Belgian guidelines for pathology reporting of neuroendocrine neoplasms of the pancreaticobiliary and gastrointestinal tract.

Since neuroendocrine neoplasms are rare tumors, registration of patient data in national and multinational registries is recommended. Indeed, this will facilitate multicenter studies on the epidemiology, efficacy and safety of diagnostic and therapeutic strategies for well-differentiated neuroendocrine tumors as well as for neuroendocrine carcinomas. In Belgium, data on patient and tumor characteristics of all newly diagnosed malignancies have been collected in the Belgian Cancer Registry since 2004 including anonymized full pathological reports. The Digestive Neuroendocrine Tumor (DNET) registry collects information on classification, staging, diagnostic tools and treatment in a prospective national online database. However, the terminology, classification and staging systems of neuroendocrine neoplasms have changed repeatedly over the past 20 years as a result of a better understanding of these rare tumors, by joining forces internationally. These frequent changes make it very difficult to exchange data or perform retrospective analyses. For optimal decision making, for a clear understanding and to allow reclassification according to the latest staging system, several items need to be described in the pathology report. This paper provides an overview of the essential items in reporting neuroendocrine neoplasms of the pancreaticobiliary and gastrointestinal tract.

Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis: the effects of substrate concentration and carnitine on the ß-oxidation pathway.

BACKGROUND: Butyrate, a colonic metabolite of carbohydrates, is considered as the major energy source for the colonic mucosa. An impaired butyrate metabolism has been reported in ulcerative colitis (UC), however, the cause still remains unknown. AIM: In the present study, we investigated whether higher butyrate concentrations could normalise the oxidation rate in UC. Furthermore, it was investigated whether carnitine could enhance the butyrate oxidation. METHODS: Mucosal biopsies from a total of 26 UC patients and 25 controls were incubated with (14)C-labelled Na-butyrate and the produced (14)CO(2) was measured. First, the rate of oxidative metabolism was compared at three different concentrations of Na-butyrate (0.05 mm, 1 mm and 10 mm). Then, incubations of biopsies were performed with carnitine alone or combined with ATP. RESULTS: Overall, butyrate oxidation in UC was significantly lower than that in controls. The maximum rate of butyrate oxidation was achieved in UC and control subjects from 1 mm onwards. Increasing the butyrate concentration to a level to be present in the colonic lumen, i.e. 10 mm, did not increase the rate of butyrate oxidation in UC to the rate observed in controls. Addition of carnitine alone or combined with ATP caused no effects. CONCLUSIONS: Saturation of butyrate kinetics was achieved from 1 mm in UC and control subjects. The rate of butyrate metabolism was significantly impaired in active ulcerative colitis. The addition of compounds interfering with the ß-oxidation pathway had no effect on the butyrate metabolism in UC.

EGFR-immunohistochemistry in colorectal cancer and non-small cell lung cancer: comparison of 3 commercially available EGFR-antibodies.

BACKGROUND: Epidermal Growth Factor Receptor (EGFR)-targeted therapies are currently used for the treatment of metastasized colorectal cancer (CRC) and non small cell lung cancer (NSCLC). Patient selection for this treatment is based on immunohistochemical (IHC) testing for EGFR. The rising amount of commercially available EGFR-antibodies makes standardisation of EGFR-IHC necessary. The goal of this study was to analyse possible discrepancies between 3 antibodies against EGFR. PATIENTS AND METHODS: 36 formalin-fixed samples of CRC (n = 26) and NSCLC (n = 10) were stained with 3 antibody-clones: 2-18C9 (Dako); 31G7 (VentanaTM) and 111.6 (Labvision Neomarkers). Interpretation of stains includes assessment of % positive cells, evaluation of cut off values and staining intensity. RESULTS: With a 1% cut-off, the 2-18C9 clone stained 86% of the cases positive, the 31G7-clone 77% and the 111.6-clone 52%. With a 10% cut-off, percentages declined to 77%, 61% and 30% respectively. The 2-18C9-clone showed the highest staining intensity. The 2-18C9 clone and the 31G7-clone showed a concordance rate of 90%. CONCLUSIONS: IHC staining with 3 different antibody clones directed against EGFR shows indeed differences in staining results: the percentage of positive cells and staining intensity are variable. A correct cut-off value for a positive result is important and can be different depending upon the antibody. Appropriate validation of an antibody is essential before it can be used for selection of patients.

