High detection rate of adenomas in familial colorectal cancer.

BACKGROUND AND AIMS: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. PATIENTS AND METHODS: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. RESULTS: A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). CONCLUSION: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.

Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients.

BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. AIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. PATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. METHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. RESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively. CONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.

The influence of omeprazole on the synthesis and secretion of pepsinogen in isolated rabbit gastric glands.

Regulation mechanisms of pepsinogen (EC 3.4.23.) synthesis and secretion were studied by following newly synthesized [14C]-labeled pepsinogen during culture of isolated rabbit gastric glands. Omeprazole, a substituted benzimidazole, while almost completely abolishing acid production at 10(-4) M, strongly stimulated secretion of preformed and newly synthesized pepsinogen. Although the pepsinogen synthesis at this concentration of omeprazole was reduced to about 55% of the control rate, a two-fold absolute increase of total secreted pepsinogen was found. This increase was not due to a non specific leakage through disruption of chief cell membranes, as no increase of lactate dehydrogenase in the culture medium could be demonstrated. The stimulated secretion was influenced neither by 10(-3) M cimetidine, 10(-3) sodium thiocyanate nor 10(-4) M atropine. No additivity was found between the carbachol (10(-4) M) or dibutyryl cyclic AMP (10(-3) M) and the omeprazole induced pepsinogen secretion.

Pepsinogen synthesis and secretion in isolated gastric glands.

De novo synthesis of pepsinogen was shown in isolated rabbit and human gastric glands after incubation of the glands in a 14C labelled amino acid enriched minimum Eagles medium. At regular intervals, glands and medium were separated and analysed by polyacrylamide gel electrophoresis. Newly synthesised pepsinogen was shown by autoradiography. Incorporation of 14C labelled amino acids was detected after only 30 min of culture and increased almost linearly in time for 4 h. By comparing the incorporation of label into total protein and into pepsinogen, it was concluded that pepsinogen formed 70-90% of the newly synthesised protein. Cimetidine, at a concentration of 160 micrograms/ml, strongly inhibited the synthesis of pepsinogen. Spontaneous secretion of pepsinogen into the medium was very low and relatively constant. Dibutyryl cyclic AMP considerably stimulated the secretion of pepsinogen into the medium. Histamine and pentagastrin did not influence the release of pepsinogen. These results show that isolated gastric glands are capable of synthesis and secretion of pepsinogen and that both can be selectively stimulated and inhibited.

Helicobacter pylori, pepsinogens and gastrin: relationship with age and development of atrophic gastritis.

BACKGROUND: Helicobacter pylori causes chronic gastritis in all infected individuals and thus may be a risk factor for the ultimate development of trophic gastritis and gastric cancer. The serum levels of pepsinogen A, pepsinogen C and gastrin can be used as markers for both non-atrophic and atrophic gastritis. METHODS: We determined the serum levels of gastrin, pepsinogen A and pepsinogen C and the pepsinogen A/C ratio in 150 H. pylori-negative and 186 H. pylori-positive individuals. RESULTS: The H. pylori infected patients had significantly higher serum levels of pepsinogen A, pepsinogen C and gastrin and a significantly lower pepsinogen A/C ratio. In the non-infected patients, none of the respective serum values changed with increasing age. In contrast, in the infected patients, the pepsinogen A level and pepsinogen A/C ratio decreased significantly with increasing age. CONCLUSION: H. pylori infection increases serum levels of pepsinogen A, pepsinogen C and gastrin and decreases the pepsinogen A/C ratio. In infected subjects, levels of pepsinogen A and the pepsinogen A/C ratio decrease with ageing. These findings support the concept of H. pylori as a risk factor for the development of atrophic gastritis.

A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial.

BACKGROUND: Proton pump inhibitors (PPIs) have proved to be effective in treating reflux oesophagitis. Until now, no study had compared the PPIs omeprazole Multiple Unit Pellet System (MUPS), lansoprazole and pantoprazole in patients with reflux oesophagitis. AIM: To compare omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg for treatment effect in symptomatic reflux oesophagitis. METHOD: Patients with grade I-IV symptomatic reflux oesophagitis were randomized to double-blind omeprazole 20 mg once morning, lansoprazole 30 mg o.m. or pantoprazole 40 mg o.m. Patient satisfaction and symptoms were evaluated after 4 and 8 weeks. Patients not satisfied after 8 weeks were treated for another 4 weeks with omeprazole 40 mg MUPS (open). Successful treatment was followed by 3 months' maintenance treatment with omeprazole MUPS 20 mg (patients satisfied after 4 or 8 weeks) or omeprazole MUPS 40 mg (patients satisfied after 12 weeks). RESULTS: On intention-to-treat (ITT) analysis (n = 461) at 4 and 8 weeks, respectively, 84% and 87% (omeprazole MUPS), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were free of heartburn. Equivalence was found between omeprazole MUPS and pantoprazole (heartburn relief), but not with lansoprazole. Patient satisfaction after 4 and 8 weeks, respectively, was 79% and 89% (omeprazole MUPS), 76% and 86% (lansoprazole), and 79% and 91% (pantoprazole). Patient satisfaction was similar in all treatment groups. During maintenance, 87% in the omeprazole MUPS 20 mg group and 81% in the omeprazole MUPS 40 mg group were satisfied after 3 months. CONCLUSIONS: Omeprazole MUPS 20 mg and pantoprazole 40 mg have equivalent efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, omeprazole MUPS 20 mg, lansoprazole 30 mg and pantoprazole 40 mg are equally effective.

