Lymphomatoid granulomatosis with pulmonary and gastrointestinal involvement.

We present a rare case of grade II lymphomatoid granulomatosis (LYG) with pulmonary and gastrointestinal involvement. LYG is considered an Epstein-Barr virus-driven lymphoproliferative disorder that often presents with multiple nodular lesions in the lungs and sometimes involvement of skin and the central nervous system. Although the aetiology is unknown, it is associated with the use of immunosuppressives. Involvement of other organ systems is very rare. We successfully treated our patients with 6 cycles of R-CHOP and autologous stem cell transplantation with a major response at 20 months follow-up.

PTEN in colorectal cancer: a report on two Cowden syndrome patients.

Heterozygous germline PTEN mutations cause Cowden syndrome. The risk of colorectal cancer in Cowden patients, however, remains a matter of debate. We describe two patients presenting with colorectal cancer at a young age (28 and 39 years) and dysmorphisms fitting the Cowden spectrum. Heterozygous germline mutations in PTEN were found in both patients. Moreover, analysis of the resected colorectal cancer specimens revealed loss of heterozygosity at the PTEN locus with retention of the mutated alleles, and greatly reduced or absent PTEN expression. Histologically and molecularly, the tumours showed resemblance with sporadic colorectal cancers, although they had prominent fibrotic stroma. Our data indicate that PTEN loss was involved in carcinogenesis in the two patients, supporting that colorectal cancer is part of the Cowden syndrome-spectrum. This is in line with data on sporadic colorectal cancer, mice studies and emerging epidemiological data on Cowden syndrome. Although the exact role of germline PTEN mutations in the carcinogenesis of colorectal cancer remains unclear, we think that Cowden syndrome should be in the differential diagnosis of colorectal cancer certainly in view of the possible prognostic and therapeutic consequences. Prospective follow-up and surveillance of PTEN mutation carriers from the age of 25 to 30 years in a study setting should clarify this issue.

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study.

OBJECTIVES: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. METHODS: We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. RESULTS: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). CONCLUSIONS: In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

[Inflammatory bowel disease and Clostridium difficile: be prepared]. / Clostridium difficile bij chronische inflammatoire darmziekten.

In this report we describe 3 female patients, aged 38, 29 and 91, with inflammatory bowel disease (IBD) and suffering from an episode of abdominal symptoms and diarrhoea. This raised suspicion of a flare-up of IBD, but all three proved to have Clostridium difficile-associated disease (CDAD). This diagnosis led to a change in management, medication being changed from ciprofloxacin into metronidazole in 2 patients. Patients known to have IBD often present with abdominal pain and diarrhoea. In such a situation an exacerbation of the IBD usually seems most likely. However, an infection with C. difficile always has to be considered, since this infection can mimic a flare-up of IBD. There is a rising incidence of C. difficile in patients with IBD. C. difficile infections in IBD-patients tend to run a more severe course. Therefore, early diagnosis of CDAD in IBD patients is important and has distinct therapeutic implications.

Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn's disease with infliximab: a double-blind placebo-controlled study.

BACKGROUND: Ciprofloxacin is effective in perianal Crohn's disease but after treatment discontinuation symptoms reoccur. Infliximab is effective but requires maintenance therapy. AIM: To evaluate the effect of combined ciprofloxacin and infliximab in perianal Crohn's disease. METHODS: A double-blind placebo-controlled study was conducted. Patients were randomly assigned to receive 500-mg ciprofloxacin twice daily or a placebo for 12 weeks. All patients received 5-mg/kg infliximab in week 6, 8 and 12 and were followed for 18 weeks. Primary end-point was clinical response, defined as a 50% or greater reduction from baseline in the number of draining fistulae. Secondary end-points were the change in Perianal Disease Activity Index and hydrogen peroxide enhanced three-dimensional endoanal ultrasonography findings. Analysis was by intention-to-treat. RESULTS: Twenty-four patients were included but two discontinued treatment. At week 18, response was 73% (eight of 11) in the ciprofloxacin group and 39% (five of 13) in the placebo group (P = 0.12). Using logistic regression analysis patients treated with ciprofloxacin tended to respond better (OR = 2.37, CI: 0.94-5.98, P = 0.07). The Perianal Disease Activity Index score only improved (P = 0.008) in the ciprofloxacin group. Three-dimensional endoanal ultrasonography improved in three patients with a clinical response. CONCLUSIONS: A combination of ciprofloxacin and infliximab tended to be more effective than infliximab alone.

