Biomarker testing in oncology - Requirements for organizing external quality assessment programs to improve the performance of laboratory testing: revision of an expert opinion paper on behalf of IQNPath ABSL.

In personalized medicine, predictive biomarker testing is the basis for an appropriate choice of therapy for patients with cancer. An important tool for laboratories to ensure accurate results is participation in external quality assurance (EQA) programs. Several providers offer predictive EQA programs for different cancer types, test methods, and sample types. In 2013, a guideline was published on the requirements for organizing high-quality EQA programs in molecular pathology. Now, after six years, steps were taken to further harmonize these EQA programs as an initiative by IQNPath ABSL, an umbrella organization founded by various EQA providers. This revision is based on current knowledge, adds recommendations for programs developed for predictive biomarkers by in situ methodologies (immunohistochemistry and in situ hybridization), and emphasized transparency and an evidence-based approach. In addition, this updated version also has the aim to give an overview of current practices from various EQA providers.

The established and future biomarkers of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12months. The MPM incidence is 1-6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed-platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application.

The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark.

BACKGROUND: National population-based medical registries in Denmark offer a unique opportunity to study eosinophilic oesophagitis (EoE) epidemiology. AIM: To determine the incidence and prevalence of EoE in Denmark, and evaluate whether an increase in endoscopy with biopsy activity explains changes in these trends. METHODS: The Danish National Pathology Registry, Danish National Patient Registry and Danish Registry of Medicinal Product Statistics were queried from 1997 to 2012. Using an EoE case-finding algorithm validated for Danish patients, EoE cases were identified during each year of the study period; we also identified all patients with oesophageal eosinophilia. Using the known population of Demark, the annual incidence and prevalence of EoE were determined. We also determined the number of oesophageal biopsies performed each year in Denmark, and compared the change in the incidence rate to the change in biopsy rate. RESULTS: Between 1997 and 2012, 1708 patients had oesophageal eosinophilia, of whom 844 met the case definition of EoE. There were seven new cases of EoE in 1997 and 145 new cases in 2012, corresponding to a 19.5-fold increase in incidence (0.13/100 000 to 2.6/100 000). There were 769 total cases in 2012 (prevalence of 13.8/100 000). Over the same time frame, the oesophageal biopsy rate increased only 1.9 fold, from 91.1/100 000 to 175.3/100 000. CONCLUSIONS: The incidence and prevalence of EoE markedly increased in Denmark over the past 15 years. This increase far outpaced the increase in oesophageal biopsy utilisation, indicating that changes in the frequency of EoE are not due to changes in biopsy rates alone.

Occupational exposure to pesticides and bile tract carcinoma in men: results from a European multicenter case-control study.

OBJECTIVES: To estimate the associations between occupational exposure to pesticides and extrahepatic biliary tract carcinoma in men, a population-based case-control study was carried out. METHODS: Cases (n = 104), aged 35-70, diagnosed in 1995-1997, were sampled by active reporting systems from hospitals. Controls (n = 1,401) were a random sample of the general male population. Information on occupation and confounding factors was obtained by questionnaires. Exposures were quantified with respect to time, application methods, and use of personal protective equipment. Intensity was evaluated by using a published algorithm which weighted the exposure assigned according to the use of personal protective equipment and mode of application. Logistic regression analyses were conducted adjusted for gallstones, age, and country. RESULTS: Being ever exposed to pesticides resulted in an odds ratio (OR) of 1.0 [95%-confidence interval (CI) 0.6-1.6]. A modestly elevated risk was found for backpack mounted sprayers OR = 1.4 [95% CI 0.7-2.6] and vine farmers OR = 2.5 [95% CI 0.9-7.2]. Using time periods and exposure frequency as intensity measure, no elevated risks were found. The only exception was year of maximum exposure which yielded an OR of 1.6 [95% CI 0.7-3.5]. However, no clear trend was observed in this analysis. CONCLUSIONS: This study does not rule out that pesticide exposure represents an occupational risk factor for extrahepatic biliary tract carcinoma, but no indication of a strong association was observed. Some modes of exposure were weakly, albeit not significantly associated with carcinoma risk. The observed estimates of effects may be influenced by a lack of precise exposure assessment. Different chemical compositions of pesticides were utilized during a long time span of pesticide exposure, and it should be considered that the exposure is assessed with substantial uncertainty that could non-differential and bias results toward the null.

Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma.

BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.

Neuronal features of oligodendrogliomas--an ultrastructural and immunohistochemical study.

