Clinical significance of stromal apoptosis in colorectal cancer.

BACKGROUND: Epithelial and stromal cells play an important role in the development of colorectal cancer (CRC). We aimed to determine the prognostic significance of both epithelial and stromal cell apoptosis in CRC. METHODS: Total apoptosis was determined by caspase-3 activity measurements in protein homogenates of CRC specimens and adjacent normal mucosa of 211 CRC patients. Epithelial apoptosis was determined by an ELISA specific for a caspase-3-degraded cytokeratin 18 product, the M30 antigen. Stromal apoptosis was determined from the ratio between total and epithelial apoptosis. RESULTS: Epithelial and stromal apoptosis, as well as total apoptosis, were significantly higher in CRC compared with corresponding adjacent normal mucosa. Low total tumour apoptosis (< or = median caspase-3 activity) was associated with a significantly worse disease recurrence (hazard ratio (HR), 95% confidence interval (95% CI): 1.77 (1.05-3.01)), independent of clinocopathological parameters. Epithelial apoptosis was not associated with clinical outcome. In contrast, low stromal apoptosis (< or = median caspase-3/M30) was found to be an independent prognostic factor for overall survival, disease-free survival and disease recurrence, with HRs (95% CI) of 1.66 (1.17-2.35), 1.62 (1.15-2.29) and 1.69 (1.01-2.85), respectively. INTERPRETATION: Stromal apoptosis, in contrast to epithelial apoptosis, is an important factor with respect to survival and disease-recurrence in CRC.

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not.

The prognostic significance of single-nucleotide polymorphisms (SNPs) and tumour protein levels of MMP-2 and MMP-9 was evaluated in 215 colorectal cancer patients. Single-nucleotide polymorphism MMP-2(-1306T) and high MMP-2 levels were significantly associated with worse survival. Extreme tumour MMP-9 levels were associated with poor prognosis but SNP MMP-9(-1562C>T) was not. Tumour MMP levels were not determined by their SNP genotypes.

Individualized population pharmacokinetic model with limited sampling for cyclosporine monitoring after liver transplantation in clinical practice.

BACKGROUND: We recently developed and validated limited sampling models (LSMs) for cyclosporine monitoring after orthotopic liver transplantation based on individualized population pharmacokinetic models with Bayesian modelling. Aim To evaluate LSM in practice, and to seek optimal balance between benefit and discomfort. METHODS: In 30 stable patients, more than 6 months after orthotopic liver transplantation, previously switched from trough- to 2 h post-dose (C2)-monitoring, we switched to 3-monthly LSM 0,1,2,3 h-monitoring. During 18 months we evaluated dose, creatinine clearance, calculated area under the curve, intra-patient pharmacokinetic variability and ability to assess systemic exposure by several previously validated LSMs. RESULTS: Within patients, there was variability of cyclosporine-area under the curve with the same dose (CV of 15%). Compared to C2-monitoring, there was no significant difference in dose (P = 0.237), creatinine clearance (P = 0.071) and number of rejections. Some models showed excellent correlation and precision with LSM 0,1,2,3 h comparing area under the curves (0,2 h: r(2) = 0.88; 0,1,3 h: r(2) = 0.91; 0,2,3 h: r(2) = 0.92, all P < 0.001) with no difference in advised dose. CONCLUSIONS: The limited sampling model, with only trough- and 2-h sampling, yields excellent accuracy and assesses systemic exposure much better than C2 with less bias and greater precision. Considering the calculated intra-patient variability, more precision is redundant, so LSM 0,2 h seems the optimal way of cyclosporine-monitoring.

Tissue level, activation and cellular localisation of TGF-beta1 and association with survival in gastric cancer patients.

Transforming growth factor-beta1 (TGF-beta1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-beta1 activation and localisation of TGF-beta1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-beta1 staining by immunohistochemistry. Active TGF-beta1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-beta1. Active TGF-beta1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-beta1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGF-beta1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGF-beta1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-beta1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-beta1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-beta1 activity levels in gastric cancer.