A comparison of 3 types of covered metal stents for the palliation of patients with dysphagia caused by esophagogastric carcinoma: a prospective, randomized study.

BACKGROUND: There are currently 3 types of covered metal stents available in Europe for palliation of patients with malignant dysphagia. Their relative merits have not been compared in a prospective, randomized study. METHODS: One hundred consecutive patients with esophagogastric carcinoma were randomized to placement of an Ultraflex stent, a Flamingo Wallstent, or a Gianturco-Z stent. Malignant strictures of the esophagus were treated by insertion of a small-diameter stent (n = 71), whereas those involving the gastric cardia were treated with a large-diameter stent (n = 29). RESULTS: At 4 weeks, dysphagia had improved in all patient groups (p < 0.001), but the degree of improvement did not differ among the 3 groups (p = 0.14). There were differences among the 3 stent types with respect to major complications (Ultraflex stent: 8/34 [24%], Flamingo Wallstent: 6/33 [18%], and Gianturco-Z stent: 12/33 [36%]), but these were not statistically significant (p = 0.23). Nine patients (26%) with an Ultraflex stent, 11 (33%) with a Flamingo Wallstent, and 8 (24%) with a Gianturco-Z stent had recurrent dysphagia (p = 0.73), mainly because of tumor overgrowth or stent migration; 12 of 13 episodes of migration involved small-diameter stents in the esophagus. CONCLUSIONS: All 3 covered metal stents evaluated offer the same degree of palliation of patients with malignant dysphagia. Placement of Gianturco-Z stents was associated with more complications as compared with Ultraflex stents and Flamingo Wallstents. Although stent migration is reduced by increasing stent diameter, tumor overgrowth remains an intractable problem that requires a new approach.

Two young Somalians with gastric outlet obstruction as a first manifestation of gastroduodenal tuberculosis.

Gastroduodenal tuberculosis (GDTB) is an uncommon condition which can mimic other gastrointestinal disorders. It usually occurs secondary to pulmonary tuberculosis. We describe two young Somalian patients who presented with abdominal pain and gastric outlet obstruction. GDTB was diagnosed in both patients and they were successfully treated with antituberculous drugs.

Bleeding into a liver cyst can be treated conservatively.

OBJECTIVE: To report the case of a patient with haemorrhage in a large hepatic cyst. PATIENT: A 66-year-old man, who presented with right shoulder pain and subsequent sudden abdominal pain. A large hepatic cyst containing blood was found at ultrasonography. INTERVENTIONS: The patient was treated conservatively. RESULTS: The patient's symptoms resolved quickly. No symptoms or complications recurred during a follow-up of 2 years. CONCLUSION: Therapy for non-parasitic liver cysts is indicated when symptoms or complications related to the cysts occur. This case shows that spontaneous haemorrhage into a non-parasitic hepatic cyst may follow a benign course and may be treated conservatively.

Primary bile acid malabsorption: a pathophysiologic and clinical entity?

Primary bile acid malabsorption is defined as chronic diarrhoea with bile acid malabsorption of unknown cause and a symptomatic response to cholestyramine. Convincing evidence of the proposed pathophysiology--a defect of the active bile acid absorption in the distal ileum--has never been substantiated. We found no evidence of a bile acid transport defect across the ileal brush border membrane in 10 patients with primary bile acid malabsorption; moreover, transport was significantly higher than in a control group. In the patients with primary bile acid malabsorption the estimated bile acid pool was significantly larger than in a control group and in a group of patients with ileal disease. In addition, the oro-anal transit time of radiopaque markers was shorter in the primary bile acid malabsorption group than in both other groups. This suggests that the bile acid pool size as well as intestinal motility could play a role in the pathophysiology of primary bile acid malabsorption.