AIMS: To assess neuronal differentiation in oligodendrogliomas (ODGs). METHODS AND RESULTS: An electron microscopic and immunohistochemical study of 41 consecutive cases was performed. In all cases, tumour cells with neuritic structures were identified ultrastructurally, including synapses and neurosecretory granules. For the immunohistochemical identification of synaptophysin, monoclonal antibody clones 27G12, Snp88 and SY38 and a polyclonal antibody were compared in optimized protocols on slides from a spectrum of tissues and 16 ODGs. 27G12 gave the best signal-to-noise ratio, while SY38 gave the poorest. When 27G12 was applied on all 41 ODGs, widespread immunoreactivity was obtained in 100%. Among three antibodies to chromogranin compared similarly, clone LK2H10 and a polyclonal antibody gave identical patterns of immunoreactivity, whereas clone DAK-A3 gave weaker reactions. When LK2H10 was applied on all tumours, staining was found in 12 (29%). All tumours but one stained strongly for glial fibrillary acidic protein and all for synapsin I. Fluorescence in situ hybridization analysis showed a concomitant 1p/19q deletion in 12/16 ODGs. CONCLUSIONS: Our study provides evidence for widespread neuronal differentiation in ODGs, suggesting that these tumours may be derived from progenitor cells with limited commitment. Antibody selection and protocol optimization are mandatory for reliable immunohistochemistry results.

Interobserver variation in interpretation of serial liver biopsies from patients with chronic hepatitis C.

Reliable and accurate assessment of liver histopathology in patients with chronic hepatitis C is important for decision regarding treatment and for evaluation of therapy. However, little data on interobserver variation have been published. In this study, five specialist histopathologists evaluated 46 liver biopsies from 20 patients treated with interferon-alpha. Knodell's and Ishak's scoring systems, De Groote's classification and a four level general necro-inflammatory activity score (GNAS) were applied. Besides kappa statistics, slide by slide analysis was performed. We defined an acceptable slide by slide agreement as eight of ten observer pairs agreed on 80% of the slides. The best agreement was seen for Knodell's and Ishak's fibrosis score, De Groote's classification and GNAS (mean weighted kappa (kappa(w)) = 0.49, 0.51, 0.50 and 0.44, respectively). By condensing data from Knodell's and Ishak's scores to presence or absence of cirrhosis and piecemeal necrosis respectively, concordance was substantial concerning cirrhosis (mean kappa = 0.69 and 0.72, respectively) but only moderate concerning piecemeal necrosis (mean kappa = 0.40 and 0.39, respectively). Slide by slide analysis showed the highest agreement on Knodell's fibrosis score and GNAS; only one point of difference in score was to be accepted to obtain 'eight of ten' agreement. In contrast, five points of difference were necessary to accept in order to reach the same agreement for Knodell's total activity score. Moreover, in serial biopsies the GNAS was sufficient to detect changes in disease activity following treatment. Thus, a simple scoring system with four category scales was reproducible and sufficient for detection of therapy induced changes.

Interferon alfa-2b alone or combined with recombinant granulocyte-macrophage colony-stimulating factor as treatment of chronic hepatitis C.

BACKGROUND: To compare the effect of combination therapy with interferon-alpha (INF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to monotherapy with INF-alpha in patients with chronic hepatitis C infection. METHODS: Forty-five consecutive patients with chronic hepatitis C, all presenting with elevated serum alanine aminotransferases and viremia, were randomized to receive either 1) INF-alpha + GM-CSF for 3 months followed by INF-alpha alone for 9 months (n = 23) or 2) INF-alpha for 12 months (n = 22). Both drugs were administered 3 times weekly in doses of 3 mU (INF-alpha) and 50-100 microg depending on body weight (GM-CSF). RESULTS: At baseline, there was no difference between the treatment groups in terms of age, sex, ALT level, viral load, genotype or histological activity and fibrosis in a pretreatment liver biopsy. After 12 months' treatment, more patients treated with GM-CSF+ INF-alpha compared to patients receiving monotherapy had normalized ALT, 65% and 32%, respectively (P = 0.03), but there was no difference in percentages of patients with viral clearance between the 2 groups, 48% and 32%, respectively (P = 0.27). At 6 months' follow-up, the biochemical response had declined to 35% in the combination therapy group and to 23% in the monotherapy group (P = 0.37); viral clearance had declined to 22% and 27%, respectively (P = 0.67), and the overall sustained response rate was 22% and 23%, respectively (P = 1.00). CONCLUSIONS: Even though patients receiving INF-alpha + GM-CSF had a significant better biochemical response during treatment compared to patients receiving monotherapy, the sustained biochemical and virological response was not increased. Thus, GM-CSF hardly plays any role in the future treatment of chronic hepatitis C.

