Causes of inconsistency in diagnosing and classifying intraductal proliferations of the breast. European Commission Working Group on Breast Screening Pathology.

It is now widely recognised that classifying ductal carcinoma in situ (DCIS) of the breast and diagnosing atypical ductal hyperplasia are associated with significant interobserver variation. Two possible reasons for this inconsistency are differences in the interpretation of specified histological features and field selection where morphology is heterogeneous. In order to investigate the relative contribution of these two factors to inconsistent interpretation of intraductal proliferations, histological sections of 32 lesions were sent to 23 European pathologists followed 3 years later by images of small parts of these sections. Kappa statistics for diagnosing hyperplasia of usual type, atypical ductal hyperplasia and ductal carcinoma in situ were 0.54, 0.35 and 0.78 for sections and 0.47, 0.29 and 0.78 for images, respectively, showing that most of the inconsistency is due to differences in morphological interpretation. Improvements can thus be expected only if diagnostic criteria or methodology are changed. In contrast, kappa for classifying DCIS by growth pattern was very low at 0.23 for sections and better at 0.47 for images, reflecting the widely recognised variation in the growth pattern of DCIS. Higher kappa statistics were obtained when any mention of an individual growth pattern was included in that category, thus allowing multiple categories per case; but kappa was still higher for images than sections. Classifying DCIS by nuclear grade gave kappa values of 0.36 for sections and 0.49 for images, indicating that intralesional heterogeneity has hitherto been underestimated as a cause of inconsistency in classifying DCIS by this method. More rigorous assessment of the proportions of the different nuclear grades present could lead to an improvement in consistency.

Gastric emptying of liquid meals measured noninvasively in humans with [13C]acetate breath test.

The aim of the present study was to develop a breath test to measure liquid gastric emptying rates that would be without radiation exposure and applicable to field testing. Four different test meals were investigated: a glucose meal, an amino acid meal, a fat meal, and a mixed meal (Ensure). The test meals were labeled with two markers, [13C]acetate and PEG-4000 (polyethylene glycol 4000). Gastric emptying rates were measured simultaneously by both breath test and the double-indicator technique in eight healthy male subjects. The appearance of 13CO2 in the breath closely reflected gastric emptying of the four test meals as measured by the double-indicator technique. It is concluded that the [13C]acetate breath test is a reliable, noninvasive test to measure gastric emptying rates of liquid test meals.

Mitochondrial function reflected by the decarboxylation of [13C]ketoisocaproate is impaired in alcoholics.

Mitochondria of patients with alcoholic liver disease exhibit structural abnormalities, and mitochondria isolated from animals exposed to ethanol are functionally deficient when studied in vitro. To assess possible functional consequences of these ethanol-associated alterations in vivo, we measured mitochondrial function in alcoholics noninvasively with a breath test. A mitochondrial function, the decarboxylation of ketoisocaproate (KICA), was assessed by measuring the exhalation of 13CO2 following the administration of 1 mg/kg 2-keto[1-13C]isocaproic acid, the decarboxylation of which occurs in mitochondria. The results of the KICA breath test in 12 alcoholic subjects were compared with the results in healthy controls and patients with nonalcoholic liver disease. The peak exhalation of 13CO2 and the fraction of the administered dose decarboxylated in 120 min were both significantly lower in alcoholics than in healthy controls and patients with nonalcoholic liver disease. In alcoholics, KICA decarboxylation was impaired in the presence of normal quantitative liver function tests such as the aminopyrine breath test and galactose elimination capacity, indicating that KICA decarboxylation does not simply reflect a decreased functional hepatic mass. The enrichment of circulating KICA with [13C]KICA was similar in alcoholics and controls, indicating that a decreased bioavailability or an increased dilution of labeled KICA cannot account for the decreased exhalation of 13CO2. It is concluded that mitochondrial function as reflected by KICA decarboxylation is impaired in chronic alcoholics. The functional impairment is specific for ethanol abuse and not a reflection of decreased global hepatic function. KICA decarboxylation could thus be useful as a marker for excessive ethanol consumption.