CD14 contributes to the adherence of human monocytes to cytokine-stimulated endothelial cells.

Monocyte adherence to endothelial cells (EC) is selectively increased during inflammation. The mechanisms underlying monocyte-EC interaction indicated the involvement of surface-adhesion molecules on monocytes and EC. In earlier studies we noticed that the monocyte-specific mAb, designated mAb 63D3, in contrast to mAb against the beta 2-integrin molecules, inhibited the monocyte binding to monolayers of rIL-1 alpha-stimulated venous EC. The aim of the present study was to further characterize the Ag recognized by mAb 63D3 and to investigate the specific contribution of this Ag to the adherence of monocytes to cultured human macrovascular venous or arterial EC. Flow cytometric analysis demonstrated that the 63D3 Ag is expressed exclusively on the surface of peripheral blood monocytes. SDS-PAGE analysis of mAb 63D3 immunoprecipitates of 125I-labeled human monocyte surface proteins revealed that the target Ag for mAb 63D3 is a 52- to 55-kDa molecule identical to the myeloid differentiation protein CD14. Stimulation of EC with rIL-1 alpha or rTNF-alpha for 4 or 24 h or rIFN-gamma for 24 h increased (p less than 0.005) the number of monocytes bound to both types of EC. This cytokine-induced increase in monocyte adherence was significantly (p less than 0.0005) inhibited when the monocytes were coated with various mAb against CD14. The binding of monocytes to nonstimulated venous or arterial EC was not inhibited by anti-CD14 mAb. Our results lead to the conclusion that CD14 molecules, which on basis of their structure and m.w. are not related to the beta 2-integrin family of heterodimeric leukocyte adhesion molecules, participate in the binding of monocytes to cytokine-stimulated EC.

Characterization of the adherence of human monocytes to cytokine-stimulated human macrovascular endothelial cells.

At sites of inflammation, interactions between monocytes and vascular endothelium play an important role in the margination and extravasation of monocytes. The aim of this study was to investigate the relative contributions of the CD11/CD18 family of leucocyte adhesion molecules on monocytes and ICAM-1 and ELAM-1 molecules on endothelial cells (EC) to the binding of monocytes to EC stimulated with recombinant interleukin-1 alpha (rIL-1 alpha), rIL-6, recombinant tumour necrosis factor-alpha (rTFN-alpha) or recombinant interferon-gamma (rIFN-gamma). The adhesiveness of EC for monocytes increased 1.8-2.3-fold after incubation of monolayers of venous or arterial EC with rIL-1 alpha or rTNF-alpha for 4 hr, and 1.6-2.0-fold after stimulation of both types of EC with rIL-1 alpha, rTNF-alpha or rIFN-gamma for 24 hr. Incubation with rIL-6 was without effect. The monoclonal antibodies (mAb) against CD11a, b, c and CD18 on monocytes did not inhibit the increase in the number of monocytes bound to rIL-1 alpha-, rTNF-alpha-, or rIFN-gamma-stimulated EC. However, mAb against ELAM-1 expressed on the surface of 4 hr rIL-1 alpha-stimulated EC slightly inhibited (15-21%) the enhanced monocyte binding. ICAM-1, which exhibited marked expression on 24 hr rIL-1 alpha-, rTNF-alpha- or rIFN-gamma-stimulated EC, did not contribute to the enhanced monocyte binding. The percentage of EC-bound monocytes which had stretched out over the surface of cytokine-stimulated venous or arterial EC was significantly increased compared to the percentage found for non-stimulated EC. It was observed that mild fixation of EC as well as treatment of EC with cytochalasin B or mAb against ICAM-1 did not affect the number of monocytes that were bound to EC, but considerably reduced the percentage of EC-bound monocytes with a stretched morphology. It is concluded that the binding of monocytes to cytokine-stimulated EC is dependent on the type of cytokine and the duration of cytokine stimulation. The increase in the binding of monocytes to cytokine-stimulated EC occurred as a result of CD11/CD18- and ICAM-1-independent factors. The subsequent morphological changes, i.e. stretching of monocytes over the surface of EC, required viable EC and ICAM-1.