Herceptest: HER2 expression and gene amplification in non-small cell lung cancer.

HER2 is an erbB/HER type 1 tyrosine kinase receptor that is frequently over-expressed in malignant epithelial tumours. Herceptin, a humanised mouse monoclonal antibody to HER2, is proven therapeutically in the management of metastatic breast cancer, significantly prolonging survival when combined with cytotoxic chemotherapeutic agents. Immunohistochemical studies suggest that non-small-cell lung cancer (NSCLC) tumours may over-express HER2. Our aim was to evaluate HER2 gene amplification and semi-quantitative immuno-expression in NSCLC. A total of 344 NSCLC cases were immunostained for HER2 expression in 2 centres using the HercepTest. Fluorescence in situ hybridisation (FISH) analysis for HER2 gene amplification was performed on most positive cases and a subset of negative cases. Fifteen cases (4.3%) demonstrated 2+ or 3+ membranous HER2 immuno-expression. There was no correlation between immuno-expression and tumour histology or grade. Tumours from higher-stage disease were more often HercepTest-positive (p < 0.001). All 4 HercepTest 3+ cases demonstrated gene amplification. One of the 5 2+ cases tested for gene amplification showed areas of borderline amplification and areas of polyploidy. None of the 19 HercepTest-negative cases demonstrated gene amplification or polyploidy (p < 0.001). Gene amplification was demonstrated in all HercepTest 3+ scoring NSCLC cases. Unlike breast cancer, gene amplification and HER2 protein over-expression assessed by the HercepTest appeared to be uncommon in NSCLC. Herceptin may therefore target only a small proportion of NSCLC tumours and be of limited clinical value in this disease, particularly in the adjuvant setting.

Eradication of Helicobacter pylori compared with long-term acid suppression in duodenal ulcer disease. A randomized trial with 2-year follow-up. The Danish Ulcer Study Group.

BACKGROUND: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition. METHODS: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/ day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was discontinuation of treatment, irrespective of reason. RESULTS: Two hundred and seventy-six patients were randomized (139 in the eradication treatment group). In the maintenance phase there were no differences in the reporting of dyspeptic symptoms or in premature withdrawal. In the passive follow-up phase only five patients in the eradication therapy group discontinued owing to relapse of dyspeptic symptoms or ulcer, compared with 51 patients initially randomized to long-term omeprazole. There were no differences in reflux symptoms or in the development of reflux oesophagitis. CONCLUSIONS: Eradication therapy and long-term omeprazole are equally effective in controlling dyspeptic symptoms and reflux in duodenal ulcer patients with healed ulcers. One-quarter of the duodenal ulcer patients who start eradication therapy continue to be symptomatic or fail therapy for other reasons over a 2-year period. Eradication therapy does not increase the risk of reflux in ulcer patients.

Liver cancer among employees in Denmark.

To test the hypothesis that occupational exposure to chemical agents-particularly organic solvents in certain industries-may cause primary liver cancer (PLC), a nested case-control study of PLC cases from the Danish Cancer Registry and an age- and sex-stratified random sample of controls from the Central Population Register in Denmark were linked with files of a national supplementary pension fund. Employment histories since April 1964 were obtained for 973 cases histologically classified as hepatocellular carcinoma, cholangiocarcinoma, or combined hepatocellular and cholangiocarcinoma and 15,348 controls. Men from 35 different industrial branches, women from 7 branches, and both men and women from 3 branches had an excess risk of PLC, with an odds ratio of (OR) > 1.0; 29 branches had an OR of liver cancer in excess of 3.0. Women from bookprinting and offset printing industries had an OR above 10. Only male farmers had an OR below unity (0.41). Employees from breweries, restaurants, hotels, motels, and distilleries had an increased OR of both PLC and esophageal cancer.

Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn's disease.

