mild oxidant stress and metal elements are still not clearly understood. Oxygen free radicals may have several functions in the expression of cytokines associated with inflammatory bowel disease. The molecular mechanism between activation, and inhibition participants of signal transduction are delicately controlled. Antioxidant-prooxidant balance of the cells can be traced back to the concentration of free-SH and its oxidised form,-S-S-. Healthy erythrocytes and plasma are rich in antioxidants, but their type of protection, differs significantly. The balance of free radicals and antioxidants is disturbed in inflammatory bowel disease. The antioxidant defence mechanism depends on concentration of metal elements, which determines enzyme activities. It seems that nutritional supplementation and adequate therapy restore the ion homeostasis, although, Zn overdose may cause disturbance in iron metabolism and consequently may influence erythrocyte functions.

[Chemoprevention of colorectal cancer]. / A vastagbélrák kemoprofilaxisa.

Although colorectal cancer is one of the most preventable forms of cancer, it remains the second leading cause of cancer death worldwide. Primary prevention involves the identification and elimination of factors, which cause or promote colorectal cancer. The goal of screening is to prevent colorectal cancer mortality through the detection and treatment of premalignant adenomas and curable-stage cancer. Most colorectal cancers are believed to arise from adenomatous polyps. Early identification and removal of adenomas can prevent the development of colorectal cancer. Chemoprevention is the use of specific chemical compounds to prevent, inhibit, or reverse carcinogenesis. Several chemoprevention options have been investigated and confirmed as effective. Aspirin and other nonsteroidal anti-inflammatory drugs are the most widely studied agents, their use has been consistently associated with reduction in the risk of mortality and the incidence of colorectal adenomas and cancers. The selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been demonstrated to decrease the number and the size of polyps in patients with familial adenomatous polyposis syndrome. Because the gastrointestinal toxicity of coxibs is lower, it might be safer than aspirin or other non-selective nonsteroidal anti-inflammatory drugs for long-term use. This review aims to summarize the recent theoretical and practical advances in the chemoprevention of colorectal cancer.

Lower prevalence of Helicobacter pylori infection in patients with inflammatory bowel disease but not with chronic obstructive pulmonary disease - antibiotic use in the history does not play a significant role.

BACKGROUND: Patients with inflammatory bowel disease have lower prevalence of Helicobacter pylori infection, but the exact reason for this is not yet clear. AIM: To examine whether the antibiotics frequently used in inflammatory bowel disease are responsible for the lower prevalence of H. pylori infection. Patients with chronic obstructive pulmonary disease on prolonged previous antibiotic therapy were used for comparison. METHODS: Presence/absence of H. pylori infection was detected by a (13)C-urea breath test in 133 patients with inflammatory bowel disease (82 ulcerative colitis, and 51 Crohn's disease) and compared with that of 135 patients with chronic obstructive pulmonary disease and with two age-matched control groups (200 patients each). Primary disease location, duration of disease and detailed analysis of previous and current medication (dose and duration of antibiotics, steroids, 5-aminosalicylic acid) were analysed in each cases. RESULTS: Seventeen of the 133 patients with inflammatory bowel disease [12.2% (10/82) of ulcerative colitis and 13.7% (7/51) of Crohn's disease] and 90/135 patients with chronic obstructive pulmonary disease (66.7%) were positive for H. pylori. A total of 78/200 (39%) for the inflammatory-bowel-disease-group-matched controls and 110/210 (55%) for the chronic-obstructive-pulmonary-disease-matched controls were positive for H. pylori. The history of any antibiotic or steroid therapy had no influence on H. pylori status of patients with inflammatory bowel disease. CONCLUSION: The prevalence of H. pylori compared to the age-matched controls is significantly lower in patients with inflammatory bowel disease but not in those with chronic obstructive pulmonary disease. Antibiotic use is not responsible for the lower prevalence of H. pylori infection in patients with inflammatory bowel disease.

[Cytokines, prostaglandins, nutritive and non-nuitritive factors in inflammatory bowel diseases]. / Citokinek, prosztaglandinok, nutritív es nem nutritív faktorok gyulladásos bélbetegségekben.