The selenium-75-homocholic acid taurine test reevaluated: combined measurement of fecal selenium-75 activity and 3 alpha-hydroxy bile acids in 211 patients.

The recommended reference values for the selenium-75-homocholic acid taurine (75SeHCAT) test, used in the analysis of chronic diarrhea, were evaluated in 211 patients by comparing simultaneous measurements of 3 alpha-hydroxy bile acids and 75Se activity in daily collected stools. An initial evaluation in 11 patients showed that the fecal collection method, which allows inspection and additional analysis of stools, was equivalent to the abdominal retention method. Selenium-75-HCAT whole-body retention half-life (WBR50) was greater than 2.8 days in less than 10% of the patients with bile acid malabsorption and less than 1.7 days in less than 10% of the normals. We recommend that a 75SeHCAT WBR50 less than 1.7 days is abnormal, a WBR50 greater than 2.8 days is normal, and a WBR50 in the range 1.7-2.8 days is equivocal, which was the case in 48% (94/195) of the patients in this study.

Primary bile acid diarrhoea without an ileal carrier defect: quantification of active bile acid transport across the ileal brush border membrane.

Unexplained bile acid malabsorption associated with diarrhoea that responds to cholestyramine was first described in 1973 but convincing evidence of the proposed mechanism--a defective active ileal bile acid transport--has never been substantiated. Active bile acid transport was quantified in vitro using brush border membrane vesicles prepared from terminal ileal biopsy specimens from 10 patients who fulfilled the criteria of idiopathic bile acid diarrhoea. They were recruited from 181 patients with bile acid malabsorption of various causes. Transport was quantified as in vitro Na+ dependent bile acid transport (INBAT), expressed as pmol taurocholate/mg brush border membrane protein/15 seconds, and in vitro Na+ dependent bile acid local transport capacity (INBALTC), expressed as pmol taurocholate/g ileal biopsy tissue/15 seconds. The lowest INBAT and INBALTC values in the 10 patients with idiopathic bile acid diarrhoea were well above the 10th centile values of a control group of 132 patients. Both INBAT (mean (range) 88 (30-136)) and INBALTC (158 (85-268)) values were significantly higher in the 10 patients than in the control group (INBAT: mean (range) 63 (1-244), INBALTC: mean (range) 98 (1-408)). Quantification of active ileal bile acid transport in these 10 patients with idiopathic bile acid malabsorption suggests that a genetic (carrier) defect is rare in adults.

Characterization of monocyte adherence to human macrovascular and microvascular endothelial cells.

The interaction of monocytes with cultured large vessel venous and arterial endothelial cells (EC) and with cultured microvascular EC was studied. Analysis of time-lapse microcinematographic video recordings showed that monocytes adhere rapidly to the surface of EC and subsequently remain spherical and fixed to the initial site of adherence. Some monocytes adherent to EC stretch out within 30 to 90 min and migrate over the EC surface or become stretched for about 10 to 30 min and then detach from the EC surface and move rapidly over the EC monolayer. It was shown that the interaction of monocytes with EC is dynamic, that the morphology of monocytes adherent to EC changes constantly, and that stretching of the monocytes over the surface of the EC is not an inevitable and irreversible consequence of binding. A quantitative adherence assay was developed in which both the morphology and the number of monocytes bound to EC were determined. For each type of EC the number of monocytes bound to a single EC was found to be linearly related to the number of monocytes added and was lower for smaller EC. The adherence of monocytes to venous and arterial EC followed a different time course than the adherence to capillary EC and adherence to both types of macrovascular EC was higher than adherence to microvascular EC was higher than adherence to microvascular EC. The percentage of adherent monocytes with a stretched morphology was lower when these cells were adherent to capillary EC than to both types of macrovascular EC and increased upon addition of serum. Adherence of monocytes to venous, arterial, and capillary EC was partially inhibited by mAb directed against the alpha-chain of lymphocyte function-associated Ag-1 or C3bi receptor (with mAb LM2/1, but not with mAb OKM1) and by mAb against the common beta-chain of the three leukocyte adhesion molecules. The degree of inhibition of monocyte adherence to EC by mAb against lymphocyte function-associated Ag-1 alpha and the common beta-chain was dependent on the type of EC and was higher for venous EC (57 to 70% inhibition) than for arterial (40 to 44% inhibition) and capillary (44 to 49% inhibition) EC. Inhibition of monocyte adherence obtained with anti-C3bi receptor-alpha mAb was similar for each EC type. mAb against p150, 95 did not affect adherence. None of the mAb could block binding completely; combinations of the mAb also did not result in increased inhibition of monocyte adherence to EC.