BACKGROUND: Only a few studies have attempted to determined the prevalence of long-standing abnormal liver function and primary sclerosing cholangitis (PSC) in patients with Crohn's disease (CD). The aim of the study was to determine the prevalence of long-standing abnormal liver function test results and to describe the clinical, biochemical, and histologic findings in patients with large-duct classic PSC and small-duct PSC (that is, normal cholangiogram) in patients with CD during a 15-year period. METHODS: Patients with CD and long-standing abnormal liver function results were investigated individually with endoscopic retrograde cholangiography and liver biopsy. RESULTS: Of 262 consecutive patients with CD, 38 (15%) had long-standing increased alkaline phosphatase (ALP) values (mean, 1065 U/l; range, 321-4165 U/l). Of these, 10 patients were classified as having hepatic disease (4%), of which 9 had PSC and 1 had a non-specific reactive hepatitis. Of nine patients with PSC (3.4%), three were classified as having large-duct PSC; five, small-duct PSC; and one, unclassified. In patients with large-bowel CD (n = 102) the prevalence of PSC was 9%. Mean age at diagnosis of PSC was 35 years (22-46 years), and the female to male ratio, 7:2. All PSC patients had large-bowel involvement (P < 0.00015), and two of them developed colonic carcinoma of the large bowel (P < 0.01). All cases of small-duct PSC were stage 1, whereas large-duct PSC were stage 2-3. During the observation period (mean, 5.4 years) no PSC patients died. CONCLUSIONS: The results of our study indicate that PSC is the major hepatic disease in patients with CD and long-standing abnormal liver function tests and is approximately as prevalent as in ulcerative colitis. Patients with PSC and CD may have a milder liver disease than patients with PSC and ulcerative colitis, perhaps because large-duct PSC is less common in patients with CD. Cholangiograms and liver biopsies are both needed to evaluate the extent of the disease.

Assessment of the diagnoses of Crohn's disease and ulcerative colitis in a Danish hospital information system.

BACKGROUND: Our aim was to estimate the completeness-that is, whether all patients were included in the system-and the validity-that is, whether the diagnostic criteria were fulfilled for the patients registered-of the diagnoses of Crohn's disease and ulcerative colitis in a Danish hospital system. METHODS: Information in a regional hospital system, in the County of North Jutland, Denmark, was compared with hospital records and information in a pathology system. RESULTS: The analysis of the completeness included 143 patients with Crohn's disease and 285 patients with ulcerative colitis. The completeness of the regional hospital system using the pathology system as a reference standard was 94% for both diseases. The analysis of the validity included 281 patients registered as having Crohn's disease and 506 patients registered as having ulcerative colitis. The validity of the two diagnoses was 97% and 90%, respectively. CONCLUSIONS: The regional hospital system showed few misclassifications of the diagnoses of Crohn's disease and ulcerative colitis. Thus the nationwide hospital system (based on the regional hospital systems) may provide a unique study base for future research.

Lung carcinoma and malignant mesothelioma in patients exposed to Thorotrast: incidence, histology and p53 status.

In a previous registry-based survey of 999 patients injected with alpha-emitting 232ThO2 (Thorotrast), we identified elevated risks for lung carcinoma and malignant mesothelioma. Since injected Thorotrast is retained lifelong mostly in liver, spleen and lymph nodes, the mesothelial surfaces of these organs are constantly irradiated. Thorotrast-administered patients also perpetually exhale 220Rn, a 232Th-daughter. Study of Thorotrast-exposed patients may, therefore, provide data with regard to carcinogenicity of radon exposure, a current public health concern, as well as the pathogenesis of malignant mesothelioma. The incidence and histologic types of lung carcinoma and malignant mesothelioma within the cohort were examined by review of available histopathologic material and medical records. Further, mutations of the p53 gene were analyzed whenever possible as it has previously been suggested that radon-associated lung carcinomas exhibit specific mutational patterns. The cumulative risk for lung carcinoma reached 11.0% based on 20 confirmed cases. Nine were small cell lung cancer (SCLC), whereas the expected frequency was 18%. The risk for malignant mesothelioma reached 2.5% based on 7 cases. The actuarial risk of malignant mesothelioma for patients given more than 20 ml Thorotrast was 7.8% compared to 1.4% for patients administered smaller amounts. Seven lung carcinomas and 5 malignant mesotheliomas were analyzed for p53 mutations; only 1 (in a lung adenocarcinoma) was detected. A possible association between Thorotrast and SCLC is suggested. In addition, a possible dose-response gradient exists for Thorotrast and malignant mesothelioma.

Mutations in the tumor suppressor gene p53 in human liver cancer induced by alpha-particles.