Substance P receptor expression in patients with inflammatory bowel disease. Determination by three different techniques, i.e., storage phosphor autoradiography, RT-PCR and immunohistochemistry.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation accompanied by changes in motility. It is known that regulatory peptides like substance P (SP) are important pro-inflammatory peptides which are also involved in neuronal conduction. To get clues for new diagnostic and therapeutic approaches we describe the SP receptor (NK-1) distribution in IBD compared to control intestinal tissue, on mRNA and protein level by three complementary techniques. Autoradiography showed differences within the intestinal wall of control patients; mucosal binding was 17 fmol/g and muscular binding was significantly (p=0.01) higher (98 fmol/g). In inflamed specimens of patients with IBD mucosal SP binding was increased compared to controls (55+/-10 vs 18+/-4 fmol/g mucosa, p=0.002). However RT-PCR showed that the mRNA content of the NK-1 receptor in these samples was not increased. In non-inflamed samples of patients with Crohn's disease (CD) and ulcerative colitis (UC) SP binding was similar as in controls, while mRNA was significantly decreased in CD patients (0.7+/-0.02 vs 4.4+/-0.7, p=0.01) but not in UC patients (4.4+/-0.7 vs 4.1+/-1.4). Immunohistochemistry identified a broad spectrum of NK-1 receptor locations in control intestine. No aberrant expression in IBD was found. This study showed that although there was no difference in location of the SP receptors in IBD patients versus controls, the quantity of SP binding was significantly increased in the inflamed mucosa of IBD patients, while the mRNA level was not increased. Further a difference in mRNA level between non-inflamed tissue of CD and UC patients was shown, with mRNA in CD being lower. These changes in SP receptor expression during chronic inflammation suggest that SP receptors are a potential target for therapeutic regulation of the inflammatory response.

Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patients with inflammatory bowel disease and the relation with Crohn's disease phenotype.

BACKGROUND AND OBJECTIVE: Matrix metalloproteinases are associated with matrix turnover in both physiological and pathological conditions. We postulate an association between aberrant matrix metalloproteinases proteolytic activity and the intestinal tissue destruction, seen in patients with Crohn's disease and/or ulcerative colitis. MATERIALS AND METHODS: Surgically resected inflamed and non-inflamed ileum and colon with/without extensive fibrosis from 122 Crohn's disease, 20 ulcerative colitis and 62 control patients were homogenized. Protein levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured by enzyme-linked immunosorbent assays (ELISA), while matrix metalloproteinases and myeloperoxidase activity were measured by specific activity assays. RESULTS: Expression of total levels of matrix metalloproteinases-1, -2, -3 and -9 relative to tissue inhibitor of metalloproteinases-1 and -2 was increased in inflamed inflammatory bowel disease compared to non-inflamed inflammatory bowel disease and control intestinal mucosa. Also, net matrix metalloproteinases-1, -2, -3 and -9 activity in inflamed inflammatory bowel disease was increased, with similar expression profiles in Crohn's disease and ulcerative colitis. Within inflamed inflammatory bowel disease, a close correlation of matrix metalloproteinases with myeloperoxidase was observed. The expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases was similar in inflamed Crohn's disease tissue with or without extensive fibrosis and not related to fistulizing disease. CONCLUSIONS: We have shown increased net matrix metalloproteinases activity in intestinal inflammatory bowel disease tissue, likely to contribute to the tissue damage and remodelling seen in inflammatory bowel disease.

The 13carbon urea breath test for the diagnosis of Helicobacter pylori infection in subjects with atrophic gastritis: evaluation in a primary care setting.