[2 patients with a non-Hodgkin lymphoma located in the pancreas]. / Twee patiënten met non-Hodgkin-lymfomen gelokaliseerd in het pancreas.

A small percentage (around 1.5%) of pancreatic malignancies are well treatable non-Hodgkin's lymphomas. Two patients with this disease are described. One patient was treated with both surgery and chemotherapy, the other with chemotherapy only. The results in both patients were excellent with complete responses being achieved. The literature on pancreatic non-Hodgkin's lymphomas is reviewed.

Mesenteric vein thrombosis as presenting manifestation of hereditary protein S deficiency.

Protein S deficiency is inherited as an autosomal dominant trait. Heterozygotes with a reduction of 50% in the plasma protein S concentration are at risk for the development of venous thromboembolism, often occurring at an early age without an apparent cause. In the majority of the patients thrombosis is restricted to the superficial or deep venous system of the legs. In this case report we describe the presence of mesenteric vein thrombosis in a 30-yr-old man with hereditary protein S deficiency. In his family protein S deficiency was also recognized in his mother, brother, and niece. Both his mother and brother had a history of thrombotic disease.

Anti-neutrophil cytoplasmic antibodies (ANCA) in sera from patients with inflammatory bowel disease (IBD). Relation to disease pattern and disease activity.

Anti-neutrophil cytoplasmic antibodies producing a perinuclear fluorescence pattern on ethanol-fixed granulocytes (p-ANCA) were found in 33 of 67 patients (49%) with ulcerative colitis (UC) but also in 14 of 35 patients (40%) with Crohn's disease (CD). In the latter condition p-ANCA were equally present in subgroups with colonic, ileocolonic, or ileal involvement only. Titers of p-ANCA were higher in patients with UC compared to CD patients, in particular when comparing patients with active disease. In contrast to findings in CD, patients with active UC had higher titers of p-ANCA than patients with inactive UC. Although p-ANCA were incidentally directed to lactoferrin, both in UC and CD, and to proteinase-3 and myeloperoxidase in UC only, the antigenic nature of p-ANCA could not be identified in most of the cases. We conclude that, within the spectrum of inflammatory bowel disease, the presence of p-ANCA is not specific for UC. When titers of p-ANCA are taken into account, the presence of high-titered p-ANCA, however, suggests active UC.

Pepsinogen synthesis and secretion by isolated gastric glands.

De novo synthesis of pepsinogens was demonstrated in gastric glands isolated from rabbit and human gastric mucosa. The isolated glands were incubated in an amino acid free, Minimum Eagles Medium supplemented with a 14C labelled amino acid mixture. The glands were centrifuged at different time intervals and aliquots of gland homogenates and medium were run on polyacrylamide slab gels. Newly synthesized pepsinogens were demonstrated by autoradiography. Incorporation of 14C was detected after 30 minutes of culture and increased almost linearily with time over 4 h. By comparing the electrophoretic patterns after autoradiography, protein and pepsinogen activity staining, it was concluded that the glands synthesize mainly pepsinogens. Cimetidine, at a concentration of 10(-4)M strongly inhibited pepsinogen synthesis. Spontaneous secretion of pepsinogens into the medium was very low and relatively constant. Cyclic dibutyryl AMP markedly stimulated the secretion of pepsinogens into the medium. The results show, that isolated gastric glands are capable of synthesis and secretion of pepsinogens and that each function can be stimulated and inhibited selectively.

Serum pepsinogen I levels in relation to pepsinogen phenotypes.

Serum PG I levels were measured by an enzyme linked immuno sorbent assay (ELISA) in 567 blood donors and 171 patients from a routine gastroscopy program to study the relationship between PG I phenotypes and serum levels. In normal subjects no association was found between PG I phenotypes and serum levels. A low serum PG I level in patients was associated with phenotypes characterized by intense PG I fraction 5. This probably reflects the high frequency of these phenotypes in patients with atrophic gastritis or gastric cancer. The mean (+/- SD) serum PG I level was 45.8 +/- 17.7 micrograms/1 in control subjects. Serum PG I levels were lower in females (41.4 +/- 17.5) than in males (47.3 +/- 17.7) and increased with advancing age up to 65 years.