The p53 tumor suppressor gene is mutated in varying fractions of almost all tumor types studied. The rate of mutations and the mutational spectrum in some tumors are specific for environmental mutagens assumed to be involved in the carcinogenic process. Thus, hepatocellular carcinomas supposedly induced by aflatoxin exposure often contain a specific point mutation in codon 249, and in lung cancers of miners with heavy radon exposure, another specific point mutation in codon 249 suggestive of an alpha-particle-specific mutation has been shown. The interpretation of studies linking the mutational spectrum with specific environmental exposures is complicated by the multifactorial or unknown genesis of most tumors. However, people given injections of the X-ray contrast medium Thorotrast (Th) in the past have experienced an enormous risk of liver tumors, and virtually all of these are supposedly induced by alpha-particles from the decay of 232Th. The examination of these tumors may provide evidence as to whether specific p53 point mutations are relevant in alpha-particle carcinogenesis. Therefore, we collected paraffin-embedded, formalin-fixed archival tissues from 18 hepatocellular carcinomas, 9 cholangiocarcinomas, and 9 hepatic angiosarcomas from Thorotrast-exposed patients. The tissues were analyzed for p53 protein expression by immunohistochemical staining by using the mAb DO-7 and for mutations of exons 5-8 by PCR and constant denaturant gel electrophoresis. G --> T transversions of the third base of codon 249 of the p53 gene were specifically screened for by restriction enzymes. No high score for p53 protein expression (i.e., positive staining of >20% of examined cells) was observed; lower scores were seen in 5 of 18 (28%) hepatocellular carcinomas, 1 of 9 (11%) cholangiocarcinomas, and 0 of 8 (0%) hepatic angiosarcomas. Only one p53 mutation, a heterozygous T --> G transversion of the first base codon 176, occurred in a hepatocellular carcinoma. The rate of p53 point mutations in alpha-particle-induced liver tumors seems to be lower than in European hepatocellular carcinomas in general. The study does not exclude the possibility that alpha-particle carcinogenesis may involve inactivation of p53 by gross deletions of the gene, but it speaks against the proposed specificity of point mutations of codon 249 in cancer supposedly induced by alpha-particles from radon progeny.

Primary liver tumors among Danish patients exposed to Thorotrast.

The potential carcinogenic effects of internally deposited alpha-particle-emitting nuclides, notably plutonium, in the liver in humans are unknown but are of concern in relation to exposures from the nuclear industry. However, patients injected with the radiographic contrast medium Thorotrast are chronically exposed to alpha-particle radiation from 232ThO2 in the liver. Among 1003 patients injected with Thorotrast, 584 of whom were alive 15 years after the injection and 40 at the end of follow-up, a total of 127 liver cancers were diagnosed, 45 of which were hepatocellular carcinomas, 41 cholangiocarcinomas and 33 hemangiosarcomas. The median time from injection to diagnosis was 35 years (range 18-48) and the cumulative frequency was 55.4% after 48 years. In univariate and multivariate analyses, the cumulative frequency of liver cancer was best described as a function of the estimated mean cumulative alpha-particle radiation dose to the liver 15 years ago, being independent of age, gender and volume of injected Thorotrast. This may be interpreted to mean that the liver cancer rate is not related to the dose rate and that the period from malignant transformation to diagnosis of cancer is 15 years. The risk of liver carcinogenesis induced by alpha-particle radiation, assuming 15 years from induction to diagnosis, was estimated to be 712 cases/10(4) persons per gray. This value is considerably higher than estimated earlier.

Primary leptomeningeal T-cell lymphoma: a case and a review of primary T-cell lymphoma of the central nervous system.

A case of primary leptomeningeal T-cell lymphoma of pleomorphic large cell type is presented. The lymphoma, which was first diagnosed at autopsy, occurred in a 67-year-old man, who had no personal or family history of immunodeficiency disorders. Review of the literature reveals only 13 immunocytochemically well-documented cases of primary T-cell lymphoma in the CNS. In five of these cases the lymphoma was apparently confined to the leptomeninges. The relatively high frequency of leptomeningeal presentation may indicate that this tumor form is more common with primary T-cell lymphoma of the CNS than with B-cell neoplasms.

Observer homogeneity in the histologic diagnosis of Helicobacter pylori. Latent class analysis, kappa coefficient, and repeat frequency.

Four pathologists independently examined 82 antral mucosal biopsy specimens for the presence of Helicobacter pylori and indicated whether their assessments were certain. The pathologists made a positive diagnosis in from 56% to 84% of the specimens (significant heterogeneity, p < 0.01). The frequency of uncertain diagnoses was from 4% to 20% (p < 0.01). Uncertain statements occurred more frequently among negative than among positive diagnoses. For the six pairs of observers the kappa coefficients were between 0.39 and 0.82. By a latent class analysis measures of diagnostic accuracy were calculated comparing the observers' assessments with an estimated consensus diagnosis. The predictive values of a positive diagnosis ranged from 0.70 to 1.00. By calculation of repeat frequencies--that is, the probability that an observer's statement was confirmed by another observer--it became evident that uncertain statements were less frequently (61%) confirmed than were certain ones (85%). It is concluded that observer homogeneity is only moderate with regard to the histologic diagnosis of H. pylori, which should be considered both in daily clinical routine and in scientific studies. Disagreement between observers was associated with negative diagnoses, presumably because the pathologists felt more uncertain in these cases.