BACKGROUND: (13)Carbon urea breath testing is reliable to detect current infection with Helicobacter pylori but has been reported to be of limited value in selected patients with atrophic body gastritis or acid-lowering medication. AIM: To evaluate the accuracy of (13)carbon urea breath testing for H. pylori detection in 20 asymptomatic patients with histologically confirmed atrophic body gastritis in a primary care setting. METHODS: (13)Carbon urea breath testing and serology were compared with H. pylori culture of a corpus biopsy as reference test. RESULTS: All tests were in agreement in 12 patients, being all positive in six and all negative in six. One patient was positive for serology and culture but negative for (13)carbon urea breath testing, five patients had only positive serology and two patients had only positive (13)carbon urea breath testing. (13)Carbon urea breath testing showed an accuracy with culture of 85% and anti-H. pylori serology with culture of 75%. (13)Carbon urea breath testing carried out in patients with positive serology showed an accuracy of 92%. Receiver operating characteristic curve analysis of (13)carbon urea breath testing shows optimal discrimination at the prescribed cut-off value. CONCLUSIONS: (13)Carbon urea breath testing can be used as diagnostic H. pylori test in asymptomatic patients with atrophic body gastritis, preferably in addition to serology, to select subjects for anti-H. pylori therapy.

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer.

Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7(-181A>G). In addition, the genotype distribution of MMP-7(-181A>G) was associated with Helicobacter pylori status (chi(2) 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2(303C>T) correlated significantly with the WHO classification (chi(2) 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2(-1306C>T) polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7(-181A>G) and TIMP-2(303C>T) polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7(-181A>G) and TIMP-2(303C>T), may be helpful in identifying gastric cancer patients with a poor clinical outcome.

Matrix metalloproteinase-2 is a consistent prognostic factor in gastric cancer.

In a pioneer study, we showed 10 years ago that enhanced tissue levels of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in gastric cancers, as determined by zymography, were related with worse overall survival of the patients. To corroborate these observations, we now assessed MMP-2 and MMP-9 with new techniques in an expanded group of gastric cancer patients (n = 81) and included for comparison MMP-7, MMP-8 and the tissue inhibitors of MMPs, TIMP-1 and -2. All MMPs and TIMP-1 were significantly increased in tumour tissue compared to normal gastric mucosa. Matrix metalloproteinase-7, -8 and -9, and the TIMPs showed some correlations with the clinicopathologic parameters TNM, WHO and Laurén classification, but their levels were not related with survival. Regardless of the determination method used, that is, enzyme-linked immunosorbent assay or bioactivity assay, an enhanced tumour MMP-2 level did not show a significant correlation with any of the clinicopathological parameters, but was confirmed to be an independent prognostic factor in gastric cancer.

Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases.

BACKGROUND/AIMS: Matrix metalloproteinases are major contributors in the breakdown and reconstitution of basement membranes and extracellular matrix in pathophysiological processes. We assessed the expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel disease. PATIENTS/METHODS: Resected tissue specimens from patients with Crohn's disease or ulcerative colitis and control tissue from patients with a colorectal carcinoma were used for enzyme-linked immunosorbent assay, zymography, activity assay, reverse transcription polymerase chain reaction and immunohistochemistry to evaluate the expression of these matrix metalloproteinases. RESULTS: Matrix metalloproteinase-2 and more strongly matrix metalloproteinase-9 protein and mRNA were markedly increased in inflammatory bowel disease tissues, with the highest levels in severely inflamed tissues. Immunohistochemistry showed that matrix metalloproteinase-2 was present in the extracellular matrix of the submucosa, with a lower but more generalised expression in the severely inflamed regions. Matrix metalloproteinase-9 was most prominent in polymorphonuclear leukocytes and was increased, also in activity, in all inflammatory bowel disease tissues. An increased matrix metalloproteinase-9 expression in the extracellular matrix was observed in relation to the severity of inflammation. CONCLUSIONS: Matrix metalloproteinases-2 and -9 are enhanced in the intestinal tissue and seem to be actively involved in the inflammatory and remodelling processes in inflammatory bowel disease, without major differences between CD and UC.

Easy-to-use, accurate and flexible individualized Bayesian limited sampling method without fixed time points for ciclosporin monitoring after liver transplantation.