Therapeutic interventions in the case of gastrointestinal disease are based on the understanding of the role of different inflammatory mediators. Reactive O2 and N2 metabolites are involved in IBD. Pro-inflammatory cytokines, apoptosis signalling and redox-response transcription factors are depended on free radicals. NO activates COX enzymes. PGE2 negatively modulates induction of NO synthase by interleukins and therefore regulation of gastric mucosal integrity by endogenous NO depends on arachidonic acid cascade. PG-s have pro-inflammatory and anti-inflammatory effects on the immune system. Dietary PUFA-s and eicosanoids have potential effects on the modulation of inflammatory processes and immune cells. The cholesterol level lowering activity of several cytokines and colony stimulating factor can be observed. Therapeutic efficacy of N-3 PUFA is described in cases of patients with chronic gastrointestinal disorders, but N-3 PUFA-s only delay early relapse of ulcerative colitis in remission. TNF is known as a pleiotropic cytokine. Strategies for TNF in IBD is very important part of therapeutical approaches. Therapy with infliximab and related ones are encouraging in critical cases. It is also believed recently, that NF-kappaB also may be a target of IBD treatment. It became known, that oxidized LDL can inhibit LPS-induced binding of the NF-kappaB to DNA and the subsequent expression of TNF-alpha and interleukin-1beta in macrophages as well as oxidized LDL modulates activation of NF-kappaB in mononuclear phagocytes by altering the degradation of I-kappaBs. 15-d-PGJ2 inhibits multiple steps in the NF-kappaB signaling pathway. 15-d-PGJ2 metabolite binds PPAR-gamma promotes adipocyte differentiation. PPAR-gamma ligand inhibits growth of cells through induction of apoptosis. Several nutritional polyphenols (the secondary metabolites of plants) are COX2 and/or LOX inhibitors and iNOS activators. The moderate nutritional customs with natural antioxidants can help restore to normal function of gastrointestinal tract, but the immoderate consumption of vitamins and polyphenol type antioxidant molecules is contraindicated.

[Free radical scavenger and lipid peroxidation inhibiting effects of medicinal plants used in phytotherapy]. / Fitoterápiában jelentos gyógynövények szabadgyökfogó es lipidperoxidációt gátló hatása.

Epidemiological and clinical studies have proved the beneficial effect of bioactive compounds of vegetables and medicinal plants used in phytotherapy on prevention of several diseases. Beyond the well-known natural antioxidants, such as vitamins, other natural substances can function as antioxidants. In 1992 the Saas Fee Declaration was published by leader nutritionist and biochemists underlining the importance of prevention in health maintenance based on scientific studies with natural compounds. According to the declaration the antioxidants are the main active and beneficial components. Authors joining with the spirit of Saas Fee Declaration have worked out a complex examination system to study the antioxidant, free radical scavenging and inhibitory effects on lipid peroxidation of isolated components, natural plant extracts and herbal preparations. The members of the system are the followings: hydrogendonating ability, reducing power, chelating activity, free radical scavenging activities measured by chemiluminescence techniques, electron paramagnetic resonance / spin trapping studies, inhibition of lipid peroxidation induced in rat brain / liver microsomes, consequencies and treatment of experimental hyperlipidemia, morphological and histological studies. Only one measurement cannot give enough information about the antioxidant properties of the products. Complex in vitro examination of a novel antioxidant can draw pictures of correlation between the chemical structure and antioxidant effect, the mechanism of its favourable effect and its presumable role in prevention of lipid peroxidation. With the use of these results planning and execution of in vivo examinations should be more precise, practical and essential.

Superoxide-dismutase activity of the gastric mucosa in patients with Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (HP) is a pathogenic factor in the development of different alterations in the gastric mucosa. Superoxide-dismutase (SOD) is a key enzyme of mucosal antioxidant protection. We have detected changes in the activity of mucosal SOD in different diseases caused by HP. MATERIALS AND METHODS: Biopsies were taken upon gastroscopy (n = 131). Activity of SOD was measured by photometry, referred to the amount of protein in the sample. RESULTS: SOD activity of the antrum of HP-positive patients was significantly higher than that of HP-negative ones. There was a significant increase in erosive gastritis. CONCLUSION: In the presence of HP there was a significant increase of the SOD activity in the antrum but not in the corpus. In chronic antral gastritis there was a positive relationship between the SOD activity and both the severity and activity of inflammation. We presume that HP-associated gastritis is predominant in the antrum.

Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis.

GOALS: To evaluate the quality of life (QoL) of patients with chronic pancreatitis before and after pancreatic enzyme replacement therapy in a prospective, multicentre, follow-up study. STUDY: Two groups of patients were evaluated. Group 1 consisted of 31 patients with newly diagnosed chronic pancreatitis who had never been treated with pancreatic enzyme preparations. Group 2 consisted of 39 patients whose disease was diagnosed on average 3.4 years before the start of the study. The latter group of patients had undergone pancreatic enzyme replacement therapy, but during follow-up this treatment proved to be insufficient. The dose of pancreatic enzyme replacement therapy was tailored in accordance with the degree of pancreatic exocrine insufficiency measured by means of exocrine pancreatic function tests. A modified European Organizaton for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to assess QoL. RESULTS: The social functioning and financial strain were significantly better, while the levels of hope and confidence were significantly reduced in group 1 compared with group 2. A significant gain in body weight and a significantly reduced defecation rate were found in both groups one month after the beginning of the pancreatic enzyme replacement therapy when compared with the pretreatment values. The prevalence of general and disease-specific symptoms and the intensity of pain were reduced in both groups after one month of enzyme substitution therapy. The working ability, the financial strain and the overall QoL scores were improved significantly in both groups, while the cognitive functioning score was found to be significantly improved during the follow-up only in group 1. The overall increase in the QoL score correlated significantly with the increase in body weight and the decrease in defecation number in both groups. CONCLUSIONS: Pancreatic enzyme replacement therapy in patients with chronic pancreatitis not only reduced the extent of steatorrhea and pain, but also significantly improved a variety of other symptoms and the patient's QoL. Individually tailored enzyme replacement therapy improved the QoL not only in the untreated chronic pancreatitis patients, but also in the inadequately treated group. This study demonstrated that the EORTC QLQ-C30 questionnaire, with the addition of two further questions about steatorrhea, is a useful tool for the evaluation of QoL in patients with chronic pancreatitis.

[Failure of Helicobacter pylori eradication--suggestions for further therapy]. / A Helicobacter pylori eradikációjának sikertelensége: szempontok a további kezelés megítéléséhez.

Success of first H. pylori eradication attempts in the literature is around 80-90% and based on urea breath test of 1027 patients in Hungary is 75%. Repeated eradication attempts are needed in 10-25% of cases. In the clinical practice in Hungary second and third eradication attempts were successful only in 36% and 20% of cases. To improve efficacy the following suggestions has to be kept in mind: 1. Do not repeat the same combination if the first attempt is failed. 2. After failure of the first PPI + amoxicillin + clarithromycin triple therapy, either the quadriple therapy (PPI + tetracycline + metronidazole + bismuth) or the replacement of PPI with ranitidine bismuth citrate in the triple therapy is suggested. 3. If PPI + amoxicillin + metronidazole/tinidazole therapy fails, the metronidazole/tinidazole can be replaced by clarythromycin. 4. Do not start with clarithromycin + metronidazole/tinidazole therapy. 5. In case of uncertain previous therapies and for third eradication treatment send the patient to specialist. Rifabutin-based combinations seem to be effective, but the use of them in general practice is not advised due to the possible development of mycobacterium tuberculosis resistance.

Immediate DNA ploidy analysis of gastrointestinal biopsies taken by endoscopy using a mechanical dissociation device.