Crohn's-like changes in the colon due to mycophenolate?

OBJECTIVE: Mycophenolate mofetil (MMF) is used for prevention of allograft rejection in kidney transplant patients. A subset of patients suffers from chronic diarrhoea of unknown origin. The aim of the study was to investigate the effect of MMF on the colonic mucosa. MATERIALS AND METHODS: Colonic mucosal biopsies from 24 kidney transplant patients receiving MMF and presenting with chronic diarrhoea were analysed using routine stainings and immunohistochemistry for Ki67 and E-cadherin. Results were compared with a control group of 19 kidney transplant patients not receiving MMF. In all patients routine clinical and laboratory investigations were performed in order to explain the diarrhoea. RESULTS: In 11 patients, the diarrhoea seemed to be of infectious origin. Furthermore, 19/24 of MMF-patients showed characteristic histological alterations of the mucosa that were Crohn's disease-like: discontinuous crypt architectural distortion, increased epithelial mucin secretion, mildly active inflammation and focal presence of dilated and inflamed crypts. Ki67 staining was abnormal in 6/24 MMF patients but also in 4/19 control patients. E-Cadherin staining was normal in most MMF and control patients. CONCLUSIONS: Diarrhoea following MMF treatment is frequently infectious in origin and associated with morphological changes with a Crohn's-like pattern in the colonic mucosa in a subset of patients. MMF does not induce major alteration in the proliferative compartment of colonic epithelium. The diarrhoea is not associated with altered E-cadherin expression in the colonic epithelium.

Inulin is an ideal substrate for a hydrogen breath test to measure the orocaecal transit time.

BACKGROUND: A better substrate is needed for a hydrogen breath test to measure the orocaecal transit time. The currently used substrate, lactulose, accelerates the orocaecal transit time by increasing the osmolality of the gut contents. The recently developed lactose 13C-ureide breath test is reliable, but a hydrogen breath test is preferred, as it allows the simultaneous investigation of the digestion and absorption of nutrients by means of 13C-labelled compounds. METHODS: The usefulness of different types of inulin as a substrate for a hydrogen breath test was studied. Raftilin HP (>99% inulin with a degree of polymerization of between 5 and 60 and <0.5% glucose, fructose and sucrose) was further evaluated and compared with lactulose with regard to its effects on gastric emptying and the digestion of protein and lipids. RESULTS: A good correlation was found between the orocaecal transit times using Raftilin HP (338 min; interquartile range, 300-383 min) and lactose 13C-ureide (353 min; interquartile range, 285-375 min) (r=0.85; P<0.001). The administration of 5 or 10 g Raftilin HP had no influence on the orocaecal transit time, whereas lactulose significantly shortened the orocaecal transit time. Neither inulin nor lactulose had a significant influence on gastric emptying or protein or lipid assimilation. CONCLUSION: Raftilin HP is an ideal substrate for a hydrogen breath test to measure the orocaecal transit time.

Magnesium chloride slows gastric emptying, but does not affect digestive functions.

BACKGROUND: An inverse relationship has been established between serum magnesium and serum lipid levels. By means of breath tests, we tested the hypothesis that magnesium inhibits intraluminal lipid digestion and subsequently causes changes in lipid metabolism. We also investigated the influence of the administration of magnesium chloride on protein digestion and gastric emptying. METHODS: Five healthy volunteers performed simultaneous breath tests for gastric emptying and intraluminal lipid digestion, and six others for gastric emptying and protein digestion. Each test was performed in basal conditions and after the intake of 800 mg of magnesium chloride dissolved in water. Breath samples were taken at regular time intervals and analysed for 13CO2 and 14CO2 enrichment in order to calculate gastric emptying and lipid and protein digestion rates. RESULTS: The oral administration of a single dose of magnesium chloride resulted in a diminished rate of intraluminal lipid and protein digestion. The most pronounced effect of magnesium chloride, however, was a decreased gastric emptying rate of both test meals. After correction for gastric emptying, no differences were noted in intraluminal lipid or protein digestion. Therefore, the lower lipid levels noted after magnesium supplementation are unlikely to be the result of altered lipid assimilation. CONCLUSION: Magnesium chloride slows gastric emptying but does not influence lipid digestion.

Vascular anatomy of the gastrointestinal tract.