BACKGROUND: New methods to estimate the systemic exposure to ciclosporin such as the level 2 h after dosing and limited sampling formulas may lead to improved clinical outcome after orthotopic liver transplantation. However, most strategies are characterized by rigid sampling times. AIM: To develop and validate a flexible individualized population-pharmacokinetic model for ciclosporin monitoring in orthotopic liver transplantation. METHODS: A total of 62 curves obtained from 31 patients at least 0.5 year after orthotopic liver transplantation were divided into two equal groups. From 31 curves, relatively simple limited sampling formulas were derived using multiple regression analysis, while using pharmacokinetic software a two-compartment population-pharmacokinetic model was derived from these same data. We then tested the ability to estimate the AUC by the limited sampling formulas and a different approach using several limited sampling strategies on the other 31 curves. The new approach consists of individualizing the mean a priori population-pharmacokinetic parameters of the two-compartment population-pharmacokinetic model by means of maximum a posteriori Bayesian fitting with individual data leading to an individualized population-pharmacokinetic limited sampling model. From the individualized pharmacokinetic parameters, AUC(0-12h) was calculated for each combination of measured blood concentrations. The calculated AUC(0-12h) both from the limited-sampling formulas and the limited-sampling model were compared with the gold standard AUC(0-12h) (trapezoidal rule) by Pearson's correlation coefficient and prediction precision and bias were calculated. RESULTS: The AUC(0-12h) value calculated by individualizing the population-pharmacokinetic model using several combinations of measured blood concentrations: 0 + 2 h (r(2) = 0.94), 0 + 1 + 2 h (r(2) = 0.94), 0 + 1 + 3 h (r(2) = 0.92), 0 + 2 + 3 h (r(2) = 0.92) and 0 + 1 + 2 + 3 h (r(2) = 0.96) had excellent correlation with AUC(0-12h), better than limited sampling formulas with less than three sampling time points. Even trough level with limited sampling method (r(2) = 0.86) correlated better than the level after 2 h of dosing (r(2) = 0.75) or trough level (r(2) = 0.64) as single values without limited sampling method. Moreover, the individualized population-pharmacokinetic model had a low prediction bias and excellent precision. CONCLUSION: Multiple rigid sampling time points limit the use of limited sampling formulas. The major advantage of the Bayesian estimation approach presented here, is that blood sampling time points are not fixed, as long as sampling time is known. The predictive performance of this new approach is superior to trough level and that after 2 h of dosing and at least as good as limited sampling formulas. It is of clear advantage in busy out-patient clinics.

[Policy in patients with epigastric complaints]. / Beleid bij patiënten met bovenbuikklachten.

In the relatively young dyspeptic patient without alarming symptoms both the test-and-treat approach and the empirical acid-inhibition therapy have proved to be effective non-invasive management strategies. When these strategies are followed, a minority of the patients subsequently need endoscopy. Additional well-designed studies are needed to compare the non-invasive management strategies test-and-treat and empirical acid inhibition in a primary-care setting. The individual general practitioner is advised to follow the guidelines applied in their region. These regional management strategies are usually based on the national guidelines and the facilities available in the region. In the absence of a regional management strategy it is recommended to follow the national guidelines.

Gastrin releasing peptide receptor expression is decreased in patients with Crohn's disease but not in ulcerative colitis.