[Helicobacter pylori resistance against metronidazole in Switzerland: implications for eradication therapy?]. / Resistenz von Helicobacter pylori gegen Metronidazol in der Schweiz: Implikationen für die Eradikationstherapie?

Gastroduodenal ulcers are strongly associated with Helicobacter pylori (HP) infection. Successful eradication drastically diminishes ulcer recurrence. Most of the eradication schemes include metronidazole (Flagyl). The present study was designed to establish the metronidazole resistance rate in Switzerland. Antral biopsies were taken in 153 patients with suspected ulcers (115 men, 38 women, mean age 46 +/- 16 [SD] years) during upper endoscopy for bacteriological testing. Metronidazole resistance (> 8 micrograms/ml) was found in 47/153 (31%) of the isolates. Resistance was found in no case to amoxicillin (Clamoxyl) (0/104 = 0%) and only in 3% (2/66) to clarithromycin (Klazid). Metronidazole resistance of HP in a third of the isolates studied is comparable to numbers found in other European countries. These findings raise the question whether eradication schemes including metronidazole without prior sensitivity testing are justified. Amoxicillin and clarithromycin appear to be valid alternatives.

Influence of Helicobacter pylori, sex, and age on serum gastrin and pepsinogen concentrations in subjects without symptoms and patients with duodenal ulcers.

The relation between Helicobacter pylori (H pylori) infection and fasting gastrin and pepsinogen-I and -II concentrations was evaluated in 278 volunteers without symptoms and the results were compared with the values obtained in 35 patients with duodenal ulcers. H pylori infection was determined with the 13C-urea breath test in subjects without symptoms and with endoscopy, biopsy (histology and culture), and quick urease test (CLO-test) in patients with duodenal ulcers. Gastrin and pepsinogen-I and -II concentrations were assayed with specific radioimmunoassay systems. The results clearly indicate that fasting gastrin and pepsinogen-I and -II concentrations were significantly higher in H pylori positive compared with H pylori negative subjects. Neither age nor sex affected basal gastrin and pepsinogen concentrations in H pylori negative subjects. Fasting gastrin, pepsinogen-I and -II concentrations in serum samples were similar in H pylori positive persons with no symptoms and those with duodenal ulcers suggesting that similar mechanisms are involved in increasing plasma concentrations of these variables in both populations. Hypergastrinaemia and hyperpepsinogenaemia are therefore probably secondary to active H pylori infection.

Evidence for hormonal inhibition of exocrine pancreatic function by somatostatin 28 in humans.

Somatostatin 28 (S-28), originating in gastrointestinal cells, is secreted into the circulation and increases in humans after ingestion of a mixed meal. To evaluate the possibility that the increased levels of S-28 post cibum might modulate the release of enzymes and bicarbonate from the exocrine pancreas, S-28 was infused intravenously into healthy volunteers to levels seen after food intake. During S-28 infusion, the output of lipase, trypsin, amylase, and bicarbonate stimulated by either exogenous cholecystokinin octapeptide or endogenous signals from intraduodenal administration of tryptophan or a mixture of amino acids was significantly reduced. It is concluded that S-28 released from the gut during food intake modulates pancreatic exocrine function in humans.

[Sensitivity and specificity of a simplified, standardized 13C-urea breath test for the demonstration of Helicobacter pylori]. / Sensitivität und Spezifität eines vereinfachten, standardisierten 13C-Urea-Atemtests zum Nachweis von Helicobacter pylori.

A simplified 13C-urea breath test (UBT) for detection of Helicobacter pylori (Hp) infection was evaluated in 50 patients. Following upper gastrointestinal endoscopy the patients received 100 ml of a liquid test meal with 100 mg 13C-urea. Breath samples were obtained at baseline and 30 minutes respectively. The UBT was positive (difference of 13CO2 enrichment exceeding 5%) in 33/35 patients with culture-proven Hp infection and negative in 14/15 patients in whom microbiological culture, histology and a urease test (CLO-test) were negative. We conclude that in view of its high sensitivity (94%) and specificity (93%) the UBT is useful for rapid, non-invasive diagnosis of Hp infection.

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans.

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.