The blood supply of the gastrointestinal system has intramural and extramural components. The intramural vascular distribution is generally well developed with plexuses in the different layers of the bowel wall and with specializations in the liver, small intestine and gastroesophageal junction, adapted to the function of these organs. The extramural arterial supply for the oesophagus is derived from the thoracic aorta or its major branches. Blood supply to the abdominal organs is provided by three major unpaired vessels arising from the abdominal aorta, namely the coeliac trunk and the superior and inferior mesenteric arteries. The branches of these vessels form anastomotic systems that provide a rich blood supply to the adjoining organs. In many areas the systems overlap while in other regions linkages are limited. Interrelations and weak points are of significant clinical importance. As well as this, there is a great individual variability in the anatomy of the gastrointestinal vasculature.

13C-egg white breath test: a non-invasive test of pancreatic trypsin activity in the small intestine.

BACKGROUND: The recent availability of egg white protein highly enriched with (13)C has allowed breath test technology to be adapted for the study of protein digestion and absorption. Pancreatic trypsin is considered to be the key enzyme in the proteolytic cascade. AIM: To evaluate trypsin activity in the small intestine of healthy volunteers and patients with pancreatic disease by a recently developed (13)C-egg white breath test. METHODS: A total of 48 healthy volunteers and 30 patients with pancreatic disease were studied after ingestion of a test meal consisting of 22 g (13)C-labelled egg protein. Breath samples were taken before and after ingestion of the meal and analysed for (13)CO(2) concentration. Moreover, pancreatic trypsin output after maximal stimulation was measured in 13 patients and nine healthy volunteers. RESULTS: The six hour cumulative (13)CO(2) excretion in breath was significantly lower in patients than controls (mean (SEM): 6.23 (0.82)% v 19.16 (0. 58)%, p<0.0001). An excellent correlation was found between the six hour cumulative (13)CO(2) excretion and trypsin activity after maximal pancreatic stimulation. CONCLUSION: The non-invasive (13)C-egg white breath test is promising as an indirect pancreatic proteolytic function test.

Contribution of morphology for the comprehension of mechanisms of fibrosis in inflammatory enterocolitis.

Strictures are a common complication of Crohn's disease and an indication for surgery in approximately 50% of patients. Morphologic studies have shown that fibrosis of the submucosa and muscularis propria are common in Crohn's disease, especially in strictures. Immunohistochemical and in situ hybridization studies have demonstrated a marked increase of various subtypes of collagens in Crohn's disease. Collagens type I and III are present in ulcerated areas where they appear around capillaries and in a linear deposition at the junction between the granulation tissue and the necrotic debris. Collagens type IV and V show a prominent perivascular expression, increased deposition in the muscularis propria and increased expression around ganglia. Initiation and maintenance of the connective tissue changes are related with the inflammatory infiltrate. Inflammatory cells can further alter smooth muscle proliferation and migration and promote the formation of myofibroblasts. These alterations together with increased collagen deposition are involved in the complex process of strictures and bowel wall alterations in Crohn's disease.

Effects of 'contact laxatives' on intestinal and colonic epithelial cell proliferation.

Experimental studies indicate that laxatives may induce epithelial damage. In addition, some laxatives induce the release of prostaglandins. Epithelial cell damage and release of prostaglandins are two pathways by which epithelial cell proliferation could be influenced. Furthermore, fermentable laxatives like lactulose may influence large intestine cell proliferation by the trophic effect of the fermentation products such as short-chain fatty acids. For these reasons an in vivo study in rats was performed to compare the short- and long-term effect of sennosides, bisacodyl, sodium picosulfate and lactulose on epithelial cell proliferation in the ileum and large intestine. Cell proliferation was examined by the BrdUrd labelling technique after 2, 6 and 12 weeks of continuous treatment. Studies in control animals show that the Labeling Index (LI) is higher in the cecum compared with other segments of the colon, and higher in the ileum than in the colon. Treatment with sennosides, bisacodyl and sodium picosulfate does not influence the LI in the ileum and induces no statistically significant increase of the LI when the treated groups are compared with the control group. The proliferative pattern along the crypts remains unchanged with all the laxatives throughout the study. It appears therefore that 'contact' laxatives have no major influence on ileal and colonic epithelial cell proliferation and should not be regarded as tumor-promoting substances.