BACKGROUND: Gastrin releasing peptide (GRP) and neuromedin B are bombesin (BN)-like peptides involved in regulating motility and inflammation in the gastrointestinal tract, which may be useful in treating inflammatory bowel disease (IBD). Three bombesin-like peptide receptors have been reported, but no studies have investigated their localisation in normal and inflamed human intestine. AIM: To localise and characterise BN receptors in normal intestine and to see whether this is modified in IBD. METHODS: Full thickness intestinal tissue samples were collected from 13 patients with Crohn's disease (CD), 11 with ulcerative colitis (UC), and 19 controls. BN receptor expression was characterised and quantified with storage phosphor autoradiography using BN, GRP, neuromedin B, and the synthetic analogue BN(6-14) as ligands. RESULTS: Only BN receptor type 2 (high affinity for GRP) was present in intestinal tissue. Minimal BN binding was detected in the mucosa. In normal colonic smooth muscle, mean BN binding was 336 fmol/g tissue in longitudinal muscle, including the myenteric plexus, and 71 fmol/g in circular muscle. In CD, colonic smooth muscle BN binding was significantly decreased (longitudinal muscle, 106; circular muscle, 19 fmol/g), in contrast to UC (377 and 62 fmol/g, respectively). In CD, a small (not significant) decrease was seen in ileal muscle compared with controls (111 v 169 and 18 v 32 fmol/g tissue for longitudinal and circular muscle, respectively). CONCLUSIONS: Only the GRP receptor is expressed in human intestine; expression is highest in longitudinal muscle and myenteric plexus of the colon. Expression is decreased in inflamed and non-inflamed colon of CD, but not in UC.

Basic fibroblast growth factor as a response parameter to infliximab in fistulizing Crohn's disease.

BACKGROUND: Fibroblast growth factors play an important role in (patho)physiological processes such as wound healing and tissue repair. We previously showed that basic fibroblast growth factor is actively involved in inflammatory bowel disease processes. In the present retrospective study, we assessed whether serum basic fibroblast growth factor levels in Crohn's disease patients reflect the response to anti-tumour necrosis factor-alpha antibody infliximab treatment. AIM AND METHODS: Serum samples, biopsies and patient data from a subgroup of patients included in two placebo-controlled trials were used. Fistulizing Crohn's disease patients (n = 42) were administered placebo or infliximab intravenously three times and evaluated for response up to 18 weeks. Biopsies from a subgroup of patients were stained for basic fibroblast growth factor using indirect immunohistochemistry. In the active Crohn's disease trial, patients (n = 24) received either placebo or infliximab once, and disease activity and serum basic fibroblast growth factor were assessed at weeks 0 and 4. RESULTS: Basic fibroblast growth factor levels at inclusion were comparable in the fistulizing Crohn's disease patients regardless of whether the fistulas did or did not respond or completely heal (median range: 9.3-10.6 pg/mL). At the end of follow-up basic fibroblast growth factor levels were lower in patients who responded (9.2 pg/mL, P = 0.06) or who were completely healed (8.9 pg/mL, P = 0.009) when compared with patients did not respond/heal (14.5 pg/mL), the latter not significantly increased from baseline. Decreases in the perianal disease activity index and open fistula scores at the end of the follow-up were significantly correlated with the decrease in basic fibroblast growth factor (R = 0.41; P = 0.012 and R = 0.35; P =0.027, respectively). Immunohistological evaluation also showed a trend towards decreased basic fibroblast growth factor expression in intestinal biopsies of these patients. Patients with active disease, i.e. a Crohn's disease activity index > or = 220 combined from the two studies, were found to have significantly (P = 0.0046) lower baseline serum basic fibroblast growth factors levels than those with inactive disease (5.3 vs. 10.3 pg/mL, respectively). Treatment of the active disease patients did not affect the serum basic fibroblast growth factor level, although a general decrease in disease activity was observed with infliximab treatment. CONCLUSIONS: Healing of fistulizing/perianal Crohn's disease seems to be reflected by a decrease in high serum basic fibroblast growth factor. Basic fibroblast growth factor levels do not relate with response in active Crohn's disease patients.

Endoscopic treatment of Barrett's oesophagus.