Familial occurrence of collagenous colitis. A report of two families.

Collagenous colitis is a rare condition characterized clinically by chronic diarrhea and histologically by a thickened subepithelial collagenous band in colonic biopsies in an endoscopically normal colon. Familial occurrence of collagenous colitis has to our knowledge never been described. Here we report two families in which two first-degree related members suffered from collagenous colitis. In one family, two sisters were affected by chronic diarrhea and autoimmune disorders such as thyroid disease, rheumatoid arthritis, and pernicious anemia. Collagenous colitis was diagnosed in one of these sisters, based on colonic biopsies. Colonic biopsies of the other sister showed microscopic colitis. Review of colonic biopsies of this patient taken 11 years earlier, however, showed definite histological features of collagenous colitis. In the other family, in a father and son, both with diarrhea for several years but not suffering from any other diseases, a diagnosis of collagenous colitis was made on colonic biopsies. Human leukocyte antigen (HLA) typing showed that only the HLA A2 antigen was present in all 4 patients.

Mean cell volume of human blood leucocytes and resident and activated murine macrophages.

The mean cell volume (MCV) of human blood leucocytes and resident and activated murine macrophages was measured with a Coulter counter connected to a 256 channelyzer. The values found for human blood monocytes, granulocytes, and lymphocytes were 421 +/- 24 femtolitre (fl), 334 +/- 32 fl, and 204 +/- 19 fl, respectively. Resident murine peritoneal macrophages were significantly smaller than rIFN-gamma-activated and BCG/PPD-activated peritoneal macrophages and resident alveolar macrophages.

Na+-dependent bile acid transport in the ileum: the balance between diarrhea and constipation.

Ileal Na+-dependent bile acid transport was quantified in vitro as the uptake of 3H-taurocholate into brush-border membrane vesicles. Vesicles were prepared from ileal biopsies of 158 patients placed in 10 diagnostic categories. Active bile acid transport (expressed as picomoles taurocholate uptake per milligram brush-border membrane protein per 15 s, median and interquartile ranges indicated) did not differ significantly in 6 categories: irritable bowel syndrome (71, 35-97; n = 21), colon polyps (42, 30-89; n = 29), colitis (62, 33-91; n = 31), postvagotomy or postcholecystectomy (69, 37-97; n = 11), diarrhea without increased bile acid loss (58, 48-85; n = 12), and lack of gastrointestinal pathology (74, 45-103; n = 22). A decreased active bile acid transport was found in 3 categories: ileal disease (4, 1-36; n = 11), partial ileal resection (5, 1-35; n = 5), and constipation (41, 22-50; n = 8). Bile acid transport was increased in patients with bile acid-losing diarrhea with endoscopically and histologically normal ilea (111, 94-135; n = 8). These findings indicate that a low fecal bile acid loss, presumed to be present in constipated patients, is associated with a low Na+-dependent ileal bile acid transport and a high bile acid loss is associated with a high active bile acid transport. Ileal bile acid transport might be regulated by the availability of bile acids to the ileal enterocytes.

Intestinal lymphangiectasia in systemic sclerosis.

Protein-losing gastroenteropathy is a well-recognized entity in systemic sclerosis, for which several mechanisms have been postulated. Acquired intestinal lymphangiectasia as a cause of increased intestinal protein loss has not previously been described in the literature. We report the first case of acquired intestinal lymphangiectasia in systemic sclerosis.