BACKGROUND: Quantitative DNA analysis of fresh biopsy material can contribute to a more accurate diagnosis and prognosis. The authors aimed to develop and test a mechanical, nuclear preparation protocol for quantitative DNA analysis. PATIENTS AND METHODS: Altogether 32 gastric (10 healthy, 17 gastritis, 7 adenocarcinoma) and 48 colon (21 healthy, 20 colitis ulcerosa, 7 adenocarcinoma) biopsy specimens were evaluated. The mechanical disruption was performed by Medimachine (DAKO, Denmark). The flow cytometry analysis was performed on a BD FACSStar flow cytometer. RESULTS: DNA Aneuploidy was found in gastric samples only in tumours. The S-phase fraction of the normal cases was 5.9 +/- 2.1%, 5.1% +/- 1.2% in gastritis and 10.7 +/- 1.6% in carcinomas. Seven out of 20 colitis ulcerosa and 4 out of 7 colon cancer samples were aneuploid. The S-phase fraction of normal colon cases was 5.7 +/- 3.4%, in colitis 8.1 +/- 4.2% and 15.1 +/- 5.7% in carcinomas, respectively. CONCLUSION: Mechanical nuclear isolation is a useful method for flow cytometric DNA ploidy analysis of fresh biopsy samples.

Mutant p53 expression and apoptotic activity of Helicobacter pylori positive and negative gastritis in correlation with the presence of intestinal metaplasia.

BACKGROUND: Mutation of the p53 gene is detectable in most cases of gastric cancer, as it is the most common genetic alteration in human malignancies. It is also well documented that Helicobacter pylori infection plays an important role in gastric carcinogenesis. There is still no clarification, however, concerning how genetic instability influences the homeostasis of gastric epithelium. We have studied the effect of H. pylori infection on apoptosis of the antral epithelium in the presence/absence of intestinal metaplasia and the expression of the p53 oncoprotein. The relationship between these two processes is analysed. METHODS: Antral biopsies were taken from 36 patients who underwent routine upper endoscopy (17 men, 19 women, mean age 61.0 years). The biopsies were fixed in formalin and embedded in paraffin. Patients were classified into two histological groups: (1) as chronic gastritis without intestinal metaplasia (n = 19), and (2) chronic gastritis with intestinal metaplasia (n = 17). An immunohistochemical method was used to detect the expression of p53 oncoprotein, and the terminal transferase mediated dUTP nick end-labelling (TUNEL) method was used to detect apoptotic cells. RESULTS: In the absence of intestinal metaplasia, both the apoptotic index (0.0272 +/- 0.011 vs 0.0128 +/- 0.006) and expresssion of p53 (35.55 +/- 31.16 vs 18.33 +/- 19.65) were significantly higher in H. pylori positive cases compared to H. pylori negative cases. In the presence of intestinal metaplasia, p53 expression was further increased (P < 0.05), but apoptosis was similar to that observed in H. pylori negative gastritis without intestinal metaplasia. In the presence of intestinal metaplasia, H. pylori infection did not influence apoptosis (0.013 +/- 0.004 vs 0.011 +/- 0.004), or p53 ratio (70.16 +/- 22.54 vs 68.50 +/- 28.96). In the sequence of gastritis-intestinal metaplasia the two indices show a close negative correlation (P < 0.05). CONCLUSION: In the absence of intestinal metaplasia H. pylori infection increases both apoptotic activity and expression of p53 oncoprotein in the gastric mucosa. The lack of increased apoptosis with a higher p53 expression in the presence of intestinal metaplasia suggests an increased genetic instability and also may suggest that mutation of the p53 gene is an early step in the multistep process of gastric carcinogenesis.

[Neuroendocrine tumors of the digestive system]. / Az emésztórendszer neuroendokrin daganatai.

Despite their rare occurrence, gastroenteropancreatic neuroendocrine tumors have been in the centre of interest because of the wide scale and variability of clinical signs and symptoms associated with oversecretion of different hormones. In the present review the authors summarize epidemiological data, pathologic findings, clinical symptoms, as well as diagnostic and therapeutic methods presently available for the management of patients with gastroenteropancreatic neuroendocrine tumors. In addition to surgical treatment and receptor-specific radionuclide therapy used in cases with surgically noncurable tumors, the therapeutic use of somatostatin analogues in recent years has resulted an important advance in the management of patients with these tumors. Somatostatin analogues alone or in combination with other pharmacological therapies may be used effectively for elimination of symptoms of hormonal oversection and, in a number of cases, for diminishing tumor progression.