Barrett's oesophagus develops as a consequence of severe gastro-oesophageal reflux. The importance of Barrett's oesophagus lies in the small risk of developing high-grade dysplasia and subsequent adenocarcinoma. Because of poor treatment results in patients with advanced adenocarcinoma, surveillance of patients with Barrett's oesophagus for the development of dysplasia, although not uncontroversial, is widely practised in the gastroenterological community. The aim of surveillance is to detect adenocarcinoma in an early stadium where surgical cure is possible. In recent years several endoscopic treatments for both high-grade dysplasia and intramucosal adenocarcinoma have been developed. In this review some basic aspects of Barrett's oesophagus are discussed together with endoscopic treatments such as endoscopic mucosal resection, local thermal treatments and photodynamic therapy. Although surgical resection is probably the treatment of choice in fit patients, local endoscopic treatments should be considered in patients with high-grade dysplasia or intramucosal carcinoma who are unfit or unwilling to have surgery.

Serum matrix metalloproteinase MMP-2 and MMP-9 in the late phase of ischemia and reperfusion injury in human orthotopic liver transplantation.

INTRODUCTION: Ischemia and reperfusion (I/R) injury during orthotopic liver transplantation (OLT) is accompanied by neutrophil infiltration and degradation of extracellular matrix. Matrix metalloproteinases (MMP) play an important role in the turnover of extracellular matrix components. We assessed the changes in level and composition of serum MMP-2 and MMP-9 in relation with I/R injury after human OLT. METHODS: Thirty-three patients were separated into two groups according to their peak level of aspartate aminotransferase (AST) after OLT (AST < 1500 IU/L: n = 22; AST > 1500 IU/L: n = 11). Serum MMP-2 and MMP-9 were measured before transplantation as well as 2 days and 1 week after OLT using ELISA (MMP protein) and BIA (enzymatic activity of MMP). RESULTS: MMP-2 and MMP-9 protein concentrations were comparable before and 2 days after OLT, whereas at 1 week MMP-2 decreased and MMP-9 increased significantly. However, there were no significant differences between patients with high or low peak AST at all time points. Also, the composition of MMP-2 and MMP-9 did not differ over time between the groups of patients. CONCLUSION: Serum MMP-2 and MMP-9 do not relate to the late phase of hepatic I/R injury after human OLT.

Surveillance for familial pancreatic cancer.

BACKGROUND: It is estimated that between 5% and 10% of pancreatic cancer (PC) cases are due to hereditary factors. METHODS: Review of the literature. RESULTS: In families with clustering of PC, germline mutations in specific genes might be responsible for the disease. It is suggested that PC progresses from precursor lesions, the pancreatic intraepithelial neoplasias (PanINs). Several key genetic alterations in oncogenes (K-ras, Her2/neu) and tumour suppressor genes (p16, p53, SMAD4) occur in the progression from PanIN lesions towards PC. PC is mostly diagnosed on clinical presentation at an advanced, no longer resectable, stage. The overall 5-year survival rate is extremely poor. Recent studies report a better survival rate of PC, providing surgery takes place at an early stage. Surveillance of family members at increased risk for PC might lead to detection of tumours at an early stage and improve overall survival. CONCLUSION: Clinicians should be aware of the tumour syndromes that are associated with an increased risk of PC. Efforts to improve PC survival must focus on identification of high-risk patients, detection of early stage disease and novel screening strategies.

The serological gastric biopsy: a non-endoscopical diagnostic approach in management of the dyspeptic patient: significance for primary care based on a survey of the literature.