Purification of the pepsinogen A isozymogens by means of high resolution ion-exchange chromatography. Evidence for post-translational modifications.

Total human pepsinogen (PG) was isolated from gastric fundic mucosa and PGA (formerly called PGI) from urine, using standard ion-exchange and gel filtration techniques. Gastric PGA was separated from PGC (formerly called PGII) either by immunoaffinity or high resolution ion-exchange chromatography (fast protein liquid chromatography, Pharmacia, Uppsala, Sweden). The individual PGA isozymogens 2, 3, 4 and 5 could be isolated to homogeneity with the aid of the same ion-exchanger. Evidence was obtained for the existence of secondary modifications of the PGA fractions 3, 4 and 5, electrophoretically overlapping the primary (genetic) isozymogens.

Discrepancies between gastric mucosal and urinary pepsinogen A patterns and in vitro synthesis and secretion of human pepsinogen.

The relationship between electrophoretic pepsinogen A (PGA) patterns from urine and gastric mucosa was studied in healthy volunteers and in patients with various gastric disorders. Discrepancies between urinary and gastric PGA patterns were found in 63.3% of the individuals. In 9% of the subjects with these discrepancies, the phenotype class in urine was different from that in gastric mucosa. The differences were found in all diagnostic groups. The highest frequency of differences was found in patients with gastric ulcer. The differences were not related to the serum PGA level. More than 80% of the differences were caused by a lower relative intensity of pepsinogen A fraction 5 (Pg5) in urine than in gastric mucosa. The possible origin of differences in PGA isozymogen patterns was studied by organ culture of gastric biopsies. In vitro synthesis and secretion of pepsinogens were studied by electrophoresis and autoradiography. The synthesis rate of PGA in biopsies of 1-2 mm diameter was 40-100 ng/hr. Posttranslational modification of PGA isozymogens was demonstrated. Pg2 and part of Pg4 probably are secondary products of Pg3 and Pg5, respectively. In some individuals the secretion rate of Pg3 was low compared to the other isozymogens. The conversion of Pg3 into Pg2 and the differential secretion of the isozymogens may explain some of the discrepancies between gastric and urinary PGA patterns.

Pepsinogen A polymorphism in gastric mucosa and urine, with special reference to patients with gastric cancer.

Electrophoretic pepsinogen A patterns were determined in gastric fundic mucosa biopsies from 601 patients with various gastric disorders and 25 healthy volunteers. Pepsinogen A patterns with an intense fraction 5 appeared to be associated with gastric cancer and premalignant changes of the stomach (p less than 10(-9)). In 60 individuals pepsinogen A patterns were determined in normal mucosa from different parts of the stomach. No differences were found between these patterns. In 29 out of 59 gastric cancer patients pepsinogen A could be demonstrated in the macroscopically malignant tissue. In two cases a different pattern compared with uninvolved fundic mucosa was observed. During a follow up study, major changes in the pepsinogen A pattern were observed in 7 out of 56 patients. In 8.6% of the examined patients urinary pepsinogen A patterns differed considerably as compared with the pattern observed in the gastric fundus. The results suggest that the highly significant association between intense Pg5 (the product of the D gene) and gastric cancer or its precursors may be caused by genetic as well as non-genetic factors.

Gastric proteases in Barrett's esophagus.

Precursors of the gastric proteases pepsinogen A (pepsinogen I) and pepsinogen C (pepsinogen II) and slow-moving protease were demonstrated in biopsy specimens from Barrett's epithelium in 21 of 22 patients with Barrett's esophagus; in 14 of them, in variable combinations at different sites. In 13 of 19 patients (68.4%) with detectable pepsinogen A, different isozymogen patterns were found between the Barrett's epithelium and the gastric corpus mucosa. Discrepancies consisted mainly of a stronger pepsinogen 5 band in the Barrett's epithelium, with a higher incidence in biopsy specimens with features of dysplasia than with no or indefinite dysplasia; the difference was, however, not statistically significant. Zymograms of 69 biopsy specimens from Barrett's epithelium were correlated with the histologic type: pepsinogen A and C were most frequently found in the fundic type, least often in the specialized intestinal type. In control gastric corpus biopsy specimens, pepsinogen A and C as well as slow-moving protease were always detectable. The observed variability of gastric protease patterns, in particular of pepsinogen A isozymograms, may be due to differences in expression within the pepsinogen A cluster, suggesting a deregulation of gene expression or partial deletion of the pepsinogen A gene cluster.