[Carcinoid tumors]. / Carcinoid tumorok.

Carcinoids are characteristically indolent, but heterogeneous tumors with respect to their site of origin, endocrine features, clinical manifestations and biologic behaviour. The authors summarize the current laboratory, endoscopic and radiologic methods used for the diagnosis of carcinoid tumors. Treatment modalities should be directed against the tumor and the hormonal excess state. The authors review the outcome of most frequently used therapies, including somatostatin-analogue and interferon treatment, chemotherapy, embolization, receptor-targeted radiotherapy and surgical intervention). Patients with carcinoid tumors, with or without carcinoid syndrome, are best managed by a multidisciplinary approach.

[Quality of life in the course of enzyme replacement therapy for chronic pancreatitis]. / Az életminóség vizsgálata a krónikus pancreatitis enzimszubsztitúciós kezelése során.

AIM: The ultimate goal of any treatment in chronic pancreatitis is to maximize the patient's quality of life. The authors evaluated the QoL of patients with chronic pancreatitis prior to and after pancreatic enzyme replacement therapy in a prospective, multicenter, follow-up study. PATIENTS AND METHODS: Two groups of patients were evaluated. Group 1: 31 patients with newly diagnosed chronic pancreatitis who had never been treated with pancreatic enzyme preparations; Group 2: 39 patients whose disease was diagnosed on average 3.4 years before the start of the study. The latter group of patients had undergone pancreatic enzyme replacement therapy, but during the follow-up this proved to be insufficient. The dose of pancreatic enzyme replacement therapy was tailored in accordance with the degree of pancreatic exocrine insufficiency measured by means of exocrine pancreatic function tests. RESULTS: A significant gain in body weight and a significantly reduced defecation rate were found in both groups 1 month after the beginning of the pancreatic enzyme replacement therapy as compared to the pretreatment values. The prevalence of general and disease-specific symptoms, and the intensity of pain were reduced in both groups after 1 month of enzyme substitution therapy. The working ability, the emotional functioning, the financial strain and the overall QoL score were improved significantly in both groups, while the cognitive functioning was found to be significantly improved during the follow-up only in Group 1. The overall increase in the QoL score correlated significantly with the increase in body weight and the decrease in defecation number in both groups. CONCLUSIONS: Individually-tailored enzyme replacement therapy improved the QoL, reduced the extents of steatorrhea and pain, increased the body weight, not only in the untreated chronic pancreatitis patients, but even in the inadequately treated group.

Effect of Helicobacter pylori infection on epidermal growth factor receptor (EGFR) expression and cell proliferation of gastric epithelial mucosa: correlation to macroscopic and microscopic diagnosis.

Our aim was to compare the expression of EGFR and proliferative cell nuclear antigen (PCNA) in different histological and endoscopic diagnostic groups, in cases of Helicobacter pylori infection, in vivo. Paraffin embedded human gastric biopsy samples (86) were analysed by EGFR and PCNA immunohistochemistry and classified both on the basis of histology and endoscopic findings. In normal epithelia (NE), a positive correlation was found between PCNA and EGFR and in H. pylori-negative gastritis with and without intestinal metaplasia (P < 0.01). On the other hand, a negative correlation was detected between the two immunohistochemical findings in H. pylori-associated gastritis with intestinal metaplasia (HPGIM) and in the atrophic gastritis (AG) group. In HPGIM the percentage of EGFR-positive cells was significantly lower (32.4 +/- 30.4) when compared to either the NE (50.3 +/- 23.7) or H. pylori-negative gastritis with intestinal metaplasia (HNGIM) (48.3 +/- 23.7). In AG, EGFR was significantly lower when compared to the NE (P < 0.05). Based on the endoscopic findings, a significant decrease of EGFR expression was found in gastric ulcer cases as compared to NE, gastritis or erosion cases (P < 0.01). PCNA showed no significant alterations between the NE and gastritis, AG groups. The presence of H. pylori has an inverse effect on PCNA and EGFR expression in HPGIM.