BACKGROUND: Measurement of the serum concentration of the secretory products of the gastric mucosa, pepsinogen A (PgA), pepsinogen C (PgC) and gastrin is called the serological gastric biopsy. Additional measurement of Helicobacter pylori antibodies and antibodies to parietal cells and intrinsic factor supports the non-invasive diagnostic value of the serum markers. In many clinical studies, the diagnostic potential of the serum markers in predicting the topography and severity of gastric mucosal disorders has been established. The aim was to assess the diagnostic value of the serological gastric biopsy for primary care. METHOD: Survey of the literature. RESULTS: The cell-physiological background of the serological gastric biopsy, the interpretation of the outcome of serum markers and the relation of these parameters to various gastric mucosal disorders are described. Measurement of PgA is a reliable way to discriminate between mucosal gastritis and functional dyspepsia. PgA is raised in duodenal, gastric and pyloric ulcer even though gastrin is normal. Both PgA and gastrin are raised in renal insufficiency and the Zollinger-Ellison syndrome. A low PgA is indicative of mucosal atrophy and a good indicator for gastric hypoacidity. An additional low PgA:C ratio is indicative of atrophic gastritis or extensive intestinal metaplasia of the stomach. A hypopepsinogenaemia can also be an alarm symptom for gastric cancer. A low PgA and a high gastrin is indicative of corpus atrophy. CONCLUSION: In primary care, the serological gastric biopsy might be a feasible and appropriate diagnostic method for management of the dyspeptic patient. Further research in general practice has to be done to validate the predictive value of the serological gastric biopsy and to define a diagnostic strategy.

Malignancies in inflammatory bowel disease: fact or fiction?

BACKGROUND: The association between ulcerative colitis (UC), Crohn disease (CD) and colorectal cancer (CRC) has been confirmed in several studies. The aim of this study was critical analysis of the relation between IBD and malignancy. METHODS: Review of the literature. RESULTS: In UC, the extent of the disease, its duration and start at a young age are risk factors for the development of CRC. Primary sclerosing cholangitis and colonic strictures are additional risk factors for development of CRC. The relation between azathioprine or 6-MP and the development of lymphomas is a subject of debate. The administration of anti-TNF-alpha has produced some concern about the development of lymphomas in CD. However, at present there is no evidence of lymphomas caused by anti-TNF-alpha in CD. On the contrary, some drugs seem to have a preventive effect on CRC development in UC. 5-aminosalicylic acid in particular and to a lesser extent sulphasalazine have prevented the development of CRC significantly in retrospective studies. In CD, there is no strong relationship between the disease and the development of CRC or other malignancies. Only the development of small-bowel carcinoma is reported with a much higher frequency. CONCLUSIONS: There is a correlation with UC and the development of CRC. For CD, this correlation is less firmly established. There is a possible, but not proven, relation between AZA/6-MP use and the development of lymphoma in IBD. There is also a probable relationship between CD and the development of small-bowel carcinoma. In some retrospective studies, the use of 5-aminosalicylic or sulphasalazine has been shown to prevent the development of CRC in UC.

Carcinoid heart disease: an update.

BACKGROUND: Carcinoid tumours are a poorly defined collection of lesions, histopathologically indistinguishable from gastroentero-pancreatic neuroendocrine tumours. In this report, we discuss epidemiology and survival, clinical presentation, carcinoid valvular heart disease (CVHD), histopathological considerations and treatment options. METHODS: Review and update of the literature. RESULTS: The term carcinoid suggests a disease entity, but with increasing knowledge it becomes progressively confusing. To avoid further confusion, it is advisable to define these tumours using differentiation, stage, primary site, known tumour products and an associated clinical syndrome. Incidence varies between 0.8 and 1.9/100,000 population. About 20% present with metastases, with a 5-year survival varying between 15% and 35%. Metastatic disease frequently accompanies the carcinoid syndrome (flushing, diarrhoea, wheezing and CVHD). CVHD incidence is about 50%, and seems unrelated to disease duration and tumour mass. An aetiological relation of CVHD with urinary 5-HIAA remains to be confirmed. Resection is the only curative option. Surgery can also offer prolonged palliation and is needed to restore bowel transit in obstructive/ischaemic bowel problems. Adequate palliation of hormone-related symptoms can also be achieved by somatostatin analogues, meta-iodo-benzyl-guanidine preparations and interferon-alpha formulations, all with a 70% response rate. Embolization of liver metastases has led to objective responses in about 50% of patients, but is accompanied by significant side effects. CONCLUSIONS: Most patients are cured by surgery. Symptom relief is the main target in metastatic disease and can be achieved by a range of equally potent biologically active medications, debulking surgery and hepatic embolization.